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  • 1.
    Bloch, K. M.
    et al.
    Univ Liverpool, Liverpool, Merseyside, England..
    Carr, D.
    Univ Liverpool, Liverpool, Merseyside, England..
    Pirmohamed, M.
    Univ Liverpool, Liverpool, Merseyside, England..
    Morris, A.
    Univ Liverpool, Liverpool, Merseyside, England..
    Maroteau, C.
    Dundee Univ, Dundee, Scotland..
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Palmer, C.
    Dundee Univ, Dundee, Scotland..
    Alfirevic, A.
    Univ Liverpool, Liverpool, Merseyside, England..
    Whole exome sequencing in individuals with statin-induced myopathy2017In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 40, no 10, p. 1026-1026Article in journal (Other academic)
  • 2. Chen, Leslie Y.
    et al.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Gwilliam, Rhian
    Bentley, David
    Deloukas, Panos
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Gamma-glutamyl carboxylase (GGCX) microsatellite and warfarin dosing2005In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 106, no 10, p. 3673-4Article in journal (Refereed)
  • 3. Deloukas, Panos
    et al.
    Kanoni, Stavroula
    Willenborg, Christina
    Farrall, Martin
    Assimes, Themistocles L
    Thompson, John R
    Ingelsson, Erik
    Saleheen, Danish
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Erdmann, Jeanette
    Goldstein, Benjamin A
    Stirrups, Kathleen
    König, Inke R
    Cazier, Jean-Baptiste
    Johansson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Hall, Alistair S
    Lee, Jong-Young
    Willer, Cristen J
    Chambers, John C
    Esko, Tõnu
    Folkersen, Lasse
    Goel, Anuj
    Grundberg, Elin
    Havulinna, Aki S
    Ho, Weang K
    Hopewell, Jemma C
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Kleber, Marcus E
    Kristiansson, Kati
    Lundmark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Lyytikäinen, Leo-Pekka
    Rafelt, Suzanne
    Shungin, Dmitry
    Strawbridge, Rona J
    Thorleifsson, Gudmar
    Tikkanen, Emmi
    van Zuydam, Natalie
    Voight, Benjamin F
    Waite, Lindsay L
    Zhang, Weihua
    Ziegler, Andreas
    Absher, Devin
    Altshuler, David
    Balmforth, Anthony J
    Barroso, Inês
    Braund, Peter S
    Burgdorf, Christof
    Claudi-Boehm, Simone
    Cox, David
    Dimitriou, Maria
    Do, Ron
    Doney, Alex S F
    Mokhtari, Noureddine El
    Eriksson, Per
    Fischer, Krista
    Fontanillas, Pierre
    Franco-Cereceda, Anders
    Gigante, Bruna
    Groop, Leif
    Gustafsson, Stefan
    Hager, Jörg
    Hallmans, Göran
    Han, Bok-Ghee
    Hunt, Sarah E
    Kang, Hyun M
    Illig, Thomas
    Kessler, Thorsten
    Knowles, Joshua W
    Kolovou, Genovefa
    Kuusisto, Johanna
    Langenberg, Claudia
    Langford, Cordelia
    Leander, Karin
    Lokki, Marja-Liisa
    Lundmark, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    McCarthy, Mark I
    Meisinger, Christa
    Melander, Olle
    Mihailov, Evelin
    Maouche, Seraya
    Morris, Andrew D
    Müller-Nurasyid, Martina
    Nikus, Kjell
    Peden, John F
    Rayner, N William
    Rasheed, Asif
    Rosinger, Silke
    Rubin, Diana
    Rumpf, Moritz P
    Schäfer, Arne
    Sivananthan, Mohan
    Song, Ci
    Stewart, Alexandre F R
    Tan, Sian-Tsung
    Thorgeirsson, Gudmundur
    Schoot, C Ellen van der
    Wagner, Peter J
    Wells, George A
    Wild, Philipp S
    Yang, Tsun-Po
    Amouyel, Philippe
    Arveiler, Dominique
    Basart, Hanneke
    Boehnke, Michael
    Boerwinkle, Eric
    Brambilla, Paolo
    Cambien, Francois
    Cupples, Adrienne L
    de Faire, Ulf
    Dehghan, Abbas
    Diemert, Patrick
    Epstein, Stephen E
    Evans, Alun
    Ferrario, Marco M
    Ferrières, Jean
    Gauguier, Dominique
    Go, Alan S
    Goodall, Alison H
    Gudnason, Villi
    Hazen, Stanley L
    Holm, Hilma
    Iribarren, Carlos
    Jang, Yangsoo
    Kähönen, Mika
    Kee, Frank
    Kim, Hyo-Soo
    Klopp, Norman
    Koenig, Wolfgang
    Kratzer, Wolfgang
    Kuulasmaa, Kari
    Laakso, Markku
    Laaksonen, Reijo
    Lee, Ji-Young
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ouwehand, Willem H
    Parish, Sarah
    Park, Jeong E
    Pedersen, Nancy L
    Peters, Annette
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Quertermous, Thomas
    Rader, Daniel J
    Salomaa, Veikko
    Schadt, Eric
    Shah, Svati H
    Sinisalo, Juha
    Stark, Klaus
    Stefansson, Kari
    Trégouët, David-Alexandre
    Virtamo, Jarmo
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Wareham, Nicholas
    Zimmermann, Martina E
    Nieminen, Markku S
    Hengstenberg, Christian
    Sandhu, Manjinder S
    Pastinen, Tomi
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Hovingh, G Kees
    Dedoussis, George
    Franks, Paul W
    Lehtimäki, Terho
    Metspalu, Andres
    Zalloua, Pierre A
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Schreiber, Stefan
    Ripatti, Samuli
    Blankenberg, Stefan S
    Perola, Markus
    Clarke, Robert
    Boehm, Bernhard O
    O'Donnell, Christopher
    Reilly, Muredach P
    März, Winfried
    Collins, Rory
    Kathiresan, Sekar
    Hamsten, Anders
    Kooner, Jaspal S
    Thorsteinsdottir, Unnur
    Danesh, John
    Palmer, Colin N A
    Roberts, Robert
    Watkins, Hugh
    Schunkert, Heribert
    Samani, Nilesh J
    Large-scale association analysis identifies new risk loci for coronary artery disease2013In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 45, no 1, p. 25-33Article in journal (Refereed)
    Abstract [en]

    Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r2 < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways.

  • 4.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    On the Prediction of Warfarin Dose2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Warfarin is one of the most widely used anticoagulants in the world. Treatment is complicated by a large inter-individual variation in the dose needed to reach adequate levels of anticoagulation i.e. INR 2.0 – 3.0. The objective of this thesis was to evaluate which factors, mainly genetic but also non-genetic, that affect the response to warfarin in terms of required maintenance dose, efficacy and safety with special focus on warfarin dose prediction.

    Through candidate gene and genome-wide studies, we have shown that the genes CYP2C9 and VKORC1 are the major determinants of warfarin maintenance dose. By combining the SNPs CYP2C9 *2, CYP2C9 *3 and VKORC1 rs9923231 with the clinical factors age, height, weight, ethnicity, amiodarone and use of inducers (carbamazepine, phenytoin or rifampicin) into a prediction model (the IWPC model) we can explain 43 % to 51 % of the variation in warfarin maintenance dose. Patients requiring doses < 29 mg/week and doses ≥ 49 mg/week benefitted the most from pharmacogenetic dosing. Further, we have shown that the difference across ethnicities in percent variance explained by VKORC1 was largely accounted for by the allele frequency of rs9923231. Other novel genes affecting maintenance dose (NEDD4 and DDHD1), as well as the replicated CYP4F2 gene, have small effects on dose predictions and are not likely to be cost-effective, unless inexpensive genotyping is available.

    Three types of prediction models for warfarin dosing exist: maintenance dose models, loading dose models and dose revision models. The combination of these three models is currently being used in the warfarin treatment arm of the European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) study. Other clinical trials aiming to prove the clinical validity and utility of pharmacogenetic dosing are also underway.

    The future of pharmacogenetic warfarin dosing relies on results from these ongoing studies, the availability of inexpensive genotyping and the cost-effectiveness of pharmacogenetic driven warfarin dosing compared with new oral anticoagulant drugs.

  • 5.
    Eriksson, Niclas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Prediction of warfarin dose: why, when and how?2012In: Pharmacogenomics (London), ISSN 1462-2416, E-ISSN 1744-8042, Vol. 13, no 4, p. 429-440Article, review/survey (Refereed)
    Abstract [en]

    Prediction models are the key to individualized drug therapy. Warfarin is a typical example of where pharmacogenetics could help the individual patient by modeling the dose, based on clinical factors and genetic variation in CYP2C9 and VKORC1. Clinical studies aiming to show whether pharmacogenetic warfarin dose predictions are superior to conventional initiation of warfarin are now underway. This review provides a broad view over the field of warfarin pharmacogenetics from basic knowledge about the drug, how it is monitored, factors affecting dose requirement, prediction models in general and different types of prediction models for warfarin dosing.

  • 6.
    Eriksson, Niclas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Wallentin, Lars
    Berglund, Lars
    Axelsson, Tomas
    Connoly, Stuart
    Eikelboom, John
    Ezekowitz, Michael
    Oldgren, Jonas
    Pare, Guillaume
    Reilly, Paul
    Siegbahn, Agneta
    Syvanen, Ann-Christine
    Wadelius, Claes
    Yusuf, Salim
    Wadelius, Mia
    Genetic determinants of warfarin response, efficacy and safety: a RE-LY genomics substudyManuscript (preprint) (Other academic)
  • 7.
    Goel, Kashish
    et al.
    Mayo Clinic, Rochester, MN, USA.
    Baheti, Saurabh
    Mayo Clinic, Rochester, MN, USA.
    Åkerblom, Axel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Goodman, Shaun
    Mayo Clinic, Rochester, MN, USA.
    Jenkins, Greg
    Mayo Clinic, Rochester, MN, USA.
    Bielinski, Suzette
    Mayo Clinic, Rochester, MN, USA.
    Roger, Veronique
    Mayo Clinic, Rochester, MN, USA.
    Rihal, Charanjit
    Mayo Clinic, Rochester, MN, USA.
    Pereira, Naveen
    Mayo Clinic, Rochester, MN, USA.
    Novel Cyp2C19 Genetic Variants associated with Stent Thrombosis: a Next Generation Sequencing Study2018In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 71, no 11, p. 1205-1205Article in journal (Other academic)
    Abstract [en]

    Background

    Commonly tested Loss-of-function (LOF) alleles in CYP2C19 are present in 30-40% of patients who experience stent thrombosis. The objective of this study was to identify novel genetic variants in CYP2C19 gene associated with stent thrombosis.

    Methods

    We included 70 patients with definite stent thrombosis while on clopidogrel who had stored DNA samples in our institutional (n=12) or PLATO trial (n=70) biorepository. Cases were matched 1:1 with controls for age, race, sex, diabetes, type of stent, and presentation. All controls were on clopidogrel and free of recurrent events. Clinical Pharmacogenetics (PGx) Implementation Consortium (CPIC) guidelines were used to determine the list of known PGx variants and dbSNP version 142 was used to assess novel variants. Whole exome sequencing was performed using the protocol for Agilent's SureSelect Human All Exon v5 + UTRs 75 MB kit and additional custom primers were designed to cover the entire CYP2C19 gene.

    Results

    Mean age was 63 ± 12 years, and 71% were male. We identified a total of 456 single nucleotide variants (SNV) in the CYP2C19 gene (cases: 376; controls: 288), of which 5 were synonymous, 6 non-synonymous, 46 indels and 449 intronic SNVs. There were 168 vs. 80 novel CYP2C19 variants and 10 vs. 5 indels in cases vs. controls, respectively. Four SNVs (3 missense and 1 synonymous) were present only in cases, whereas 3 SNVs (1 misssense, 1 synonymous and 1 intron) were unique to controls. There were no detectable differences in the frequency of LOF CYP2C19*2 allele (cases 34% vs. controls 31%) or other CPIC annotated PGx variants in cases and controls. After excluding the known PGx variants, there were 10 indels (all intronic) out of which 7 were novel in cases and were not present in controls.

    Conclusion

    We describe several novel genetic variants in the CYP2C19 gene in patients treated with clopidogrel after coronary stenting. We identified 168 novel SNVs and 10 novel indels in the CYP2C19 gene of patients with stent thrombosis. Four SNVs and 9 indels were unique to cases. Functional validation of these CYP2C19 genetic variants may provide important insights of CYP2C19 and the pathophysiology of stent thrombosis in clopidogrel treated patients.

  • 8.
    Hagström, Emil
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Johansson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Bertilsson, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Barratt, Bryan J.
    Becker, Richard C.
    Himmelmann, Anders
    James, Stefan K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Katus, Hugo A.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Steg, Philippe G.
    Storey, Robert F.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Varenhorst, Christoph
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Åkerblom, Axel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Are There Any Causal Relations Between Growth Differentiation Factor 15 and Outcomes in Patients With Acute Coronary Syndrome?: - A Report From the Plato Gwas Study2013In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 128, no 22Article in journal (Other academic)
  • 9.
    Hallberg, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Ibanez, Luisa
    Univ Autonoma Barcelona, Hosp Univ Vall dHebron, Fundacio Inst Catala Farmacol, E-08193 Barcelona, Spain..
    Bondon-Guitton, Emmanuelle
    Univ Toulouse, Serv Pharmacol Med & Clin, Ctr Hosp Univ, Fac Med, Toulouse, France..
    Kreutz, Reinhold
    Charite, Inst Klin Pharmakol & Toxikol, D-13353 Berlin, Germany..
    Carvajal, Alfonso
    Univ Valladolid, Ctr Estudios Seguridad Medicamentos, Valladolid, Spain..
    Isabel Lucena, M.
    Univ Malaga, Hosp Univ Virgen de la Victoria, Inst Invest Biomed Malaga, Farmacol Clin S, E-29071 Malaga, Spain.;Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain..
    Sancho Ponce, Esther
    Hosp Gen Cataluna, Serv Hematol & Banc Sang, Sant Cugat Del Valles, Spain..
    Molokhia, Mariam
    Guys & St Thomas NHS Fdn Trust, Res Biomed Res Ctr, Natl Inst Hlth, Dept Primary Care & Publ Hlth Sci, London, England.;Kings Coll London, London WC2R 2LS, England..
    Martin, Javier
    CSIC, Inst Parasitol & Biomed Lopez Neyra, Granada, Spain..
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Yue, Qun-Ying
    Med Prod Agcy, Uppsala, Sweden..
    Magnusson, Patrik K. E.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Swedish Twin Registry, Stockholm, Sweden..
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Genetic variants associated with antithyroid drug-induced agranulocytosis: a genome-wide association study in a European population2016In: The Lancet Diabetes and Endocrinology, ISSN 2213-8587, E-ISSN 2213-8595, Vol. 4, no 6, p. 507-516Article in journal (Refereed)
    Abstract [en]

    Background: Drug-induced agranulocytosis is a potentially life-threatening adverse reaction. Genome-wide association studies (GWASs) in ethnic Chinese people in Taiwan and Hong Kong have shown an association between agranulocytosis induced by antithyroid drugs and the HLA alleles HLA-B*38:02 and HLA-DRB1*08:03. We aimed to identify genetic variants associated with antithyroid drug-induced agranulocytosis in a white European population.

    Methods: We did a GWAS in 234 European adults with any non-chemotherapy drug-induced agranulocytosis (absolute neutrophil count <= 0.5 x 10(9)/L [<= 500/mu L]) and 5170 population controls. 39 of the 234 patients had agranulocytosis that was induced by antithyroid drugs (thiamazole [methimazole], carbimazole, or propylthiouracil). After imputation and HLA allele prediction, 9 380 034 single nucleotide polymorphisms (SNPs) and 180 HLA alleles were tested for association. The genome-wide significance threshold was p<5 x 10(-8).

    Findings: Agranulocytosis induced by non-chemotherapy drugs in general was significantly associated with the HLA region on chromosome 6, with odds ratios (ORs) of 3.24 (95% CI 2.31-4.55, p = 1.20 x 10(-11)) for HLA-B*27:05 and 3.57 (2.61-4.90, p = 2.32 x 10(-15)) for the top SNP (rs114291795). Drug-specific analysis showed that the association with HLA-B*27: 05 was largely driven by cases induced by antithyroid drugs. In a multiple logistic regression model, the OR for HLA-B*27: 05 was 7.30 (3.81-13.96) when antithyroid drug-induced agranulocytosis was compared with population controls (p= 1.91 x 10(-9)) and 16.91 (3.44-83.17) when compared with a small group of hyperthyroid controls (p = 5.04 x 10(-4)). Three SNPs were strongly associated with antithyroid drug-induced agranulocytosis: rs652888 (OR 4.73, 95% CI 3.00-7.44, p= 1.92 x 10(-11)) and rs199564443 (17.42, 7.38-41.12, p = 7.04 x 10(-11)), which were independent of HLA-B*27:05, and rs1071816 (5.27, 3.06-9.10, p = 2.35 x 10(-9)) which was in moderate linkage disequilibrium with HLA-B*27:05. In heterozygous carriers of all three SNPs, the predicted probability of antithyroid drug-induced agranulocytosis was about 30% (OR 753, 95% CI 105-6812). To avoid one case of agranulocytosis, based on the possible risk reduction if all three SNPs are genotyped and carriers are treated or monitored differently from non-carriers, roughly 238 patients would need to be genotyped.

    Interpretation: In white European people, antithyroid drug-induced agranulocytosis was associated with HLA-B* 27: 05 and with other SNPs on chromosome 6. In the future, carriers of these variants could be placed under intensified monitoring or offered alternative treatment for hyperthyroidism.

  • 10.
    Hallberg, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Persson, Matilda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cavalli, Marco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Norling, Pia
    Sickla Hlth Ctr, Nacka, Sweden..
    Johansson, Hans-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Yue, Qun-Ying
    Med Prod Agcy, Uppsala, Sweden..
    Magnusson, Patrik K. E.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Swedish Twin Registry, Stockholm, Sweden..
    Wadelius, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Genetic variants associated with angiotensin-converting enzyme inhibitor-induced cough: a genome-wide association study in a Swedish population2017In: Pharmacogenomics (London), ISSN 1462-2416, E-ISSN 1744-8042, Vol. 18, no 3, p. 201-213Article in journal (Refereed)
    Abstract [en]

    Aim: We conducted a genome-wide association study on angiotensin-converting enzyme inhibitor-induced cough and used our dataset to replicate candidate genes iden-tified in previous studies. Patients & methods: A total of 124 patients and 1345 treated controls were genotyped using Illumina arrays. The genome-wide significance level was set to p < 5 x 10(-8). Results: We identified nearly genome-wide significant associations in CLASP1, PDE11A, KCNMB2, TGFA, SLC38A6 and MMP16. The strongest association was with rs62151109 in CLASP1 (odds ratio: 3.97; p = 9.44 x 10(-8)). All top hits except two were located in intronic or noncoding DNA regions. None of the candidate genes were significantly associated in our study. Conclusion: Angiotensin-converting enzyme inhibitor-induced cough is potentially associated with genes that are independent of bradykinin pathways.

  • 11.
    Hallberg, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Smedje, Hans
    Division of Child and Adolescent Psychiatry, Karolinska Institutet, Stockholm, Sweden.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kohnke, Hugo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Daniilidou, Makrina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Öhman, Inger
    Centre for Pharmacoepidemiology, Karolinska Institutet, Stockholm, Sweden.
    Yue, Qun-Ying
    Medical Products Agency, Uppsala, Sweden.
    Cavalli, Marco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wadelius, Claes
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Magnusson, Patrik K. E.
    Swedish Twin Registry, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Landtblom, Anne-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pandemrix-induced narcolepsy is associated with genes related to immunity and neuronal survival2019In: EBioMedicine, E-ISSN 2352-3964, Vol. 40, p. 595-604Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The incidence of narcolepsy rose sharply after the swine influenza A (H1N1) vaccination campaign with Pandemrix. Narcolepsy is an immune-related disorder with excessive daytime sleepiness. The most frequent form is strongly associated with HLA-DQB1*06:02, but only a minority of carriers develop narcolepsy. We aimed to identify genetic markers that predispose to Pandemrix-induced narcolepsy.

    METHODS: We tested for genome-wide and candidate gene associations in 42 narcolepsy cases and 4981 controls. Genotyping was performed on Illumina arrays, HLA alleles were imputed using SNP2HLA, and single nucleotide polymorphisms were imputed using the haplotype reference consortium panel. The genome-wide significance threshold was p < 5 × 10-8, and the nominal threshold was p < 0.05. Results were replicated in 32 cases and 7125 controls. Chromatin data was used for functional annotation.

    FINDINGS: Carrying HLA-DQB1*06:02 was significantly associated with narcolepsy, odds ratio (OR) 39.4 [95% confidence interval (CI) 11.3, 137], p = 7.9 × 10-9. After adjustment for HLA, GDNF-AS1 (rs62360233) was significantly associated, OR = 8.7 [95% CI 4.2, 17.5], p = 2.6 × 10-9, and this was replicated, OR = 3.4 [95% CI 1.2-9.6], p = 0.022. Functional analysis revealed variants in high LD with rs62360233 that might explain the detected association. The candidate immune-gene locus TRAJ (rs1154155) was nominally associated in both the discovery and replication cohorts, meta-analysis OR = 2.0 [95% CI 1.4, 2.8], p = 0.0002.

    INTERPRETATION: We found a novel association between Pandemrix-induced narcolepsy and the non-coding RNA gene GDNF-AS1, which has been shown to regulate expression of the essential neurotrophic factor GDNF. Changes in regulation of GDNF have been associated with neurodegenerative diseases. This finding may increase the understanding of disease mechanisms underlying narcolepsy. Associations between Pandemrix-induced narcolepsy and immune-related genes were replicated.

  • 12.
    Hernefalk, Björn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Borg, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Estimating pre-traumatic quality of life in patients with surgically treated acetabular fractures and pelvic ring injuries: Does timing matter?2016In: Injury, ISSN 0020-1383, E-ISSN 1879-0267, Vol. 47, no 2, p. 389-394Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND PURPOSE: Evaluation of patient-assessed functional outcome in traumatic conditions has specific challenges. To obtain pre-traumatic data to allow for comparison during follow-up, retrospective assessments are needed. How such data is affected by posttraumatic time-point chosen for evaluation is unknown. The primary purpose of this study was to investigate how the time-point chosen for retrospective assessment of pre-traumatic quality of life (QoL) in patients with surgically treated acetabular fractures and pelvic ring injuries influenced the results. A secondary purpose was to examine the pre-traumatic QoL-profile in patients with these injuries.

    PATIENTS AND METHODS: 73 patients were included, where 50 had an acetabular fracture and 23 a pelvic ring injury. Pre-traumatic QoL was evaluated using the generic instruments SF-36 and EQ5D in conjunction with the condition-specific Pelvic Trauma Questionnaire (PTQ). Questionnaires were completed at three time points: 0, 1 and 2 months post-surgery.

    RESULTS: Number of responders were 73 patients at 0 months, 61 patients at 1 month and 53 patients at 2 months. 50 patients answered the questionnaires at all three time-points. A trend was observed with all instruments where patients estimated a better pre-traumatic status with narrower distributions when assessment was delayed. At 2 months, scores for 4 out of 8 SF-36 domains where significantly higher compared to 0 months. For EQ5D, EQ VAS improved at 1 and 2 months compared to month 0 results but no other significant differences between time-points were found. Results from the PTQ demonstrated no significant differences over time. Pre-traumatic quality of life was high and for SF-36 comparable to a population norm. A very low level of pre-existing discomfort from the pelvic region was reported through the PTQ.

    CONCLUSION: Patients with surgically treated acetabular fractures and pelvic ring injuries estimate a higher pre-traumatic functional status when assessment is carried out at 1 or 2 months post-surgery compared to perioperative measurements. The SF-36 seems to be more sensitive than the EQ5D in this respect. Pre-traumatic QoL in patients with surgically treated acetabular fractures and pelvic ring injuries is generally high and pre-existing discomfort from the pelvic region is uncommon.

  • 13. Horne, B D
    et al.
    Lenzini, P A
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Jorgensen, A L
    Kimmel, S E
    Ridker, P M
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Anderson, J L
    Pirmohamed, M
    Limdi, N A
    Pendleton, R C
    McMillin, G A
    Burmester, J K
    Kurnik, D
    Stein, C M
    Caldwell, M D
    Eby, C S
    Rane, A
    Lindh, J D
    Shin, J-G
    Kim, H-S
    Angchaisuksiri, P
    Glynn, R J
    Kronquist, K E
    Carlquist, J F
    Grice, G R
    Barrack, R L
    Li, J
    Gage, B F
    Pharmacogenetic warfarin dose refinements remain significantly influenced by genetic factors after one week of therapy2012In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 107, no 2, p. 232-240Article in journal (Refereed)
    Abstract [en]

    By guiding initial warfarin dose, pharmacogenetic (PGx) algorithms may improve the safety of warfarin initiation. However, once international normalised ratio (INR) response is known, the contribution of PGx to dose refinements is uncertain. This study sought to develop and validate clinical and PGx dosing algorithms for warfarin dose refinement on days 6-11 after therapy initiation. An international sample of 2,022 patients at 13 medical centres on three continents provided clinical, INR, and genetic data at treatment days 6-11 to predict therapeutic warfarin dose. Independent derivation and retrospective validation samples were composed by randomly dividing the population (80%/20%). Prior warfarin doses were weighted by their expected effect on S-warfarin concentrations using an exponential-decay pharmacokinetic model. The INR divided by that "effective" dose constituted a treatment response index . Treatment response index, age, amiodarone, body surface area, warfarin indication, and target INR were associated with dose in the derivation sample. A clinical algorithm based on these factors was remarkably accurate: in the retrospective validation cohort its R2 was 61.2% and median absolute error (MAE) was 5.0 mg/week. Accuracy and safety was confirmed in a prospective cohort (N=43). CYP2C9 variants and VKORC1-1639 G→A were significant dose predictors in both the derivation and validation samples. In the retrospective validation cohort, the PGx algorithm had: R2= 69.1% (p<0.05 vs. clinical algorithm), MAE= 4.7 mg/week. In conclusion, a pharmacogenetic warfarin dose-refinement algorithm based on clinical, INR, and genetic factors can explain at least 69.1% of therapeutic warfarin dose variability after about one week of therapy.

  • 14.
    Johansson, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Alfredsson, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Genome-Wide Association Study Identifies That the ABO Blood Group System Influences Interleukin-10 Levels and the Risk of Clinical Events in Patients with Acute Coronary Syndrome2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 11, article id e0142518Article in journal (Refereed)
    Abstract [en]

    Introduction Acute coronary syndrome (ACS) is a major cause of mortality worldwide. We have previously shown that increased interleukin-10 (IL-10) levels are associated with poor outcome in ACS patients. Method We performed a genome-wide association study in 2864 ACS patients and 408 healthy controls, to identify genetic variants associated with IL-10 levels. Then haplotype analyses of the identified loci were done and comparisons to levels of IL-10 and other known ACS related biomarkers. Results Genetic variants at the ABO blood group locus associated with IL-10 levels (top SNP: rs676457, P = 4.4 x 10(-10)) were identified in the ACS patients. Haplotype analysis, using SNPs tagging the four main ABO antigens (A1, A2, B and O), showed that O and A2 homozygous individuals, or O/A2 heterozygotes have much higher levels of IL-10 compared to individuals with other antigen combinations. In the ACS patients, associations between ABO antigens and von Willebrand factor (VWF, P = 9.2 x 10(-13)), and soluble tissue factor (sTF, P = 8.6 x 10(-4)) were also found. In the healthy control cohort, the associations with VWF and sTF were similar to those in ACS patients (P = 1.2 x 10(-15) and P = 1.0 x 10(-5) respectively), but the healthy cohort showed no association with IL-10 levels (P>0.05). In the ACS patients, the O antigen was also associated with an increased risk of cardiovascular death, all causes of death, and recurrent myocardial infarction (odds ratio [OR] = 1.24-1.29, P = 0.029-0.00067). Conclusion Our results suggest that the ABO antigens play important roles, not only for the immunological response in ACS patients, but also for the outcome of the disease.

  • 15.
    Johansson, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Becker, Richard C.
    Storey, Robert F.
    Himmelmann, Anders
    Hagström, Emil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Varenhorst, Christoph
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Axelsson, Tomas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Barratt, Bryan J.
    James, Stefan K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Katus, Hugo A.
    Steg, Philippe Gabriel
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    NLRC4 Inflammasome Is an Important Regulator of Interleukin-18 Levels in Patients With Acute Coronary Syndromes Genome-Wide Association Study in the PLATelet inhibition and patient Outcomes Trial (PLATO)2015In: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 8, no 3, p. 498-506Article in journal (Refereed)
    Abstract [en]

    Background Interleukin 18 (IL-18) promotes atherosclerotic plaque formation and is increased in patients with acute coronary syndromes. However the relative contribution of genetic variants to the IL-18 levels has not been fully determined. Methods and Results Baseline plasma IL-18 levels were measured in 16633 patients with acute coronary syndrome, of whom 9340 had genetic data that passed genotype quality control. A 2-stage genome-wide association study was performed, followed by combined analyses using >10 million genotyped or imputed genetic markers. Single nucleotide polymorphisms at 3 loci (IL18, NLRC4, and MROH6) were identified (P<3.15x10(-8)) in the discovery cohort (n=3777) and replicated in the remaining patients (n=5563). In the pooled data (discovery+replication cohort), 7 independent associations, in 5 chromosomal regions, were associated with IL-18 levels (minimum P=6.99x10(-72)). Six single nucleotide polymorphisms are located in predicted promoter regions of which one disrupts a transcription factor binding site. One single nucleotide polymorphism in NLRC4 is a rare missense variant, predicted to be deleterious to the protein. Altogether, the identified genetic variants explained 8% of the total variation in IL-18 levels in the cohort. Conclusions Our results show that genetic variants play an important role in determining IL-18 levels in patients with acute coronary syndrome and we have identified genetic variants located in the IL-18 gene (IL18) or close to genes that are involved in procaspase-1 activation (NLRC4 and CARD16, CARD17, and CARD18). These associations also highlight the importance of the NLRC4 inflammasome for IL-18 production in acute coronary syndrome patients.

  • 16.
    Johansson, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lindholm, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Varenhorst, Christoph
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    James, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Barratt, Bryan J.
    AstraZeneca R&D, Alderley Pk SK10 4TF, Cheshire, England..
    Becker, Richard C.
    Acad Hlth Ctr, Div Cardiovasc Hlth & Dis, Heart Lung & Vasc Inst, Cincinnati, OH 45267 USA..
    Himmelmann, Anders
    AstraZeneca Res & Dev, S-43150 Molndal, Sweden..
    Katus, Hugo A.
    Univ Klinikum Heidelberg, Med Klin, D-69120 Heidelberg, Germany..
    Steg, Philippe Gabriel
    INSERM, Unite 1148, F-75019 Paris, France.;Hop Bichat Claude Bernard, AP HP, Dept Hosp Univ FIRE, F-75018 Paris, France.;Univ Paris Diderot, Sorbonne Paris Cite, F-75013 Paris, France.;Royal Brompton Hosp, ICMS, NHLI Imperial Coll, London SW3 6NP, England..
    Storey, Robert F.
    Univ Sheffield, Dept Cardiovasc Sci, Sheffield S10 2RX, S Yorkshire, England..
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Genome-wide association and Mendelian randomization study of NT-proBNP in patients with acute coronary syndrome2016In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 25, no 7, p. 1447-1456Article in journal (Refereed)
    Abstract [en]

    N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a strong predictor of mortality in coronary artery disease and is widely employed as a prognostic biomarker. However, a causal relationship between NT-proBNP and clinical endpoints has not been established. We have performed a genome-wide association and Mendelian randomization study of NT-proBNP. We used a discovery set of 3740 patients from the PLATelet inhibition and patient Outcomes (PLATO) trial, which enrolled 18 624 patients with acute coronary syndrome (ACS). A further set of 5492 patients, from the same trial, was used for replication. Genetic variants at two novel loci (SLC39A8 and POC1B/GALNT4) were associated with NT-proBNP levels and replicated together with the previously known NPPB locus. The most significant SNP (rs198389, pooled P = 1.07 x 10(-15)) in NPPB interrupts an E-box consensus motif in the gene promoter. The association in SLC39A8 is driven by a deleterious variant (rs13107325, pooled P = 5.99 x 10(-10)), whereas the most significant SNP in POC1B/GALNT4 (rs11105306, pooled P = 1.02 x 10(-16)) is intronic. The SLC39A8 SNP was associated with higher risk of cardiovascular (CV) death (HR = 1.39, 95% CI: 1.08-1.79, P = 0.0095), but the other loci were not associated with clinical endpoints. We have identified two novel loci to be associated with NT-proBNP in patients with ACS. Only the SLC39A8 variant, but not the NPPB variant, was associated with a clinical endpoint. Due to pleotropic effects of SLC39A8, these results do not suggest that NT-proBNP levels have a direct effect on mortality in ACS patients. PLATO Clinical Trial Registration: ; NCT00391872.

  • 17.
    Karlsson Sundbaum, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Lulea Univ Technol, Dept Hlth Sci, Lulea, Sweden.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lehto, Niklas
    Lulea Univ Technol, Dept Hlth Sci, Lulea, Sweden.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Methotrexate treatment in rheumatoid arthritis and elevated liver enzymes: A long-term follow-up of predictors, surveillance, and outcome in clinical practice2019In: INTERNATIONAL JOURNAL OF RHEUMATIC DISEASES, ISSN 1756-1841, Vol. 22, no 7, p. 1226-1232Article in journal (Refereed)
    Abstract [en]

    Aim: To assess predictors of alanine aminotransferase (ALT) elevation in methotrexate (MTX) treated rheumatoid arthritis (RA) patients, and to describe the monitoring of liver enzymes, including handling and outcome of elevated ALT.

    Methods: All RA patients starting MTX in January, 2005 to April, 2013 at a rheumatology clinic, (Uppsala University Hospital, Sweden) were identified from electronic medical records. Clinical and laboratory data were obtained from medical records, supplemented by telephone interviews. Predictors for ALT >1.5x over the upper limit of normal (ULN) were identified by multiple regression analysis.

    Results: The study comprised 213 RA patients starting MTX. During a mean follow-up of 4.3 years, 6288 ALT tests were performed; 7% of tests with ALT were >ULN. ALT >1.5x ULN was observed in 44 (21%) patients and the strongest predictor was a pre-treatment elevation of ALT (adjusted odds ratio = 6.8, 95% CI 2.2-20.5). Recurrent elevations occurred in 70% of patients who continued treatment, and the proportion was similar in those with and without interventions, for example MTX dose reduction (67% vs 73%, P = 0.43). Seven patients (3%) permanently stopped MTX due to ALT elevation, and two were eventually diagnosed with non-alcoholic fatty liver disease. No patient developed hepatic failure.

    Conclusion: Only a small number of ALT tests performed during MTX therapy in RA capture an elevation. A pre-treatment elevation of ALT was the strongest predictor for early and recurrent ALT elevations during therapy. This study supports a more individualized approach to monitoring and handling of ALT elevations during MTX therapy in RA than recommended in current guidelines.

  • 18.
    Kharazmi, Mohammad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Schilcher, Jorg
    Linkoping Univ, Fac Hlth Sci, Dept Clin & Expt Med, Linkoping, Sweden.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala Univ, Dept Med Sci, Uppsala, Sweden.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    A Genome-Wide Association Study of Bisphosphonate-Associated Atypical Femoral Fracture2019In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 105, no 1, p. 51-67Article in journal (Refereed)
    Abstract [en]

    Atypical femoral fracture is a well-documented adverse reaction to bisphosphonates. It is strongly related to duration of bisphosphonate use, and the risk declines rapidly after drug withdrawal. The mechanism behind bisphosphonate-associated atypical femoral fracture is unclear, but a genetic predisposition has been suggested. With the aim to identify common genetic variants that could be used for preemptive genetic testing, we performed a genome-wide association study. Cases were recruited mainly through reports of adverse drug reactions sent to the Swedish Medical Products Agency on a nation-wide basis. We compared atypical femoral fracture cases (n=51) with population-based controls (n=4891), and to reduce the possibility of confounding by indication, we also compared with bisphosphonate-treated controls without a current diagnosis of cancer (n=324). The total number of single-nucleotide polymorphisms after imputation was 7,585,874. A genome-wide significance threshold of p<5x10(-8) was used to correct for multiple testing. In addition, we performed candidate gene analyses for a panel of 29 genes previously implicated in atypical femoral fractures (significance threshold of p<5.7x10(-6)). Compared with population controls, bisphosphonate-associated atypical femoral fracture was associated with four isolated, uncommon single-nucleotide polymorphisms. When cases were compared with bisphosphonate-treated controls, no statistically significant genome-wide association remained. We conclude that the detected associations were either false positives or related to the underlying disease, i.e., treatment indication. Furthermore, there was no significant association with single-nucleotide polymorphisms in the 29 candidate genes. In conclusion, this study found no evidence of a common genetic predisposition for bisphosphonate-associated atypical femoral fracture. Further studies of larger sample size to identify possible weakly associated genetic traits, as well as whole exome or whole-genome sequencing studies to identify possible rare genetic variation conferring a risk are warranted.

  • 19.
    Olsson, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research Center.
    Ståhle, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Thelin, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    The Swedish Heart Surgery Register: Data quality for proximal thoracic aortic operations2006In: Scandinavian Cardiovascular Journal, ISSN 1401-7431, E-ISSN 1651-2006, Vol. 40, no 6, p. 348-353Article in journal (Refereed)
    Abstract [en]

    Objectives. To review the data quality and validity in the nationwide Swedish Heart Surgery register for patients operated on the proximal thoracic aorta. Design. Medical records from a random sample of 300 patients in The Swedish Heart Surgery register were reviewed with register data items systematically re-reported. Variable reporting frequency, proportion of adequately reported data, and number and correctness of diagnostic and procedural codes were analysed. Results. After exclusions, 251 patients (84%) remained in the analysis. Reporting frequency for individual items varied from 12% to 100% (median 61%). For core variables, reporting frequency was 96%-100%. In 40 of 43 (93%) reviewed variables, registry data were at least 85% correct. A total of 485 diagnoses and 673 procedures were reported, compared to 617 diagnoses and 758 procedures identified in the review process. Conclusions. The register data quality and validity for patients operated on the proximal thoracic aorta was satisfactory overall, but need further improvement for complications. The register coverage and completeness was very high. Register-based reports should be accompanied by review of data quality.

  • 20.
    Parker, William A E
    et al.
    University of Sheffield, Immunity and Cardiovascular Disease, Department of Infection, Sheffield , United Kingdom.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Becker, Richard C
    University of Cincinnati College of Medicine, Heart, Lung and Vascular Institute, Division of Cardiovascular Health and Disease, Cincinnati, OH, USA.
    Voora, Deepak
    Duke University Medical Center, Duke Clinical Research Institute, Durham, NC, USA.
    Åkerblom, Axel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Himmelmann, Anders
    AstraZeneca Research and Development, Gothenburg, Sweden.
    James, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Storey, Robert F
    University of Sheffield, Immunity and Cardiovascular Disease, Department of Infection, Sheffield , United Kingdom.
    Equilibrative nucleoside transporter 1 gene polymorphisms and clinical outcomes following acute coronary syndromes: findings from the PLATelet inhibition and patient Outcomes (PLATO) study2018In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 30, no 5, p. 579-588Article in journal (Refereed)
    Abstract [en]

    In the PLATelet inhibition and patient Outcomes (PLATO) study, the P2Y12 inhibitors ticagrelor and clopidogrel were compared in the treatment of acute coronary syndromes (ACS). Ticagrelor was shown to reduce occurrence of the primary end point - a composite of death from vascular causes, myocardial infarction, or stroke - compared to clopidogrel. Ticagrelor's pleiotropic effects on reuptake of adenosine via inhibition of equilibrative nucleoside transporter 1 (ENT1) have been hypothesized to contribute to this. Several polymorphisms of ENT1 are known to exist. We explored the interaction between ENT1 polymorphisms and clinical outcomes in ACS patients participating in the PLATO genetic substudy. Using genotyping data obtained in a genome-wide association study, the gene region encoding ENT1 was assessed and 94 polymorphisms were identified. After quality control filtering, data from 9943 participants were included. Subjects were divided into discovery (phase 1, n = 3970) and replication (phase 2, n = 5973) cohorts. Cox-regression analysis of the relationship between variants and seven efficacy and safety outcomes was performed in discovery, replication, and combined cohorts. Treatment-marker interactions were also determined. Although 35 variants were found with associations to the investigated outcomes reaching p < 0.05 in the discovery cohort, only one of these was replicated in phase 2 of the analysis and also reached the predetermined level of statistical significance in the combined data, taking into account the number of tests performed: the rare polymorphism rs141034817, with a frequency of 0.2%, was significantly associated with bleeding. Thirty-three treatment-marker interactions were found with a significance level of p < 0.05 in phase 1, but none was replicated in phase 2. We found no significant interaction between ENT1 genotype and clinical outcomes in ACS patients treated with ticagrelor or clopidogrel, apart from the association between a rare polymorphism and bleeding that requires further study. If ticagrelor's pleiotropic effects on adenosine uptake are clinically relevant, these do not appear to be significantly affected by variation in the ENT1 gene.

  • 21. Paré, Guillaume
    et al.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lehr, Thorsten
    Connolly, Stuart
    Eikelboom, John
    Ezekowitz, Michael D
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Haertter, Sebastian
    Oldgren, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Reilly, Paul
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Wadelius, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Zimdahl-Gelling, Heike
    Yusuf, Salim
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Genetic Determinants of Dabigatran Plasma Levels and Their Relation to Bleeding2013In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 127, no 13, p. 1404-Article in journal (Refereed)
    Abstract [en]

    Background

    Fixed-dose unmonitored treatment with dabigatran etexilate is effective and has a favorable safety profile in prevention of stroke in atrial fibrillation patients compared to warfarin. We hypothesized that genetic variants could contribute to inter-individual variability in blood concentrations of the active metabolite of dabigatran etexilate, and influence the safety and efficacy of dabigatran.

    Methods and Results

    We successfully conducted a genome-wide association study in 2,944 RE-LY participants. The CES1 SNP rs2244613 was associated with trough concentrations, and the ABCB1 SNP rs4148738 and CES1 SNP rs8192935 were associated with peak concentrations at genome-wide significance (P<9 x 10-8) with a gene-dose effect. Each minor allele of the CES1 SNP rs2244613 was associated with lower trough concentrations (15% decrease per allele, 95%CI 10-19%; P=1.2 x 10-8) and a lower risk of any bleeding (OR=0.67, 95%CI 0.55-0.82; P=7 x 10-5) in dabigatran-treated participants, with a consistent but non-significant lower risk of major bleeding (OR=0.66, 95%CI 0.43-1.01). The interaction between treatment (warfarin versus all dabigatran) and carrier status was statistically significant (P=0.002) with carriers having less bleeding with dabigatran than warfarin (HR=0.59, 95%CI 0.46-0.76; P=5.2 x 10-5) in contrast to no difference in noncarriers (HR=0.96, 95%CI 0.81-1.14; P=0.65). There was no association with ischemic events, and neither rs4148738 nor rs8192935 was associated with bleeding or ischemic events.

    Conclusions

    Genome-wide association analysis identified that carriage of CES1 rs2244613 minor allele occurred in 32.8% of patients in RELY and was associated with lower exposure to active dabigatran metabolite. The presence of the polymorphism was associated with a lower risk of bleeding.

  • 22.
    Patel, Riyaz S.
    et al.
    UCL, Inst Cardiovasc Sci, Fac Populat Hlth Sci, London, England;St Bartholomews Hosp, Barts Heart Ctr, London, England.
    Schmidt, Amand F.
    UCL, Inst Cardiovasc Sci, Fac Populat Hlth Sci, London, England;UMC, Dept Cardiol, Div Heart & Lungs, Utrecht, Netherlands.
    Tragante, Vinicius
    UMC, Dept Cardiol, Div Heart & Lungs, Utrecht, Netherlands.
    McCubrey, Raymond O.
    Intertermt Med Ctr, Intermt Heart Inst, Salt Lake City, UT USA.
    Holmes, Michael, V
    Univ Oxford, Clin Trial Serv Unit, Nuffield Dept Populat Hlth, Oxford, England;Univ Oxford, Epidemiol Studies Unit, Nuffield Dept Populat Hlth, Oxford, England;Univ Oxford, Med Res Council Populat Hlth Res Unit, Oxford, England;Univ Oxford, Natl Inst Hlth Res, Oxford Biomed Res Ctr, Oxford, England.
    Howe, Laurence J.
    UCL, Inst Cardiovasc Sci, Fac Populat Hlth Sci, London, England.
    Direk, Kenan
    UCL, Inst Cardiovasc Sci, Fac Populat Hlth Sci, London, England.
    Åkerblom, Axel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Leander, Karin
    Karolinska Inst, Inst Environm Med, Stockholm, Sweden.
    Virani, Salim S.
    Baylor Coll Med, Sect Cardiovasc Res, Michael & DeBakey Vet Affairs Med Ctr, Sect Cardiol, Houston, TX 77030 USA;Baylor Coll Med, Dept Med, Sect Cardiol, Houston, TX 77030 USA.
    Kaminski, Karol A.
    Med Univ Bialystok, Dept Populat Med & Civilizat Dis Prevent, Bialystok, Poland;Med Univ Bialystok, Dept Cardiol, Bialystok, Poland.
    Muehlschlegel, Jochen D.
    UCL, Inst Cardiovasc Sci, Fac Populat Hlth Sci, London, England;St Bartholomews Hosp, Barts Heart Ctr, London, England;Harvard Med Sch, 75 Francis St, Boston, MA 02115 USA.
    Dube, Marie-Pierre
    Univ Montreal, Fac Med, Montreal, PQ, Canada.
    Allayee, Hooman
    USC, Dept Prevent Med, Los Angeles, CA USA;USC, Dept Biochem & Mol Med, Los Angeles, CA USA.
    Almgren, Peter
    Lund Univ, Dept Clin Sci, Malmo, Sweden.
    Alver, Maris
    Univ Tartu, Inst Mol & Cell Biol, Dept Biotechnol, Tartu, Estonia.
    Baranova, Ekaterina, V
    Univ Med Ctr, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht, Netherlands.
    Behlouli, Hassan
    McGill Univ Hlth Ctr, Res Inst, Montreal, PQ, Canada;German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany.
    Boeckx, Bram
    Katholieke Univ Leuven, Dept Human Genet, Lab Translat Genet, Leuven, Belgium;VIB, VIB Ctr Canc Biol, Lab Translat Genet, Ghent, Belgium.
    Braund, Peter S.
    Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England;Univ Leicester, Dept Hlth Sci, Leicester, Leics, England;Glenfield Hosp, NIHR, Leicester, Leics, England.
    Breitling, Lutz P.
    McGill Univ Hlth Ctr, Res Inst, Montreal, PQ, Canada;German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany.
    Delgado, Graciela
    Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Mannheim, Germany.
    Duarte, Nubia E.
    Univ Sao Paulo, Heart Inst, Sao Paulo, Brazil.
    Dufresne, Line
    McGill Univ Hlth Ctr, Res Inst, Montreal, PQ, Canada;McGill Univ Hlth Ctr, Prevent & Genom Cardiol, Montreal, PQ, Canada.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Foco, Luisa
    Univ Lubeck, Affiliated Inst, Eurac Res, Inst Biomed, Bolzano, Italy.
    Gijsberts, Crystel M.
    UMC, Lab Expt Cardiol, Utrecht, Netherlands.
    Gong, Yan
    Univ Florida, Dept Pharmacotherapy & Translat Res, Gainesville, FL USA;Univ Florida, Ctr Pharmacogen, Gainesville, FL USA.
    Hartiala, Jaana
    USC, Dept Prevent Med, Los Angeles, CA USA;USC, Dept Biochem & Mol Med, Los Angeles, CA USA;USC, Keck Sch Med, Inst Genet Med, Los Angeles, CA USA.
    Heydarpour, Mahyar
    Brigham & Womens Hosp, Dept Anesthesiol Perioperat & Pain Med, 75 Francis St, Boston, MA 02115 USA;Harvard Med Sch, 75 Francis St, Boston, MA 02115 USA.
    Hubacek, Jaroslav A.
    Inst Clin & Expt Med, Ctr Expt Med, Prague, Czech Republic.
    Kleber, Marcus
    Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Mannheim, Germany.
    Kofink, Daniel
    UMC, Dept Cardiol, Div Heart & Lungs, Utrecht, Netherlands.
    Kuukasjarvi, Pekka
    Univ Tampere, Fac Med & Life Sci, Finnish Cardiovasc Res Ctr, Dept Cardiothorac Surg, Tampere, Finland.
    Lee, Vei-Vei
    Texas Heart Inst, Dept Biostat & Epidemiol, Houston, TX 77025 USA.
    Leiherer, Andreas
    VIVIT, Feldkirch, Austria;Private Univ Principal Liechtenstein, Triesen, Liechtenstein;Med Cent Labs, Feldkirch, Austria.
    Lenzini, Petra A.
    Washington Univ, Sch Med, Dept Genet, Stat Genom Div, St Louis, MO 63110 USA;Univ Sao Paulo, Hosp Univ, Ctr Pesquisa Clin, Sao Paulo, Brazil.
    Levin, Daniel
    Univ Dundee, Sch Med, Div Mol & Clin Med, Dundee, Scotland.
    Lyytikainen, Leo-Pekka
    Univ Tampere, Fac Med & Life Sci, Finnish Cardiovasc Res Ctr, Dept Clin Chem, Tampere, Finland;Fimlab Labs, Dept Clin Chem, Tampere, Finland.
    Martinelli, Nicola
    Univ Verona, Dept Med, Verona, Italy.
    Mons, Ute
    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany.
    Nelson, Christopher P.
    Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England;Univ Leicester, Dept Hlth Sci, Leicester, Leics, England;Glenfield Hosp, NIHR, Leicester, Leics, England.
    Nikus, Kjell
    Univ Tampere, Fac Med & Life Sci, Finnish Cardiovasc Res Ctr, Dept Cardiol, Tampere, Finland;Tampere Univ Hosp, Dept Cardiol, Heart Ctr, Tampere, Finland.
    Pilbrow, Anna P.
    Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Sch Med, Atlanta, GA 30322 USA.
    Ploski, Rafal
    Med Univ Warsaw, Dept Med Genet, Warsaw, Poland.
    Sun, Yan, V
    Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Sch Med, Atlanta, GA 30322 USA;Emory Univ, Sch Med, Dept Biomed Informat, Atlanta, GA 30322 USA.
    Tanck, Michael W. T.
    Univ Utrecht, Dept Internal Med, Sect Gerontol & Geriatr, Utrecht, Netherlands.
    Tang, W. H. Wilson
    Cleveland Clin, Lerner Res Inst, Dept Cellular & Mol Med, Cleveland, OH 44106 USA;Cleveland Clin, Dept Cardiovasc Med, Heart & Vasc Inst & Ctr Microbiome & Human Hlth, Cleveland, OH 44106 USA.
    Trompet, Stella
    Univ Utrecht, Dept Internal Med, Sect Gerontol & Geriatr, Utrecht, Netherlands;Univ Utrecht, Dept Cardiol, Utrecht, Netherlands.
    van der Laan, Sander W.
    Univ Med Ctr, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht, Netherlands;Univ Utrecht, Div Labs Pharm & Biomed Genet, Leiden Univ Med Ctr, Lab Clin Chem & Hematol, Utrecht, Netherlands.
    van Setten, Jessica
    ICIN Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, Utrecht, Netherlands.
    Vilmundarson, Ragnar O.
    Ruddy Canadian Cardiovasc Genet Ctr, Ottawa, ON, Canada;Univ Ottawa, Dept Biochem Microbiol & Immunol, Ottawa, ON, Canada.
    Anselmi, Chiara Viviani
    Humanitas Clin & Res Ctr, Dept Cardiovasc Med, Milan, Italy.
    Vlachopoulou, Efthymia
    Univ Helsinki, Transplantat Lab, Med, Helsinki, Finland.
    Boerwinkle, Eric
    Univ Texas Houston, Sch Publ Hlth, Houston, TX USA.
    Briguori, Carlo
    Clin Mediterranea, Naples, Italy.
    Carlquist, John F.
    Intertermt Med Ctr, Intermt Heart Inst, Salt Lake City, UT USA;Univ Utah, Dept Internal Med, Cardiol Div, Salt Lake City, UT 84112 USA.
    Carruthers, Kathryn F.
    Univ Edinburgh, Cardiovasc Sci, Edinburgh, Midlothian, Scotland.
    Casu, Gavino
    ATS Sardegna, ASL 3, Nuoro, Italy.
    Deanfield, John
    INESSS, Unite Evaluat Cardiovasc, Montreal, PQ, Canada.
    Deloukas, Panos
    Barts & London Med Sch, William Harvey Res Inst, London, England;Queen Mary Univ London, Ctr Genom Hlth, London, England.
    Dudbridge, Frank
    BHF Cardiovasc Res Ctr, Leicester, Leics, England.
    Fitzpatrick, Natalie
    UCL, Inst Hlth Informat, Fac Populat Hlth Sci, London, England.
    Gigante, Bruna
    UMC, Dept Clin Chem & Hematol, Utrecht, Netherlands.
    James, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lokki, Marja-Liisa
    Univ Helsinki, Transplantat Lab, Med, Helsinki, Finland.
    Lotufo, Paulo A.
    Jagiellonian Univ, Med Coll, Dept Internal Med, Krakow, Poland.
    Marziliano, Nicola
    ATS Sardegna, ASL 3, Nuoro, Italy.
    Mordi, Ify R.
    Univ Dundee, Sch Med, Div Mol & Clin Med, Dundee, Scotland.
    Muhlestein, Joseph B.
    Univ Utah, Dept Internal Med, Cardiol Div, Salt Lake City, UT 84112 USA.
    Cheh, Chris Newton
    Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston & Program Med & Populat Genet, Brd Inst, Cambridge, MA USA;Massachusetts Gen Hosp, Ctr Human Genet Res, Boston & Program Med & Populat Genet, Brd Inst, Cambridge, MA USA.
    Pitha, Jan
    Inst Clin & Expt Med, Ctr Expt Med, Prague, Czech Republic.
    Saely, Christoph H.
    UCL, Inst Hlth Informat, Fac Populat Hlth Sci, London, England;VIVIT, Feldkirch, Austria;Private Univ Principal Liechtenstein, Triesen, Liechtenstein.
    Samman-Tahhan, Ayman
    Emory Univ, Sch Med, Dept Med, Emory Clin Cardiovasc Res Inst, Atlanta, GA USA.
    Sandesara, Pratik B.
    Emory Univ, Sch Med, Dept Med, Emory Clin Cardiovasc Res Inst, Atlanta, GA USA.
    Teren, Andrej
    Heart Ctr Leipzig, Acad Teaching Hosp Feldkirch, Dept Med & Cardiol, Leipzig, Germany;Univ Leipzig, LIFE Res Ctr Civilizat Dis, Leipzig, Germany.
    Timmis, Adam
    UCL, Inst Hlth Informat, Fac Populat Hlth Sci, London, England;St Bartholomews Hosp, Barts Heart Ctr, London, England.
    Van de Werf, Frans
    Katholieke Univ Leuven, Dept Cardiovasc Sci, Leuven, Belgium.
    Wauters, Els
    Katholieke Univ Leuven, Univ Hosp, Dept Resp Med, Resp Oncol Unit, Leuven, Belgium.
    Wilde, Arthur A. M.
    Princess Jawhara Brah Ctr Excellence Res Heredita, Jeddah, Saudi Arabia.
    Ford, Ian
    Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland.
    Stott, David J.
    Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland.
    Algra, Ale
    Univ Med Ctr, Dept Neurol & Neurosurg, Brain Ctr Rudolf Magnus, Utrecht, Netherlands;Univ Med Ctr, Dept Neurol & Neurosurg, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands.
    Andreassi, Maria G.
    CNR, Inst Clin Physiol, Pisa, Italy.
    Ardissino, Diego
    Parma Univ Hosp, Cardiol Dept, Parma, OH USA.
    Arsenault, Benoit J.
    Inst Univ cardiol & Pneumol Quebec, Ctr Rech, Quebec City, PQ, Canada;Univ Laval, Fac Med, Dept Med, Laval, PQ, Canada.
    Ballantyne, Christie M.
    Baylor Coll Med, Sect Cardiovasc Res, Michael & DeBakey Vet Affairs Med Ctr, Sect Cardiol, Houston, TX 77030 USA;Baylor Coll Med, Dept Med, Sect Cardiol, Houston, TX 77030 USA.
    Bergmeijer, Thomas O.
    St Antonius Hosp, Dept Cardiol, Nieuwegein, Netherlands.
    Bezzina, Connie R.
    Univ Amsterdam, Clin Epidemiol & Biostat, AMC Heart Ctr, Amsterdam, Netherlands.
    Body, Simon C.
    Harvard Med Sch, 75 Francis St, Boston, MA 02115 USA;Beth Israel Deaconess Med Ctr, Dept Anesthesia Pain & Crit Care, Boston, MA 02215 USA.
    Bogaty, Peter
    Inst Univ Cardiol & Pneumol Quebec, Dept Multidisciplinaire Cardiol, Serv Cardiol, Quebec City, PQ, Canada;INESSS, Unite Evaluat Cardiovasc, Montreal, PQ, Canada;Laval Univ, Inst Univ Cardiol & Pnemol Quebec, Quebec City, PQ, Canada.
    de Borst, Gert J.
    Univ Utrecht, Univ Med Ctr Utrecht, Dept Vasc Surg, Utrecht, Netherlands.
    Brenner, Hermann
    ICIN Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, Utrecht, Netherlands.
    Burkhardt, Ralph
    Univ Leipzig, LIFE Res Ctr Civilizat Dis, Leipzig, Germany;Univ Hosp Regensburg, Inst Clin Chem & Lab Med, Regensburg, Germany.
    Carpeggiani, Clara
    CNR, Inst Clin Physiol, Pisa, Italy.
    Condorelli, Gianluigi
    Humanitas Clin & Res Ctr, Dept Cardiovasc Med, Milan, Italy;Humanitas Univ, Dept Biomed Sci, Milan, Italy.
    Cooper-DeHoff, Rhonda M.
    Univ Florida, Dept Pharmacotherapy & Translat Res, Gainesville, FL USA;Univ Florida, Ctr Pharmacogen, Gainesville, FL USA.
    Cresci, Sharon
    Washington Univ, Sch Med, Dept Genet, Stat Genom Div, St Louis, MO 63110 USA;Washington Univ, Sch Med, Dept Med, Cardiovasc Div, St Louis, MO 63110 USA.
    de Faire, Ulf
    Karolinska Inst, Inst Environm Med, Stockholm, Sweden.
    Doughty, Robert N.
    Univ Auckland, Heart Hlth Res Grp, Auckland, New Zealand.
    Drexel, Heinz
    VIVIT, Feldkirch, Austria;Private Univ Principal Liechtenstein, Triesen, Liechtenstein;Drexel Univ, Coll Med, Philadelphia, PA USA.
    Engert, James C.
    McGill Univ Hlth Ctr, Res Inst, Montreal, PQ, Canada;Royal Victoria Hosp, Dept Med, Div Cardiol, Montreal, PQ, Canada;McGill Univ Hlth Ctr, Prevent & Genom Cardiol, Montreal, PQ, Canada.
    Fox, Keith A. A.
    Univ Edinburgh, Cardiol, Edinburgh, Midlothian, Scotland.
    Girelli, Domenico
    Univ Verona, Dept Med, Verona, Italy.
    Hagström, Emil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Hazen, Stanley L.
    Cleveland Clin, Lerner Res Inst, Dept Cellular & Mol Med, Cleveland, OH 44106 USA;Cleveland Clin, Dept Cardiovasc Med, Heart & Vasc Inst, Cleveland, OH 44106 USA;Cleveland Clin, Dept Cardiovasc Med, Ctr Microbiome & Human Hlth, Cleveland, OH 44106 USA.
    Held, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Hemingway, Harry
    UCL, Inst Hlth Informat, Fac Populat Hlth Sci, London, England.
    Hoefer, Imo E.
    UMC, Dept Clin Chem & Hematol, Utrecht, Netherlands.
    Hovingh, G. Kees
    Acad Med Ctr, Dept Vasc Med, Amsterdam, Netherlands.
    Johnson, Julie A.
    Univ Florida, Dept Pharmacotherapy & Translat Res, Gainesville, FL USA;Univ Florida, Ctr Pharmacogen, Gainesville, FL USA;Univ Florida, Coll Med, Div Cardiovasc Med, Gainesville, FL USA.
    De Jong, Pim A.
    Univ Med Ctr, Dept Radiol, Utrecht, Netherlands.
    Jukema, J. Wouter
    Univ Utrecht, Dept Cardiol, Utrecht, Netherlands;Inter Univ, Cardiol Inst Netherlands, Utrecht, Netherlands.
    Kaczor, Marcin P.
    Jagiellonian Univ, Med Coll, Dept Internal Med, Krakow, Poland.
    Kahonen, Mika
    Univ Tampere, Fac Med & Life Sci, Finnish Cardiovasc Res Ctr, Dept Clin Physiol, Tampere, Finland;Tampere Univ Hosp, Dept Clin Physiol, Tampere, Finland.
    Kettner, Jiri
    Inst Clin & Expt Med, Cardiol Ctr, Prague, Czech Republic.
    Kiliszek, Marek
    Mil Inst Med, Dept Cardiol & Internal Dis, Warsaw, Poland.
    Klungel, Olaf H.
    Univ Med Ctr, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht, Netherlands.
    Lagerqvist, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Lambrechts, Diether
    Katholieke Univ Leuven, Dept Human Genet, Lab Translat Genet, Leuven, Belgium.
    Laurikka, Jari O.
    Univ Tampere, Fac Med & Life Sci, Finnish Cardiovasc Res Ctr, Dept Cardiothorac Surg, Tampere, Finland;Tampere Univ Hosp, Heart Ctr, Dept Cardiothorac Surg, Tampere, Finland.
    Lehtimaki, Terho
    Univ Tampere, Fac Med & Life Sci, Finnish Cardiovasc Res Ctr, Dept Clin Chem, Tampere, Finland;Fimlab Labs, Dept Clin Chem, Tampere, Finland.
    Lindholm, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Mahmoodi, Bakhtawar K.
    St Antonius Hosp, Dept Cardiol, Nieuwegein, Netherlands.
    Maitland-van der Zee, Anke H.
    Univ Med Ctr, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht, Netherlands;Univ Amsterdam, Acad Med Ctr, Dept Resp Med, Clin & Expt Cardiol, Amsterdam, Netherlands.
    McPherson, Ruth
    Univ Ottawa Heart Inst, Ottawa, ON, Canada;Univ Ottawa, Dept Med, Ottawa, ON, Canada;Univ Ottawa, Dept Biochem, Ottawa, ON, Canada;Univ Ottawa, Dept Microbiol & Immunol, Ottawa, ON, Canada.
    Melander, Olle
    Lund Univ, Dept Clin Sci, Malmo, Sweden;Skane Univ Hosp, Dept Internal Med, Malmo, Sweden.
    Metspalu, Andres
    Univ Tartu, Estonian Genome Ctr, Inst Genom, Tartu, Estonia;Univ Tartu, Inst Mol & Cell Biol, Dept Biotechnol, Tartu, Estonia.
    Pepinski, Witold
    Med Univ Bialystok, Dept Forens Med, Bialystok, Poland.
    Olivieri, Oliviero
    Univ Verona, Dept Med, Verona, Italy.
    Opolski, Grzegorz
    Med Univ Warsaw, Dept Cardiol, Warsaw, Poland.
    Palmer, Colin N.
    Ninewells Hosp & Med Sch, Div Mol & Clin Med, Pat Macpherson Ctr Pharmacogenet & Pharmacogen, Dundee, Scotland.
    Pasterkamp, Gerard
    UMC, Dept Clin Chem, Utrecht, Netherlands.
    Pepine, Carl J.
    Univ Florida, Coll Med, Div Cardiovasc Med, Gainesville, FL USA.
    Pereira, Alexandre C.
    Univ Sao Paulo, Heart Inst, Sao Paulo, Brazil.
    Note, Louise
    Humanitas Univ, Dept Biomed Sci, Milan, Italy.
    Quyyumi, Arshed A.
    Emory Univ, Sch Med, Dept Med, Emory Clin Cardiovasc Res Inst, Atlanta, GA USA.
    Richards, A. Mark
    Univ Otago, Christchurch Heart Inst, Dunedin, New Zealand;Natl Univ Singapore, Cardiovasc Res Inst, Singapore, Singapore.
    Sanak, Marek
    Jagiellonian Univ, Med Coll, Dept Internal Med, Krakow, Poland.
    Scholz, Markus
    Univ Leipzig, LIFE Res Ctr Civilizat Dis, Leipzig, Germany;Univ Leipzig, Inst Med Informat Stat & Epidemiol, Leipzig, Germany.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Sinisalo, Juha
    Univ Helsinki, Helsinki Univ Hosp, Heart & Lung Ctr, Helsinki, Finland.
    Smith, J. Gustav
    Lund Univ, Dept Cardiol Clin Sci, Lund, Sweden;Skane Univ Hosp, Malmo, Sweden;Wallenberg Ctr Mol Med, Malmo, Sweden;Lund Univ, Lund Univ Diabet Ctr, Lund, Sweden.
    Spertus, John A.
    St Lukes Mid Amer Heart Inst, Kansas City, MO USA;Univ Missouri, St Lukes Hlth Syst, Kansas City, MO 64110 USA.
    Stewart, Alexandre F. R.
    Ruddy Canadian Cardiovasc Genet Ctr, Ottawa, ON, Canada;Univ Ottawa, Dept Biochem Microbiol & Immunol, Ottawa, ON, Canada.
    Szczeklik, Wojciech
    Jagiellonian Univ, Med Coll, Dept Internal Med, Krakow, Poland.
    Szpakowicz, Anna
    Med Univ Bialystok, Dept Cardiol, Bialystok, Poland.
    ten Berg, Jurrien M.
    Intertermt Med Ctr, Intermt Heart Inst, Salt Lake City, UT USA;St Antonius Hosp, Dept Cardiol, Nieuwegein, Netherlands.
    Thanassoulis, George
    Med Univ Bialystok, Dept Forens Med, Bialystok, Poland;Royal Victoria Hosp, Dept Med, Div Cardiol, Montreal, PQ, Canada;McGill Univ Hlth Ctr, Prevent & Genom Cardiol, Montreal, PQ, Canada.
    Thieiy, Joachim
    Univ Leipzig, LIFE Res Ctr Civilizat Dis, Leipzig, Germany;Univ Hosp, Clin Chem & Mol Diagnost, Inst Lab Med, Leipzig, Germany.
    van der Graaf, Yolanda
    Univ Med Ctr, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands.
    Visseren, Frank L. J.
    McGill Univ Hlth Ctr, Ctr Outcomes Res & Evaluat, Res Inst, Montreal, PQ, Canada.
    Waltenberger, Johannes
    Univ Munster, Dept Cardiovasc Med, Munster, Germany.
    Van der Harst, Pim
    Univ Groningen, Univ Med Ctr, Groningen, Netherlands.
    Tardif, Jean-Claude
    Univ Montreal, Montreal Heart Inst, Montreal, PQ, Canada;Univ Montreal, Fac Med, Montreal, PQ, Canada.
    Sattar, Naveed
    Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland.
    Lang, Chim C.
    Univ Dundee, Sch Med, Div Mol & Clin Med, Dundee, Scotland.
    Pare, Guillaume
    McMaster Univ, Dept Pathol & Mol Med, Hamilton, ON, Canada;Populat Hlth Res Inst, Hamilton, ON, Canada.
    Brophy, James M.
    McGill Univ Hlth Ctr, Res Inst, Montreal, PQ, Canada.
    Anderson, Jeffrey L.
    Intertermt Med Ctr, Intermt Heart Inst, Salt Lake City, UT USA;Univ Utah, Dept Internal Med, Cardiol Div, Salt Lake City, UT 84112 USA.
    Maerz, Winfried
    Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Mannheim, Germany;Synlab Holding Deutschland GmbH, Synlab Acad, Mannheim, Germany;Med Univ Graz, Clin Inst Med, Graz, Austria;Med Univ Graz, Chem Lab Diagnost, Graz, Austria.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Cameron, Vicky A.
    Univ Otago, Christchurch Heart Inst, Dunedin, New Zealand.
    Horne, Benjamin D.
    UMC, Lab Expt Cardiol, Utrecht, Netherlands;Univ Utah, Dept Biomed Informat, Salt Lake City, UT USA.
    Samani, Nilesh J.
    Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England;Univ Leicester, Dept Hlth Sci, Leicester, Leics, England.
    Hingorani, Aroon D.
    UCL, Inst Cardiovasc Sci, Fac Populat Hlth Sci, London, England.
    Asselbergs, Folkert W.
    UCL, Inst Cardiovasc Sci, Fac Populat Hlth Sci, London, England;UCL, Inst Hlth Informat, Fac Populat Hlth Sci, London, England;UMC, Dept Cardiol, Div Heart & Lungs, Utrecht, Netherlands.
    Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events: A GENIUS-CHD Study of Individual Participant Data2019In: Circulation: Genomic and Precision Medicine, ISSN 2574-8300, Vol. 12, no 4, article id e002471Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk.

    METHODS: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD.

    RESULTS: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUSCHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction < 0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09).

    CONCLUSIONS: In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.

  • 23.
    Patel, Riyaz S.
    et al.
    UCL, Inst Cardiovasc Sci, Fac Populat Hlth Sci, London, England;St Bartholomews Hosp, Barts Heart Ctr, London, England.
    Tragante, Vinicius
    UMC Utrecht, Div Heart & Lungs, Dept Cardiol, Utrecht, Netherlands.
    Schmidt, Amand F.
    UCL, Inst Cardiovasc Sci, Fac Populat Hlth Sci, London, England;UMC Utrecht, Div Heart & Lungs, Dept Cardiol, Utrecht, Netherlands.
    McCubrey, Raymond O.
    Intermt Med Ctr, Intermt Heart Inst, Salt Lake City, UT USA.
    Holmes, Michael, V
    Univ Oxford, Nuffield Dept Populat Hlth, Med Res Council Populat Hlth Res Unit, Clin Trial Serv Unit, Oxford, England;Univ Oxford, Nuffield Dept Populat Hlth, Med Res Council Populat Hlth Res Unit, Epidemiol Studies Unit, Oxford, England;Oxford Univ Hosp, Natl Inst Hlth Res, Oxford Biomed Res Ctr, Oxford, England.
    Howe, Laurence J.
    UCL, Inst Cardiovasc Sci, Fac Populat Hlth Sci, London, England.
    Direk, Kenan
    UCL, Inst Cardiovasc Sci, Fac Populat Hlth Sci, London, England;UMC Utrecht, Div Heart & Lungs, Dept Cardiol, Utrecht, Netherlands.
    Åkerblom, Axel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Leander, Karin
    Karolinska Inst, Inst Environm Med, Stockholm, Sweden.
    Virani, Salim S.
    Michael E DeBakey VA Med Ctr, Sect Cardiol, Houston, TX USA;Baylor Coll Med, Sect Cardiovasc Res, Dept Med, Houston, TX 77030 USA.
    Kaminski, Karol A.
    Med Univ Bialystok, Dept Populat Med & Civilizat Dis Prevent, Bialystok, Poland;Med Univ Bialystok, Dept Cardiol, Bialystok, Poland.
    Muehlschlegel, Jochen D.
    Brigham & Womens Hosp, Dept Anesthesiol Perioperat & Pain Med, 75 Francis St, Boston, MA 02115 USA;Harvard Med Sch, Boston, MA 02115 USA.
    Allayee, Hooman
    USC, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA;USC, Keck Sch Med, Dept Biochem, Los Angeles, CA USA;USC, Keck Sch Med, Dept Mol Med, Los Angeles, CA USA.
    Almgren, Peter
    Lund Univ, Dept Clin Sci, Malmo, Sweden.
    Alver, Maris
    Univ Tartu, Estonian Genome Ctr, Dept Biotechnol, Inst Genom,Inst Mol & Cell Biol, Tartu, Estonia.
    Baranova, Ekaterina, V
    Univ Utrecht, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht, Netherlands.
    Behloui, Hassan
    McGill Univ, Hlth Ctr, Ctr Outcomes Res & Evaluat, Res Inst, Montreal, PQ, Canada.
    Boeckx, Bram
    Katholieke Univ Leuven, Lab Translat Genet, Dept Human Genet, Leuven, Belgium;VIB Ctr Canc Biol, Lab Translat Genet, Leuven, Belgium.
    Braund, Peter S.
    Univ Leicester, Dept Cardiovasc Sci, BHF Cardiovasc Res Ctr, Leicester, Leics, England;Glenfield Hosp, NIHR Leicester Biomed Res Ctr, Leicester, Leics, England.
    Breitling, Lutz P.
    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany.
    Delgado, Gradela
    Heidelberg Univ, Dept Med 5, Med Fac Mannheim, Heidelberg, Germany.
    Duarte, Nubia E.
    Univ Sao Paulo, Heart Inst, Sao Paulo, Brazil.
    Dube, Marie-Pierre
    Montreal Heart Inst, Montreal, PQ, Canada;Univ Montreal, Fac Med, Montreal, PQ, Canada.
    Dufresne, Line
    McGill Univ, Hlth Ctr, Ctr Outcomes Res & Evaluat, Res Inst, Montreal, PQ, Canada;McGill Univ Hlth Ctr, Prevent & Genom Cardiol, Montreal, PQ, Canada.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Foco, Luisa
    Univ Lubeck, Inst Biomed, Eurac Res, Affiliated Inst, Bolzano, Italy.
    Scholz, Markus
    Univ Leipzig, Inst Med Informat Stat & Epidemiol, Leipzig, Germany;Univ Leipzig, LIFE Res Ctr Civilizat Dis, Leipzig, Germany.
    Gijsberts, Crystel M.
    UMC Utrecht, Lab Expt Cardiol, Utrecht, Netherlands.
    Glinge, Charlotte
    Copenhagen Univ Hosp, Rigshosp, Dept Cardiol, Heart Ctr, Amsterdam, Netherlands;Univ Amsterdam, Amsterdam UMC, Clin & Expt Cardiol, Amsterdam Cardiovasc Sci,AMC Heart Ctr, Amsterdam, Netherlands.
    Gong, Yan
    Univ Florida, Dept Pharmacotherapy & Translat Res, Ctr Pharmacogen, Gainesville, FL USA.
    Hartiala, Jaana
    USC, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA;USC, Keck Sch Med, Dept Biochem, Los Angeles, CA USA;USC, Keck Sch Med, Dept Mol Med, Los Angeles, CA USA;USC, Keck Sch Med, Inst Genet Med, Los Angeles, CA USA.
    Heydarpour, Mahyar
    Brigham & Womens Hosp, Dept Anesthesiol Perioperat & Pain Med, 75 Francis St, Boston, MA 02115 USA;Harvard Med Sch, Boston, MA 02115 USA.
    Hubacek, Jaroslav A.
    Inst Clin & Expt Med, Ctr Expt Med, Prague, Czech Republic.
    Kleber, Marcus
    Heidelberg Univ, Dept Med 5, Med Fac Mannheim, Heidelberg, Germany.
    Kofink, Daniel
    Montreal Heart Inst, Montreal, PQ, Canada.
    Kotti, Salma
    URCEST CRCEST CRB HUEP UPMC, AP HP, Dept Clin Pharmacol, Platform Clin Res East Paris, Paris, France.
    Kuukasjarvi, Pekka
    Univ Tampere, Dept Cardiothorac Surg, Tampere, Finland.
    Lee, Vei-Vei
    Texas Heart Inst, Dept Biostat & Epidemiol, Houston, TX 77025 USA.
    Leiherer, Andreas
    VIVIT, Feldkirch, Austria;Private Univ Principal Liechtenstein, Triesen, Liechtenstein;Med Cent Labs, Feldkirch, Austria.
    Lenzini, Petra A.
    Washington Univ, Sch Med, Dept Genet, Stat Genom Div, St Louis, MO 63110 USA.
    Levin, Daniel
    Univ Dundee, Div Mol & Clin Med, Sch Med, Dundee, Scotland.
    Lyytikainen, Leo-Pekka
    Univ Tampere, Dept Clin Chem, Tampere, Finland;Fimlab Labs, Dept Clin Chem, Tampere, Finland.
    Martinelli, Nicola
    Univ Verona, Dept Med, Verona, Italy.
    Mons, Ute
    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany.
    Nelson, Christopher P.
    Univ Leicester, Dept Cardiovasc Sci, BHF Cardiovasc Res Ctr, Leicester, Leics, England;Glenfield Hosp, NIHR Leicester Biomed Res Ctr, Leicester, Leics, England.
    Nikus, Kjell
    Univ Tampere, Dept Cardiol, Tampere, Finland;Tampere Univ Hosp, Dept Cardiol, Heart Ctr, Tampere, Finland.
    Pilbrow, Anna P.
    Univ Otago, Christchurch Heart Inst, Christchurch, New Zealand.
    Ploski, Rafal
    Med Univ Warsaw, Dept Med Genet, Warsaw, Poland.
    Sun, Yan, V
    Emory Univ, Dept Epidemiol, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA;Emory Univ, Sch Med, Dept Biomed Informat, Emory Clin Cardiovasc Res Inst, Atlanta, GA 30322 USA.
    Tanck, Michael W. T.
    Univ Amsterdam, Amsterdam UMC, Clin Epidemiol & Biostat, Amsterdam, Netherlands.
    Tang, W. H. Wilson
    Cleveland Clin, Lerner Res Inst, Dept Cellular & Mol Med, Cleveland, OH 44106 USA;Cleveland Clin, Dept Cardiovasc Med, Heart & Vasc Inst, Cleveland, OH 44106 USA;Cleveland Clin, Ctr Clin Genom, Cleveland, OH 44106 USA.
    Trompet, Stella
    Cleveland Clin, Sect Gerontol & Geriatr, Dept Internal Med, Cleveland, OH 44106 USA;Leiden Univ, Dept Cardiol, Med Ctr, Leiden, Netherlands.
    van der Laan, Sander W.
    Univ Utrecht, Div Labs Pharm & Biomed Genet, Lab Clin Chem & Hematol, UMC Utrecht, Utrecht, Netherlands.
    Van Setten, Jessica
    Univ Utrecht, Div Heart & Lungs, Dept Cardiol, UMC Utrecht, Utrecht, Netherlands.
    Vilmundarson, Ragnar O.
    Univ Ottawa, Heart Inst, Ruddy Canadian Cardiovasc Genet Ctr, Ottawa, ON, Canada;Univ Ottawa, Dept Biochem Microbiol & Immunol, Ottawa, ON, Canada.
    Anselmi, Chiara Viviani
    Humanitas Clin & Res Ctr, Dept Cardiovasc Med, Milan, Italy.
    Vlachopoulou, Efthymia
    Helsinki Univ Hosp, Transplantat Lab, Helsinki, Finland;Univ Helsinki, Helsinki, Finland.
    Al Ali, Lawien
    Univ Groningen, Univ Med Ctr, Groningen, Netherlands.
    Boerwinkle, Eric
    Univ Texas Houston, Sch Publ Hlth, Houston, TX USA.
    Briguori, Carlo
    Clin Mediterranea, Naples, Italy.
    Carlquist, John F.
    Intermt Med Ctr, Intermt Heart Inst, Salt Lake City, UT USA;Univ Utah, Cardiol Div, Dept Internal Med, Salt Lake City, UT USA.
    Carruthers, Kathryn F.
    Univ Edinburgh, Cardiovasc Sci, QMRI, Edinburgh, Midlothian, Scotland.
    Casu, Gavino
    Humanitas Clin & Res Ctr, Dept Cardiovasc Med, Milan, Italy;ASSL Nuoro Osped San Francesco, ATS Sardegna, Nuoro, Italy.
    Deanfield, John
    UCL, Inst Cardiovasc Sci, Fac Populat Hlth Sci, London, England;St Bartholomews Hosp, Barts Heart Ctr, London, England.
    Deloukas, Panos
    Queen Mary Univ London, William Harvey Res Inst, Barts & London Med Sch, London, England;Queen Mary Univ London, Ctr Genom Hlth, London, England.
    Dudbridge, Frank
    Univ Leicester, Dept Hlth Sci, Leicester, Leics, England.
    Engstrom, Thomas
    Copenhagen Univ Hosp, Rigshosp, Dept Cardiol, Heart Ctr, Amsterdam, Netherlands;Lund Univ, Dept Cardiol, Lund, Sweden.
    Fitzpatrick, Natalie
    UCL, Inst Hlth Informat, Fac Populat Hlth Sci, London, England.
    Fox, Kim
    Royal Brompton Hosp, Natl Heart & Lung Inst, Imperial Coll, London, England;Royal Brompton Hosp, Natl Heart & Lung Inst, Inst Cardiovasc Med & Sci, London, England.
    Gigante, Bruna
    Karolinska Inst, Inst Environm Med, Stockholm, Sweden.
    James, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Lokki, Marja-Liisa
    Helsinki Univ Hosp, Transplantat Lab, Helsinki, Finland;Univ Helsinki, Helsinki, Finland.
    Lotufo, Paulo A.
    Univ Sao Paulo, Hosp Univ, Ctr Pesquisa Clin, Sao Paulo, Brazil.
    Marziliano, Nicola
    ATS Sardegna, ASL Nuoro 3, Nuoro, Italy.
    Mordi, Ify R.
    Univ Dundee, Div Mol & Clin Med, Sch Med, Dundee, Scotland.
    Muhlestein, Joseph B.
    Intermt Med Ctr, Intermt Heart Inst, Salt Lake City, UT USA;Univ Utah, Cardiol Div, Dept Internal Med, Salt Lake City, UT USA.
    Newton-Cheh, Christopher
    Massachusetts Gen Hosp, Cardiovasc Res Ctr, Ctr Human Genet Res, Boston, MA 02114 USA;Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.
    Pitha, Jan
    Inst Clin & Expt Med, Ctr Expt Med, Prague, Czech Republic.
    Saely, Christoph H.
    VIVIT, Feldkirch, Austria;Private Univ Principal Liechtenstein, Triesen, Liechtenstein;Acad Teaching Hosp Feldkirch, Dept Med & Cardiol, Feldkirch, Austria.
    Samman-Tahhan, Ayman
    Emory Univ, Sch Med, Div Cardiol, Dept Med,Emory Clin Cardiovasc Res Inst, Atlanta, GA 30322 USA.
    Sandesara, Pratik B.
    Emory Univ, Sch Med, Div Cardiol, Dept Med,Emory Clin Cardiovasc Res Inst, Atlanta, GA 30322 USA.
    Teren, Andrej
    Univ Leipzig, LIFE Res Ctr Civilizat Dis, Leipzig, Germany;Heart Ctr Leipzig, Leipzig, Germany.
    Timmis, Adam
    UCL, Inst Hlth Informat, Fac Populat Hlth Sci, London, England;St Bartholomews Hosp, Barts Heart Ctr, London, England.
    Van de Werf, Frans
    Katholieke Univ Leuven, Dept Cardiovasc Sci, Leuven, Belgium.
    Wauters, Els
    Univ Hosp KU Leuven, Resp Oncol Unit, Dept Resp Med, Leuven, Belgium.
    Wilde, Arthur A. M.
    Univ Amsterdam, Amsterdam UMC, Clin & Expt Cardiol, Amsterdam Cardiovasc Sci,AMC Heart Ctr, Amsterdam, Netherlands;Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah, Saudi Arabia.
    Ford, Ian
    Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland.
    Stott, David J.
    Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland.
    Algra, Ale
    Univ Utrecht, Dept Neurol & Neurosurg, Brain Ctr Rudolf Magnus & Julius Ctr Hlth Sci & P, UMC Utrecht, Utrecht, Netherlands.
    Andreassi, Maria G.
    CNR, Inst Clin Physiol, Pisa, Italy.
    Ardissino, Diego
    Parma Univ Hosp, Cardiol Dept, Parma, Italy.
    Arsenault, Benoit J.
    Inst Univ Cardiol & Pneumol Quebec, Ctr Rech, Quebec City, PQ, Canada;Univ Laval, Dept Med, Fac Med, Laval, PQ, Canada.
    Ballantyne, Christie M.
    Baylor Coll Med, Sect Cardiovasc Res, Dept Med, Houston, TX 77030 USA.
    Bergmeijer, Thomas O.
    St Antonius Hosp, Dept Cardiol, Nieuwegein, Netherlands.
    Bezzina, Connie R.
    Univ Amsterdam, Amsterdam UMC, Clin & Expt Cardiol, Amsterdam Cardiovasc Sci,AMC Heart Ctr, Amsterdam, Netherlands.
    Body, Simon C.
    Harvard Med Sch, Boston, MA 02115 USA;Beth Israel Deaconess Med Ctr, Boston, MA USA.
    Boersma, Eric H.
    Erasmus MC, Dept Cardiol, Thoraxctr, Rotterdam, Netherlands;Erasmus Med Ctr COEUR, Cardiovasc Res Sch, Rotterdam, Netherlands.
    Bogaty, Peter
    Laval Univ, Inst Univ Cardiol & Pneumol Quebec, Quebec City, PQ, Canada.
    Bots, Michiel L.
    Univ Utrecht, Julius Ctr Hlth Sci & Primary Care, UMC Utrecht, Utrecht, Netherlands.
    Brenner, Hermann
    Heidelberg Univ, Network Aging Res, Heidelberg, Germany.
    Brugts, Jasper J.
    Erasmus MC, Dept Cardiol, Thoraxctr, Rotterdam, Netherlands.
    Burkhardt, Ralph
    Univ Leipzig, LIFE Res Ctr Civilizat Dis, Leipzig, Germany;Univ Hosp Regensburg, Inst Clin Chem & Lab Med, Regensburg, Germany.
    Carpeggiani, Clara
    CNR, Inst Clin Physiol, Pisa, Italy.
    Condorelli, Gianluigi
    Humanitas Univ, Dept Biomed Sci, Milan, Italy.
    Cooper-DeHoff, Rhonda M.
    Univ Florida, Dept Pharmacotherapy & Translat Res, Ctr Pharmacogen, Gainesville, FL USA;Univ Florida, Div Cardiovasc Med, Coll Med, Gainesville, FL USA.
    Cresci, Sharon
    Washington Univ, Sch Med, Dept Genet, Stat Genom Div, St Louis, MO 63110 USA;Washington Univ, Dept Med, Cardiovasc Div, St Louis, MO 63110 USA.
    Danchin, Nicolas
    Univ Paris 05, Hop Europeen Georges Pompidou, AP HP, Dept Cardiol, Paris, France;Univ Paris 05, FACT, Paris, France;Univ Paris 05, Paris, France.
    de Faire, Ulf
    Karolinska Inst, Inst Environm Med, Stockholm, Sweden.
    Doughty, Robert N.
    Univ Auckland, Heart Hlth Res Grp, Auckland, New Zealand.
    Drexel, Heinz
    VIVIT, Feldkirch, Austria;Private Univ Principal Liechtenstein, Triesen, Liechtenstein;Drexel Univ, Coll Med, Philadelphia, PA 19104 USA.
    Engert, James C.
    McGill Univ, Res Inst, Hlth Ctr, Montreal, PQ, Canada;McGill Univ Hlth Ctr, Prevent & Genom Cardiol, Montreal, PQ, Canada;McGill Univ Hlth Ctr, Royal Victoria Hosp, Dept Med, Div Cardiol, Montreal, PQ, Canada.
    Fox, Keith A. A.
    Univ Edinburgh, Edinburgh, Midlothian, Scotland.
    Girelli, Domenico
    Univ Verona, Dept Med, Verona, Italy.
    Grobbee, Diederick E.
    Univ Utrecht, Julius Ctr Hlth Sci & Primary Care, UMC Utrecht, Utrecht, Netherlands.
    Hagström, Emil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Hazen, Stanley L.
    Cleveland Clin, Lerner Res Inst, Dept Cellular & Mol Med, Cleveland, OH 44106 USA;Cleveland Clin, Dept Cardiovasc Med, Ctr Microbiome & Human Hlth, Heart & Vasc Inst, Cleveland, OH 44106 USA.
    Held, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Hemingway, Harry
    UCL, Inst Hlth Informat, Fac Populat Hlth Sci, London, England.
    Hoefer, Imo E.
    UMC Utrecht, Dept Clin Chem & Hematol, Utrecht, Netherlands.
    Hovingh, G. Kees
    Acad Med Ctr, Dept Vasc Med, Amsterdam, Netherlands.
    Jabbari, Reza
    Copenhagen Univ Hosp, Rigshosp, Dept Cardiol, Heart Ctr, Amsterdam, Netherlands.
    Johnson, Julie A.
    Univ Florida, Dept Pharmacotherapy & Translat Res, Ctr Pharmacogen, Gainesville, FL USA;Univ Florida, Div Cardiovasc Med, Coll Med, Gainesville, FL USA.
    Jukema, J. Wouter
    Leiden Univ, Dept Cardiol, Med Ctr, Leiden, Netherlands;LUMC, Einthoven Lab Expt Vasc Med, Leiden, Netherlands;Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands.
    Kaczor, Marcin P.
    Jagiellonian Univ, Dept Internal Med, Med Coll, Krakow, Poland.
    Kahonen, Mika
    Univ Tampere, Dept Clin Physiol, Tampere, Finland;Tampere Univ Hosp, Dept Clin Physiol, Tampere, Finland.
    Kettner, Jiri
    Inst Clin & Expt Med, Cardiol Ctr, Prague, Czech Republic.
    Kiliszek, Marek
    Mil Inst Med, Dept Cardiol & Internal Dis, Warsaw, Poland.
    Klungel, Olaf H.
    Univ Utrecht, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht, Netherlands.
    Lagerqvist, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Lambrechts, Diether
    Katholieke Univ Leuven, Lab Translat Genet, Dept Human Genet, Leuven, Belgium;VIB Ctr Canc Biol, Lab Translat Genet, Leuven, Belgium.
    Laurikka, Jari O.
    Univ Tampere, Dept Cardiothorac Surg, Finnish Cardiovasc Res Ctr, Fac Med & Life Sci, Tampere, Finland;Tampere Univ Hosp, Dept Cardio Thorac Surg, Heart Ctr, Tampere, Finland.
    Lehtimaki, Terho
    Univ Tampere, Dept Clin Chem, Tampere, Finland;Fimlab Labs, Dept Clin Chem, Tampere, Finland.
    Lindholm, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Mahmoodi, B. K.
    St Antonius Hosp, Dept Cardiol, Nieuwegein, Netherlands.
    Maitland-van der Zee, Anke H.
    Univ Utrecht, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht, Netherlands;Univ Amsterdam, Dept Resp Med, Acad Med Ctr, Amsterdam, Netherlands.
    McPherson, Ruth
    Univ Ottawa, Heart Inst, Ruddy Canadian Cardiovasc Genet Ctr, Ottawa, ON, Canada;Univ Ottawa, Dept Med, Ottawa, ON, Canada;Univ Ottawa, Dept Biochem, Ottawa, ON, Canada;Univ Ottawa, Dept Microbiol & Immunol, Ottawa, ON, Canada.
    Melander, Olle
    Lund Univ, Dept Clin Sci, Malmo, Sweden;Skane Univ Hosp, Dept Internal Med, Malmo, Sweden.
    Metspalu, Andres
    Univ Tartu, Estonian Genome Ctr, Dept Biotechnol, Inst Genom,Inst Mol & Cell Biol, Tartu, Estonia.
    Niemcunowicz-Janica, Anna
    Med Univ Bialystok, Dept Forens Med, Bialystok, Poland.
    Olivieri, Oliviero
    Univ Verona, Dept Med, Verona, Italy.
    Opolski, Grzegorz
    Med Univ Warsaw, Chair 1, Warsaw, Poland;Med Univ Warsaw, Dept Cardiol, Warsaw, Poland.
    Palmer, Colin N.
    Ninewells Hosp & Med Sch, Pat Macpherson Ctr Pharmacogenet & Pharmacogen, Div Mol & Clin Med, Dundee, Scotland.
    Pasterkamp, Gerard
    UMC Utrecht, Dept Clin Chem, Utrecht, Netherlands.
    Pepine, Carl J.
    Univ Florida, Div Cardiovasc Med, Coll Med, Gainesville, FL USA.
    Pereira, Alexandre C.
    Univ Sao Paulo, Heart Inst, Sao Paulo, Brazil.
    Pilote, Louise
    McGill Univ, Hlth Ctr, Ctr Outcomes Res & Evaluat, Res Inst, Montreal, PQ, Canada;McGill Univ Hlth Ctr, Dept Med, Montreal, PQ, Canada.
    Quyyumi, Arshed A.
    Emory Univ, Sch Med, Div Cardiol, Dept Med,Emory Clin Cardiovasc Res Inst, Atlanta, GA 30322 USA.
    Richards, A. Mark
    Univ Otago, Christchurch Heart Inst, Christchurch, New Zealand;Natl Univ Singapore, Cardiovasc Res Inst, Singapore, Singapore.
    Sanak, Marek
    Jagiellonian Univ, Dept Internal Med, Med Coll, Krakow, Poland.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Simon, Tabassome
    Sorbonne Univ, Platform Clin Res East Paris URCEST CRCEST CRB HU, Dept Clin Pharmacol, AP HP,FACT, Paris, France;Paris Sorbonne Univ, UPMC Site St Antoine, Paris, France.
    Sinisalo, Juha
    Heart and Lung Centre (J.S.), Helsinki University Hospital and University of Helsinki, Finland.
    Smith, J. Gustav
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA;Lund Univ, Dept Cardiol Clin Sci, Skane Univ Hosp, Lund, Sweden;Lund Univ, Wallenberg Ctr Mol Med, Diabet Ctr, Lund, Sweden.
    Spertus, John A.
    Univ Missouri, St Lukes Mid Amer Heart Inst, Kansas City, MO 64110 USA;St Lukes Mid Amer Heart Insti, Kansas City, MO USA.
    Stender, Steen
    Copenhagen Univ Hosp, Dept Clin Biochem, Gentofte, Denmark.
    Stewart, Alexandre F. R.
    Univ Ottawa, Heart Inst, Ruddy Canadian Cardiovasc Genet Ctr, Ottawa, ON, Canada;Univ Ottawa, Dept Biochem Microbiol & Immunol, Ottawa, ON, Canada.
    Szczeklik, Wojciech
    Jagiellonian Univ, Dept Internal Med, Med Coll, Krakow, Poland.
    Szpakowicz, Anna
    Med Univ Bialystok, Dept Cardiol, Bialystok, Poland.
    Tardif, Jean-Claude
    Montreal Heart Inst, Montreal, PQ, Canada;Univ Montreal, Fac Med, Montreal, PQ, Canada.
    ten Berg, Jurrien M.
    St Antonius Hosp, Dept Cardiol, Nieuwegein, Netherlands.
    Tfelt-Hansen, Jacob
    Univ Leipzig, LIFE Res Ctr Civilizat Dis, Leipzig, Germany;Copenhagen Univ Hosp, Rigshosp, Dept Cardiol, Heart Ctr, Copenhagen, Denmark;Univ Copenhagen, Fac Med Sci, Dept Forens Med, Copenhagen, Denmark.
    Thanassoulis, George
    McGill Univ, Hlth Ctr, Ctr Outcomes Res & Evaluat, Res Inst, Montreal, PQ, Canada;McGill Univ Hlth Ctr, Prevent & Genom Cardiol, Montreal, PQ, Canada;McGill Univ Hlth Ctr, Royal Victoria Hosp, Dept Med, Div Cardiol, Montreal, PQ, Canada.
    Thiery, Joachim
    Univ Hosp, Inst Lab Med, Clin Chem & Mol Diagnost, Leipzig, Germany.
    Torp-Pedersen, Christian
    Aalborg Univ Hosp, Dept Hlth Sci & Technol, Unit Epidemiol & Biostat, Aalborg, Denmark.
    van der Graaf, Yolanda
    Univ Utrecht, Julius Ctr Hlth Sci & Primary Care, UMC Utrecht, Utrecht, Netherlands.
    Visseren, Frank L. J.
    Univ Utrecht, Dept Vasc Med, UMC Utrecht, Utrecht, Netherlands.
    Waltenberger, Johannes
    Univ Munster, Dept Cardiovasc Med, Munster, Germany.
    Weeke, Peter E.
    Herlev & Gentofte Hosp, Dept Cardiol, Hellerup, Denmark.
    Van der Harst, Pim
    Univ Groningen, Univ Med Ctr, Groningen, Netherlands.
    Lang, Chim C.
    Univ Dundee, Div Mol & Clin Med, Sch Med, Dundee, Scotland.
    Sattar, Naveed
    Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland.
    Cameron, Vicky A.
    Univ Otago, Christchurch Heart Inst, Christchurch, New Zealand.
    Anderson, Jeffrey L.
    Intermt Med Ctr, Intermt Heart Inst, Salt Lake City, UT USA;Univ Utah, Cardiol Div, Dept Internal Med, Salt Lake City, UT USA.
    Brophy, James M.
    McGill Univ, Hlth Ctr, Ctr Outcomes Res & Evaluat, Res Inst, Montreal, PQ, Canada;McGill Univ Hlth Ctr, Dept Med, Montreal, PQ, Canada.
    Pare, Guillaume
    McMaster Univ, Dept Pathol & Mol Med, Hamilton, ON, Canada;Populat Hlth Res Inst, Hamilton, ON, Canada.
    Horne, Benjamin D.
    Intermt Med Ctr, Intermt Heart Inst, Salt Lake City, UT USA;Univ Utah, Dept Biomed Informat, Salt Lake City, UT USA.
    Marz, Winfried
    Heidelberg Univ, Dept Med 5, Med Fac Mannheim, Heidelberg, Germany;Synlab Holding Deutschland GmbH, Synlab Acad, Mannheim, Germany;Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Samani, Nilesh J.
    Univ Leicester, Dept Cardiovasc Sci, BHF Cardiovasc Res Ctr, Leicester, Leics, England;Glenfield Hosp, NIHR Leicester Biomed Res Ctr, Leicester, Leics, England.
    Hingorani, Aroon D.
    Institute of Cardiovascular Science, Faculty of Population Health Science, University College London, United Kingdom.
    Asselbergs, Folkert W.
    UCL, Inst Cardiovasc Sci, Fac Populat Hlth Sci, London, England;UCL, Inst Hlth Informat, Fac Populat Hlth Sci, London, England;UMC Utrecht, Div Heart & Lungs, Dept Cardiol, Utrecht, Netherlands;ICIN Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, Utrecht, Netherlands.
    Subsequent Event Risk in Individuals With Established Coronary Heart Disease: Design and Rationale of the GENIUS-CHD Consortium2019In: Circulation: Genomic and Precision Medicine, ISSN 2574-8300, Vol. 12, no 4, article id e002470Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD.

    METHODS: The consortium currently includes 57 studies from 18 countries, recruiting 185 614 participants with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events.

    RESULTS: Enrollment into the individual studies took place between 1985 to present day with a duration of follow-up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (hazard ratio, 1.15; 95% CI, 1.14-1.16) per 5-year increase, male sex (hazard ratio, 1.17; 95% CI, 1.13-1.21) and smoking (hazard ratio, 1.43; 95% CI, 1.35-1.51) with risk of subsequent CHD death or myocardial infarction and differing associations with other individual and composite cardiovascular endpoints.

    CONCLUSIONS: GENIUS-CHD is a global collaboration seeking to elucidate genetic and nongenetic determinants of subsequent event risk in individuals with established CHD, to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators.

  • 24. Pirmohamed, Munir
    et al.
    Burnside, Girvan
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Jorgensen, Andrea L.
    Toh, Cheng Hock
    Nicholson, Toby
    Kesteven, Patrick
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wahlström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Stafberg, Christina
    Zhang, J. Eunice
    Leathart, Julian B.
    Kohnke, Hugo
    Maitland-van der Zee, Anke H.
    Williamson, Paula R.
    Daly, Ann K.
    Avery, Peter
    Kamali, Farhad
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    A Randomized Trial of Genotype-Guided Dosing of Warfarin2013In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 369, no 24, p. 2294-2303Article in journal (Refereed)
    Abstract [en]

    Background: The level of anticoagulation in response to a fixed-dose regimen of warfarin is difficult to predict during the initiation of therapy. We prospectively compared the effect of genotype-guided dosing with that of standard dosing on anticoagulation control in patients starting warfarin therapy.

    Methods: We conducted a multicenter, randomized, controlled trial involving patients with atrial fibrillation or venous thromboembolism. Genotyping for CYP2C9*2, CYP2C9*3, and VKORC1 (-1639GA) was performed with the use of a point-of-care test. For patients assigned to the genotype-guided group, warfarin doses were prescribed according to pharmacogenetic-based algorithms for the first 5 days. Patients in the control (standard dosing) group received a 3-day loading-dose regimen. After the initiation period, the treatment of all patients was managed according to routine clinical practice. The primary outcome measure was the percentage of time in the therapeutic range of 2.0 to 3.0 for the international normalized ratio (INR) during the first 12 weeks after warfarin initiation.

    Results: A total of 455 patients were recruited, with 227 randomly assigned to the genotype-guided group and 228 assigned to the control group. The mean percentage of time in the therapeutic range was 67.4% in the genotype-guided group as compared with 60.3% in the control group (adjusted difference, 7.0 percentage points; 95% confidence interval, 3.3 to 10.6; P<0.001). There were significantly fewer incidences of excessive anticoagulation (INR 4.0) in the genotype-guided group. The median time to reach a therapeutic INR was 21 days in the genotype-guided group as compared with 29 days in the control group (P<0.001).

    Conclusions: Pharmacogenetic-based dosing was associated with a higher percentage of time in the therapeutic INR range than was standard dosing during the initiation of warfarin therapy. 

  • 25. Pirmohamed, Munir
    et al.
    Burnside, Girvan
    Stoddern, Jenni
    Prince, Clare
    Toh, Cheng Hok
    Nicholson, Toby
    Kesteven, Patrick
    Jorgensen, Andrea
    Daly, Ann
    Maitland-van der Zee, Anke-Hilse
    Williamson, Paula
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Avery, Peter
    Kamali, Farhad
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    A Randomized Trial Comparing Genotype-Guided Dosing of Warfarin to Standard Dosing: The EU Pharmacogenetics of Anticoagulant Therapy (EU-PACT) Warfarin Study2013In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 128, no 24, p. 2710-2711Article in journal (Other academic)
  • 26. Ross, Stephanie
    et al.
    Eikelboom, John
    Anand, Sonia S.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Gerstein, Hertzel C.
    Mehta, Shamir
    Connolly, Stuart J.
    Rose, Lynda
    Ridker, Paul M.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Chasman, Daniel I.
    Yusuf, Salim
    Pare, Guillaume
    Association of cyclooxygenase-2 genetic variant with cardiovascular disease2014In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 35, no 33, p. 2242-2248Article in journal (Refereed)
    Abstract [en]

    Aim Agenetic variant (rs20417) of the PTGS2 gene, encoding for COX-2, has been associated with decreased COX-2 activity and a decreased risk of cardiovascular disease (CVD). However, this genetic association and the role of COX-2 in CVD remain controversial. Methods and results The association of rs20417 with CVD was prospectively explored in 49 232 subjects (ACTIVE-A, CURE, epiDREAM/DREAM, ONTARGET, RE-LY, and WGHS) and the effect of potentially modifiable risk factors on the genetic association was further explored in 9363 INTERHEART participants. The effect of rs20417 on urinary thromboxane and prostacyclin metabolite concentrations was measured in 117 healthy individuals. Carriage of the rs20417 minor allele was associated with a decreased risk of major CVD outcomes (OR = 0.78, 95% CI: 0.70-0.87; P = 1.2 x 10(-5)). The genetic effect was significantly stronger in aspirin users (OR: 0.74, 95% CI: 0.64-0.84; P = 1.20 x 10(-5)) than non-users (OR: 0.87, 95% CI: 0.72-1.06; P = 0.16) (interaction P-value: 0.0041). Among patients with previous coronary artery disease (CAD), rs20417 carriers had a stronger protective effect on risk of major adverse events when compared with individuals without previous CAD (interaction P-value: 0.015). Carriers had significantly lower urinary levels of thromboxane (P = 0.01) and prostacyclin (P = 0.01) metabolites when compared with non-carriers. Conclusion The rs20417 polymorphism is associated with a reduced risk of major cardiovascular events and lower levels of thromboxane and prostacyclin. Our results suggest that a genetic decrease in COX-2 activity may be beneficial with respect to CVD risk, especially, in higher risk patients on aspirin.

  • 27.
    Siegbahn, Agneta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Johansson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Hagström, Emil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Varenhorst, Christoph
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Åkerblom, Axel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Bertilsson, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Barratt, Bryan J.
    Becker, Richard C.
    Himmelmann, Anders
    James, Stefan K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Katus, Hugo A.
    Steg, Philippe G.
    Storey, Robert F.
    Syvanen, Ann-Christine
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Evaluation of the Effect of Interleukin 18 Associated Genetic Polymorphisms on Risk of Cardiovascular Events in Patients With Acute Coronary Syndrome2013In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 128, no 22Article in journal (Other academic)
  • 28.
    Soveri, Inga
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Abedini, Sadollah
    Holdaas, Halvard
    Jardine, Alan
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Graft Loss Risk in Renal Transplant Recipients with Metabolic Syndrome: Subgroup Analyses of the ALERT Trial2012In: JN. Journal of Nephrology (Milano. 1992), ISSN 1121-8428, E-ISSN 1724-6059, Vol. 25, no 2, p. 245-254Article in journal (Refereed)
    Abstract [en]

    Background: Several nonimmunologic risk factors for late renal graft loss (RGL) are also known components of metabolic syndrome (MS). We aimed to study MS as a risk factor for RGL. Also, the effect of statin treatment in reducing renal risk in renal transplant recipients (RTRs) with MS was studied. Methods: Nondiabetic RTRs (n=1,706) from the ALERT trial were followed for 7-8 years. MS was defined according to National Cholesterol Education Program Adult Treatment Panel III definition with waist girth replaced by BMI =30 (calculated as kg/m2). Renal end points included death-censored RGL and graft loss or doubling of serum creatinine. Results: During the follow-up, 284 patients experienced RGL, and there were 343 cases of graft loss or doubling of serum creatinine. Those with MS had increased risk for RGL (relative risk = 1.28, 95% confidence interval, 1.00-1.63; p=0.047), but not for the combined end point. After adjustment for other known and potential risk factors, MS was no longer associated with increased risk for RGL. The association between MS and RGL risk was attenuated once adjustment for creatinine was made. Statin treatment did not reduce the risk for renal end points in RTRs with or without MS. Conclusion: MS had no independent association with RGL risk. Adjustment for renal function attenuated the association between MS and RGL.

  • 29.
    Varenhorst, Christoph
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Johansson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Barratt, Bryan J.
    Hagström, Emil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Åkerblom, Axel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Becker, Richard C.
    James, Stefan K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Katus, Hugo A.
    Husted, Steen
    Steg, Ph. Gabriel
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Voora, Deepak
    Teng, Renli
    Storey, Robert F.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Effect of genetic variations on ticagrelor plasma levels and clinical outcomes2015In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 36, no 29, p. 1901-1912Article in journal (Refereed)
    Abstract [en]

    Aims Ticagrelor, a direct-acting P2Y(12)-receptor antagonist, is rapidly absorbed and partly metabolized to the major metabolite AR-C124910XX (ARC). To identify single-nucleotide polymorphisms (SNPs) associated with pharmacokinetics of ticagrelor and clinical outcomes, we performed a genome-wide association study (GWAS) in patients treated with ticagrelor in the PLATO trial. Methods and results A two-stage design was used for the GWAS with discovery (discovery phase: n = 1812) and replication cohorts (replication phase: n = 1941). The steady-state area under the curve (AUCss) values, estimated by the population pharmacokinetic (PK) models, were log transformed and analysed on a genome-wide scale using linear regression. SNPs were analysed against clinical events using Cox-regression in 4990 patients. An SNP (rs113681054) in SLCO1B1 was associated with levels of ticagrelor (P = 1.1 x 10(-6)) and ARC (P = 4.6 x 10(-13)). This SNP is in linkage disequilibrium with a functional variant (rs4149056) that results in decreased OATP1B1 transporter activity. Ticagrelor levels were also associated with two independent SNPs (rs62471956, P = 7.7 x 10(-15) and rs56324128, P = 9.7 x 10(-12)) in the CYP3A4 region. Further, ARC levels were associated with rs61361928 (P = 3.0 x 10(-14)) in UGT2B7. At all loci, the effects were small. None of the identified SNPs that affected ticagrelor PK were associated with the primary composite outcome (cardiovascular death myocardial infarction, and stroke), non-CABG-related bleeds or investigator-reported dyspnoea. Conclusion In patients with ACS, ticagrelor pharmacokinetics is influenced by three genetic loci (SLCO1B1, UGT2B7, and CYP3A4). However, the modest genetic effects on ticagrelor plasma levels did not translate into any detectable effect on efficacy or safety during ticagrelor treatment.

  • 30.
    Wadelius, Mia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Chen, Leslie Y.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Bumpstead, Suzannah
    Ghori, Jilur
    Wadelius, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Bentley, David
    McGinnis, Ralph
    Deloukas, Panos
    Association of warfarin dose with genes involved in its action and metabolism2007In: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 121, no 1, p. 23-34Article in journal (Refereed)
    Abstract [en]

    We report an extensive study of variability in genes encoding proteins that are believed to be involved in the action and biotransformation of warfarin. Warfarin is a commonly prescribed anticoagulant that is difficult to use because of the wide interindividual variation in dose requirements, the narrow therapeutic range and the risk of serious bleeding. We genotyped 201 patients for polymorphisms in 29 genes in the warfarin interactive pathways and tested them for association with dose requirement. In our study, polymorphisms in or flanking the genes VKORC1, CYP2C9, CYP2C18, CYP2C19, PROC, APOE, EPHX1, CALU, GGCX and ORM1-ORM2 and haplotypes of VKORC1, CYP2C9, CYP2C8, CYP2C19, PROC, F7, GGCX, PROZ, F9, NR1I2 and ORM1-ORM2 were associated with dose (P < 0.05). VKORC1, CYP2C9, CYP2C18 and CYP2C19 were significant after experiment-wise correction for multiple testing (P < 0.000175), however, the association of CYP2C18 and CYP2C19 was fully explained by linkage disequilibrium with CYP2C9*2 and/or *3. PROC and APOE were both significantly associated with dose after correction within each gene. A multiple regression model with VKORC1, CYP2C9, PROC and the non-genetic predictors age, bodyweight, drug interactions and indication for treatment jointly accounted for 62% of variance in warfarin dose. Weaker associations observed for other genes could explain up to approximately 10% additional dose variance, but require testing and validation in an independent and larger data set. Translation of this knowledge into clinical guidelines for warfarin prescription will be likely to have a major impact on the safety and efficacy of warfarin.

  • 31.
    Wadelius, Mia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Chen, L.Y.
    Downes, K.
    Ghori, J.
    Hunt, S.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Wallerman, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wadelius, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Bentley, D.
    Deloukas, P.
    Common VKORC1 and GGCX polymorphisms associated with warfarin dose2005In: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 5, no 4, p. 262-70Article in journal (Refereed)
    Abstract [en]

    We report a novel combination of factors that explains almost 60% of variable response to warfarin. Warfarin is a widely used anticoagulant, which acts through interference with vitamin K epoxide reductase that is encoded by VKORC1. In the next step of the vitamin K cycle, gamma-glutamyl carboxylase encoded by GGCX uses reduced vitamin K to activate clotting factors. We genotyped 201 warfarin-treated patients for common polymorphisms in VKORC1 and GGCX. All the five VKORC1 single-nucleotide polymorphisms covary significantly with warfarin dose, and explain 29-30% of variance in dose. Thus, VKORC1 has a larger impact than cytochrome P450 2C9, which explains 12% of variance in dose. In addition, one GGCX SNP showed a small but significant effect on warfarin dose. Incorrect dosage, especially during the initial phase of treatment, carries a high risk of either severe bleeding or failure to prevent thromboembolism. Genotype-based dose predictions may in future enable personalised drug treatment from the start of warfarin therapy.The Pharmacogenomics Journal advance online publication, 10 May 2005; doi:10.1038/sj.tpj.6500313.

  • 32.
    Wadelius, Mia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Waran doseras bättre efter genanalys2014In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 111, no 1-2, p. 22-22Article in journal (Refereed)
  • 33.
    Wadelius, Mia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kreutz, Reinhold
    Universitätsmedizin Berlin, Institut für Klinische Pharmakologie und Toxikologie, Berlin, Germany.
    Bondon-Guitton, Emmanuelle
    Service de Pharmacologie Médicale et Clinique, Centre Hospitalier Universitaire, Faculté de Médecine de l'Université de Toulouse, Toulouse, France.
    Ibañez, Luisa
    Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Fundació Institut Català de Farmacologia, Barcelona, Spain.
    Carvajal, Alfonso
    Centro de Estudios sobre la Seguridad de los Medicamentos, Universidad de Valladolid, Valladolid, Spain.
    Lucena, M Isabel
    S Farmacologia Clinica, Instituto de Investigación Biomedica de Málaga (IBIMA), H Universitario Virgen de la Victoria, Universidad de Málaga, CIBERehd, Madrid, Spain.
    Sancho Ponce, Esther
    Servei d'Hematologia i Banc de Sang, Hospital General de Catalunya, Sant Cugat del Vallès, Spain.
    Molokhia, Mariam
    NIHR Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London Department of Primary Care and Public Health Sciences, London, U.
    Martin, Javier
    Instituto de Parasitologia y Biomedicina Lopez-Neyra, CSIC, Granada, Spain.
    Axelsson, Tomas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Kohnke, Hugo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Yue, Qun-Ying
    Medical Products Agency, Uppsala, Sweden.
    Magnusson, Patrik K E
    Swedish Twin Registry, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Bengtsson, Mats
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sulfasalazine-Induced Agranulocytosis Is Associated With the Human Leukocyte Antigen Locus.2018In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 103, no 5, p. 843-853Article in journal (Refereed)
    Abstract [en]

    Agranulocytosis is a serious, although rare, adverse reaction to sulfasalazine, which is used to treat inflammatory joint and bowel disease. We performed a genome‐wide association study comprising 9,380,034 polymorphisms and 180 HLA alleles in 36 cases of sulfasalazine‐induced agranulocytosis and 5,170 population controls. Sulfasalazine‐induced agranulocytosis was significantly associated with the HLA region on chromosome 6. The top hit (rs9266634) was located close to HLA‐B, odds ratio (OR) 5.36 (95% confidence interval (CI) (2.97, 9.69) P = 2.55 × 10−8). We HLA‐sequenced a second cohort consisting of 40 cases and 142 treated controls, and confirmed significant associations with HLA‐B*08:01, OR = 2.25 (95% CI (1.02, 4.97) P = 0.0439), in particular the HLA‐B*08:01 haplotype HLA‐DQB1*02:01‐DRB1*03:01‐B*08:01‐C*07:01, OR = 3.79 (95% CI (1.63, 8.80) P = 0.0019), and with HLA‐A*31:01, OR = 4.81 (95% CI (1.52, 15.26) P = 0.0077). The number needed to test for HLA‐B*08:01 and HLA‐A*31:01 to avoid one case was estimated to be 1,500. We suggest that intensified monitoring or alternative treatment should be considered for known carriers of HLA‐B*08:01 or HLA‐A*31:01.

  • 34.
    Wadelius, Mia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Smedje, H.
    Karolinska Inst, Div Child & Adolescent Psychiat, Stockholm, Sweden.
    Yue, Q. -Y
    Med Prod Agcy, Uppsala, Sweden.
    Magnusson, P. K. E.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Genome‐Wide Association Study of Pandemrix‐Induced Narcolepsy in Sweden – A Possible Role for Glial Derived Neurotrophic Factor (GDNF)2018In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 123, no S1, p. 12-13Article in journal (Other academic)
  • 35. Wieloch, Mattias
    et al.
    Jonsson, Karl M.
    Sjalander, Anders
    Lip, Gregory Y. H.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Svensson, Peter J.
    Estimated glomerular filtration rate is associated with major bleeding complications but not thromboembolic events, in anticoagulated patients taking warfarin2013In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 131, no 6, p. 481-486Article in journal (Refereed)
    Abstract [en]

    Background: Decreased glomerular filtration rate is an established risk factor for bleeding but there are limited data on its association with bleeding risk in well-controlled anticoagulated patients taking warfarin. Objectives: The aim was to investigate the relationship between glomerular filtration rate, major bleeding and thromboembolic complications in patients with tight anticoagulation control. Patients/Methods: A cohort study of patients from a Swedish quality register for anticoagulation, including all the registered patients that received anticoagulation during 2008 in the anticoagulation center of Skane University Hospital, Malmo. Key outcome measures were major bleeding and arterial or venous thrombosis during 2008. A total of 3536 patients (2875 treatment years) were included. Results: Total rates of 2.6 (2.0-3.2) bleeding events and 1.8 (1.3-2.3) thrombotic events per 100 treatment years were recorded (75 bleeding and 51 thromboembolic events). Data on estimated glomerular filtration rate were available in 3349 patients. Mean time in therapeutic range (international normalized ratio 2.0-3.0) was 74.5% (n=2894). Major bleeding events were significantly related to age and percentage of time with international normalized ratio >3.0 (P<0.001). Glomerular filtration rate levels <30 ml/min/1.73 m(2) were particularly associated with high risk of bleeding, especially in elderly patients. No correlation between glomerular filtration rate and thromboembolic events was seen. Conclusions: With good anticoagulation control as measured by time in therapeutic range, patients had a relatively low risk for major bleeding if their renal function is normal. Despite good anticoagulation control, severely impaired kidney function is associated with a very high yearly risk of major bleeding events.

  • 36.
    Zewinger, Stephen
    et al.
    Saarland Univ Hosp, Dept Internal Med 4, Homburg, Germany..
    Kleber, Marcus E.
    Friedrich Schiller Univ, Inst Nutr, Jena, Germany..
    Tragante, Vinicius
    McCubrey, Raymond O.
    Univ Utah Sch Med, Intermountain Heart Inst, Intermountain Med Ctr, Salt Lake City, UT USA..
    Schmidt, Amand F.
    Direk, Kenan
    Laufs, Ulrich
    Saarland Univ Hosp, Dept Internal Med 3, Homburg, Germany..
    Werner, Christian
    Saarland Univ Hosp, Dept Internal Med 3, Homburg, Germany..
    Koenig, Wolfgang
    Univ Ulm Med Ctr, Dept Internal Med Cardiol 2, Ulm, Germany.;Tech Univ Munich, Deutsch Herzzentrum M nchen, Munich, Germany.;Partner site Munich Heart Alliance, German Ctr Cardiovasc Res DZHK, Munich, Germany..
    Rothenbacher, Dietrich
    German Canc Ctr DKFZ, Div Clin Epidemiol & Ageing Res, Heidelberg, Germany.;Univ Ulm, Inst Epidemiol & Med Biometry, Ulm, Germany.;German Ctr Cardiovasc Res DZHK eV, Kiel, Germany..
    Mons, Ute
    German Canc Ctr DKFZ, Div Clin Epidemiol & Ageing Res, Heidelberg, Germany..
    Breitling, Lutz P.
    German Canc Ctr DKFZ, Div Clin Epidemiol & Ageing Res, Heidelberg, Germany.;Univ Heart Ctr Hamburg, Clin Gen & Intervent Cardiol, Hamburg, Germany..
    Brenner, Herrmann
    Heidelberg Univ, Dept Med, Network Ageing Res, Mannheim, Germany.;German Canc Ctr DKFZ, Div Clin Epidemiol & Ageing Res, Heidelberg, Germany..
    Jennings, Richard T.
    Saarland Univ Hosp, Dept Internal Med 4, Homburg, Germany.;Univ Heart Ctr Hamburg, Clin Gen & Intervent Cardiol, Hamburg, Germany..
    Petrakis, Ioannis
    Saarland Univ Hosp, Dept Internal Med 4, Homburg, Germany..
    Triem, Sarah
    Saarland Univ Hosp, Dept Internal Med 4, Homburg, Germany..
    Klug, Mira
    Saarland Univ Hosp, Dept Internal Med 4, Homburg, Germany..
    Filips, Alexandra
    Saarland Univ Hosp, Dept Internal Med 4, Homburg, Germany.;UCL, Inst Cardiovasc Sci Facultyof Populat Hlth Sc, London, England..
    Blankenberg, Stefan
    Waldeyer, Christoph
    Sinning, Christoph
    Schnabel, Renate B.
    Lackner, Karl J.
    Univ Med Ctr Mainz, Inst Clin Chem & Lab Med, Mainz, Germany..
    Vlachopoulou, Efthymia
    Univ Helsinki, Haartman Inst, Transplantat Lab, Helsinki, Finland..
    Nygard, Ottar
    Univ Bergen, Dept Clin Sci, Bergen, Norway.;Haukeland Hosp, Dept Heart Dis, Bergen, Norway..
    Svingen, Gard Frodahl Tveitevag
    Univ Bergen, Dept Clin Sci, Bergen, Norway.;Haukeland Hosp, Dept Heart Dis, Bergen, Norway..
    Pedersen, Eva Ringdal
    Univ Bergen, Dept Clin Sci, Bergen, Norway.;Haukeland Hosp, Dept Heart Dis, Bergen, Norway..
    Tell, Grethe S.
    Univ Bergen, Dept Global Publ Hlth & Primary Care, Bergen, Norway.;Helsinki Univ Hosp, Heart & Lung Ctr, Helsinki, Finland..
    Sinisalo, Juha
    Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria..
    Nieminen, Markku S.
    Natl Univ Singapore, Cardiovasc Res Inst, Singapore, Singapore..
    Laaksonen, Reijo
    Tampere Univ, Sch Med, Tampere, Finland.;Tampere Univ Hosp, Finnish Clin Biobank Tampere, Tampere, Finland..
    Trompet, Stella
    German Ctr Cardiovasc Res DZHK eV, Kiel, Germany.;Leiden Univ Med Ctr, Dept Geriat & Gerontol, Leiden, Netherlands.;Leiden Univ Med Ctr, Dept Cardiol, Leiden, Netherlands.;Leiden Univ Med Ctr, Einthoven Lab Expt Vasc Med, Leiden, Netherlands..
    Smit, Roelof A. J.
    Univ Utah Sch Med, Intermountain Heart Inst, Intermountain Med Ctr, Salt Lake City, UT USA.;Leiden Univ Med Ctr, Dept Geriat & Gerontol, Leiden, Netherlands.;Leiden Univ Med Ctr, Dept Cardiol, Leiden, Netherlands..
    Sattar, Naveed
    Heidelberg Univ, Dept Med, Mannheim, Germany.;Helsinki Univ Hosp, Heart & Lung Ctr, Helsinki, Finland..
    Jukema, J. Wouter
    Helsinki Univ Hosp, Heart & Lung Ctr, Helsinki, Finland.;Leiden Univ Med Ctr, Einthoven Lab Expt Vasc Med, Leiden, Netherlands.;Leiden Univ Med Ctr, Einthoven Lab Expt Vasc Med, Leiden, Netherlands.;Inst Netherlands, Interunivers Cardiol, Utrecht, Netherlands..
    Groesdonk, Heinrich V.
    Saarland Univ Hosp, Dept Anesthesiol Intens Care Med & Pain Med, Homburg, Germany.;German Ctr Cardiovasc Res DZHK eV, Kiel, Germany.;Leiden Univ Med Ctr, Einthoven Lab Expt Vasc Med, Leiden, Netherlands.;Leiden Univ Med Ctr, Einthoven Lab Expt Vasc Med, Leiden, Netherlands.;Univ Otago, Christchurch Heart Inst, Christchurch, New Zealand..
    Delgado, Graciela
    Univ Utah Sch Med, Intermountain Heart Inst, Intermountain Med Ctr, Salt Lake City, UT USA.;Univ Glasgow, Inst Cardiovascular & Med Sci, Cardiovascular Res Ctr, BHF Glasgow, Glasgow, Lanark, Scotland.;Inst Netherlands, Interunivers Cardiol, Utrecht, Netherlands..
    Stojakovic, Tatjana
    Heidelberg Univ, Dept Med, Mannheim, Germany.;Leiden Univ Med Ctr, Einthoven Lab Expt Vasc Med, Leiden, Netherlands.;Univ Glasgow, Inst Cardiovascular & Med Sci, Cardiovascular Res Ctr, BHF Glasgow, Glasgow, Lanark, Scotland..
    Pilbrow, Anna P.
    Leiden Univ Med Ctr, Einthoven Lab Expt Vasc Med, Leiden, Netherlands..
    Cameron, Vicky A.
    Heart & Lungs Div, Dept Cardiol, Utrecht, Netherlands.;Helsinki Univ Hosp, Heart & Lung Ctr, Helsinki, Finland.;Univ Glasgow, Inst Cardiovascular & Med Sci, Cardiovascular Res Ctr, BHF Glasgow, Glasgow, Lanark, Scotland.;Univ Otago, Christchurch Heart Inst, Christchurch, New Zealand..
    Richards, A. Mark
    Univ Otago, Christchurch Heart Inst, Christchurch, New Zealand.;Natl Univ Singapore, Cardiovasc Res Inst, Singapore, Singapore..
    Doughty, Robert N.
    Univ Glasgow, Inst Cardiovascular & Med Sci, Cardiovascular Res Ctr, BHF Glasgow, Glasgow, Lanark, Scotland.;Univ Auckland, Hlth Res Grp, Auckland, New Zealand..
    Gong, Yan
    Heart & Lungs Div, Dept Cardiol, Utrecht, Netherlands.;Univ Utah Sch Med, Intermountain Heart Inst, Intermountain Med Ctr, Salt Lake City, UT USA.;Univ Glasgow, Inst Cardiovascular & Med Sci, Cardiovascular Res Ctr, BHF Glasgow, Glasgow, Lanark, Scotland..
    Cooper-DeHoff, Rhonda
    Johnson, Julie
    German Ctr Cardiovasc Res DZHK eV, Kiel, Germany.;Univ Otago, Christchurch Heart Inst, Christchurch, New Zealand..
    Scholz, Markus
    Univ Utah Sch Med, Intermountain Heart Inst, Intermountain Med Ctr, Salt Lake City, UT USA.;Natl Univ Singapore, Cardiovasc Res Inst, Singapore, Singapore.;Univ Leipzig, D-RES CTR C Leipzig, Germany..
    Beutner, Frank
    Univ Leipzig, Leipzig, Germany..
    Thiery, Joachim
    Univ Hosp, Leipzig, Germany..
    Smith, J. Gustav
    Lund Univ, Dept Cardiol, Clin Sci, Lund, Sweden.;Skane Univ Hoswpital, Lund, Sweden..
    Vilmundarson, Ragnar O.
    Univ Ottawa Heart Inst, Ruddy Canadian Cardiovasc Genet Ctr, Ottawa, ON, Canada..
    McPherson, Ruth
    Univ Ottawa Heart Inst, Ruddy Canadian Cardiovasc Genet Ctr, Ottawa, ON, Canada..
    Stewart, Alexandre F. R.
    Natl Univ Singapore, Cardiovasc Res Inst, Singapore, Singapore.;Univ Florida, Dept Pharmacotherapy, Colleges Pharm, Gainesville, FL USA.;Univ Florida, Dept Pharmacotherapy, Translat Res & Ctr Pharmac, Gainesville, FL USA.;Univ Ottawa Heart Inst, Ruddy Canadian Cardiovasc Genet Ctr, Ottawa, ON, Canada.;Washington Univ, Sch Med, St Louis, MO USA..
    Cresci, Sharon
    Univ Ottawa Heart Inst, Ruddy Canadian Cardiovasc Genet Ctr, Ottawa, ON, Canada.;Washington Univ, Sch Med, Dept Med, St Louis, MO USA.;Washington Univ, Sch Med, Dept Genet, St Louis, MO USA..
    Lenzini, Petra A.
    Inst Med Informat, Stat & Epidemiol, Leipzig, Germany.;Univ Ottawa Heart Inst, Ruddy Canadian Cardiovasc Genet Ctr, Ottawa, ON, Canada.;Washington Univ, Sch Med, Stat Genom Div, Dept Genet, St Louis, MO USA..
    Spertus, John A.
    Inst Med Informat, Stat & Epidemiol, Leipzig, Germany.;St Lukes Mid Amer Heart Inst, Kansas City, MO USA.;Univ Missouri, Dept Biomed Hlth Informat, Kansas City, MO USA..
    Olivieri, Oliviero
    Heart & Lungs Div, Dept Cardiol, Utrecht, Netherlands.;Univ Verona, Dept Med, Verona, Italy..
    Girelli, Domenico
    Univ Florida, Dept Pharmacotherapy, Colleges Pharm, Gainesville, FL USA.;Univ Florida, Dept Pharmacotherapy, Translat Res & Ctr Pharmac, Gainesville, FL USA.;Univ Verona, Dept Med, Verona, Italy..
    Martinelli, Nicola I.
    Univ Verona, Dept Med, Verona, Italy..
    Leiherer, Andreas
    Univ Florida, Dept Pharmacotherapy, Colleges Pharm, Gainesville, FL USA.;Univ Florida, Dept Pharmacotherapy, Translat Res & Ctr Pharmac, Gainesville, FL USA.;Inst Med Informat, Stat & Epidemiol, Leipzig, Germany.;Vorarlberg Inst Vasc Invest & Treatment, Feldkirch, Austria.;Principal Liechtenstein, Private Univ, Triesen, Liechtenstein..
    Saely, Christoph H.
    Vorarlberg Inst Vasc Invest & Treatment, Feldkirch, Austria.;Principal Liechtenstein, Private Univ, Triesen, Liechtenstein..
    Drexel, Heinz
    Heart & Lungs Div, Dept Cardiol, Utrecht, Netherlands.;Univ Florida, Dept Pharmacotherapy, Colleges Pharm, Gainesville, FL USA.;Univ Florida, Dept Pharmacotherapy, Translat Res & Ctr Pharmac, Gainesville, FL USA.;Vorarlberg Inst Vasc Invest & Treatment, Feldkirch, Austria.;Principal Liechtenstein, Private Univ, Triesen, Liechtenstein.;Acad Teaching Hosp Feldkirch, Dept Med & Cardiol, Feldkirch, Austria.;Drexel Univ, Coll Med, Philadelphia, PA USA..
    Muendlein, Axel
    Vorarlberg Inst Vasc Invest & Treatment, Feldkirch, Austria..
    Braund, Peter S.
    Univ Florida, Dept Pharmacotherapy, Colleges Pharm, Gainesville, FL USA.;Univ Florida, Dept Pharmacotherapy, Translat Res & Ctr Pharmac, Gainesville, FL USA.;Univ Leicester, Glenfield Hosp, Dept Cardiovascular Sci, BHF Cardiovascular Res Ctr, Leicester, Leics, England..
    Nelson, Christopher P.
    Univ Leicester, Glenfield Hosp, Dept Cardiovascular Sci, BHF Cardiovascular Res Ctr, Leicester, Leics, England..
    Samani, Nilesh J.
    Heart & Lungs Div, Dept Cardiol, Utrecht, Netherlands.;Leicester NIHR Biomed Res Unit Cardiovasc Dis, Glenfield Hosp, Leicester, Leics, England.;Uppsala Univ, Uppsala Clin Res Ctr, Uppsala, Sweden.;Uppsala Univ, Dept Med Sci, Cardiol, Uppsala, Sweden..
    Kofink, Daniel
    Hoefer, Imo E.
    Pasterkamp, Gerard
    Quyyumi, Arshed A.
    Emory Univ, Emory Clin Cardiovascular Res Inst, Atlanta, GA USA.;Uppsala Univ, Uppsala Clin Res Ctr, Uppsala, Sweden.;Uppsala Univ, Dept Med Sci, Clin Chem, Uppsala, Sweden..
    Ko, Yi-An
    Hartiala, Jaana A.
    Univ Southern Calif, Los Angeles, CA USA.;Uppsala Univ, Dept Med Sci, Cardiol, Uppsala, Sweden..
    Allayee, Hooman
    Tang, W. H. Wilson
    Hazen, Stanley L.
    Heidelberg Univ, Dept Med, Mannheim, Germany..
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Held, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Hagström, Emil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Åkerblom, Axel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Siegbahn, A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Karp, Igor
    Univ Western Ontario, Schulich Sch Med & Dent, Dept Epidemiol & Biostat, London, England..
    Labos, Christopher
    Uppsala Univ, Dept Med Sci, Cardiol, Uppsala, Sweden.;McGill Univ, Dept Med, Montreal, PQ, Canada..
    Pilote, Louise
    McGill Univ, Dept Med, Montreal, PQ, Canada..
    Engert, James C.
    McGill Univ, Dept Med, Montreal, PQ, Canada..
    Brophy, James M.
    McGill Univ, Dept Med, Montreal, PQ, Canada.;Univ Laval, Dept Med, Laval, PQ, Canada..
    Thanassoulis, George
    McGill Univ, Dept Med, Montreal, PQ, Canada..
    Bogaty, Peter
    McGill Univ, Dept Med, Montreal, PQ, Canada..
    Szczeklik, Wojciech
    Uppsala Univ, Dept Med Sci, Cardiol, Uppsala, Sweden.;Jagielonian Univ, Coll Med, Krakow, Poland..
    Kaczor, Marcin
    Jagielonian Univ, Coll Med, Krakow, Poland..
    Sanak, Marek
    Jagielonian Univ, Coll Med, Krakow, Poland..
    Virani, Salim S.
    Baylor Coll Med, Cardiol Sect, Michael DeBakey Vet Affairs Med Ctr, Houston, TX USA..
    Ballantyne, Christie M.
    Baylor Coll Med, Sect Cardiovasc, Dept Med, Houston, TX USA..
    Lee, Vei-Vei
    Texas Heart Inst, Dept Biostat 7, Houston, TX USA..
    Boerwinkle, Eric
    Uppsala Univ, Dept Med Sci, Cardiol, Uppsala, Sweden.;Univ Texas Houston, Sch Publ Hlth, Houston, TX USA..
    Holmes, Michael V.
    Univ Oxford, Med Res Council Populat Hlth Res Unit, Oxford, England.;Univ Oxford, Natl Inst Hlth Res Oxford Biomed Res Ctr, Oxford, England..
    Horne, Benjamin D.
    Univ Oxford, Clin Trial Serv Unit, Oxford, England.;Univ Oxford, Epidemiol Studies Unit CTSU, Nuffield Dept Populat Hlth, Oxford, England..
    Hingorani, Aroon
    Asselbergs, Folkert W.
    Durrer Ctr Cardiogenet Res, ICIN, Utrecht, Netherlands..
    Patel, Riyaz S.
    Kraemer, Bernhard K.
    Scharnagl, Hubert
    Fliser, Danilo
    Maerz, Winfried
    Saarland Univ Hosp, Dept Internal Med 4, Homburg, Germany.;Synlab Acad, Synlab Holding, Mannheim, Germany..
    Speer, Thimoteus
    Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study2017In: The Lancet Diabetes and Endocrinology, ISSN 2213-8587, E-ISSN 2213-8595, Vol. 5, no 7, p. 534-543Article in journal (Refereed)
    Abstract [en]

    Background: Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear.

    Methods: We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts.

    Findings: The median follow-up was 9.9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1.44, 95% CI 1.14-1.83) and the presence of either LPA SNP (1.88, 1.40-2.53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0.95, 0.81-1.11 and either LPA SNP 1.10, 0.92-1.31) or cardiovascular mortality (0.99, 0.81-1.2 and 1.13, 0.90-1.40, respectively) or in the validation studies.

    Interpretation: In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established.

  • 37.
    Åkerblom, Axel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Becker, Richard C.
    Duke Clinical Research Institute, Durham, NC, USA.
    Budaj, Andrzej
    Postgraduate Medical School, Grochowski Hospital, Warsaw, Poland.
    Himmelmann, Anders
    AstraZeneca Research and Development, Mölndal, Sweden.
    Husted, Steen
    Department of Cardiology, Århus University Hospital, Århus, Denmark.
    Storey, Robert F.
    Department of Cardiovascular Science, University of Sheffield, Sheffield, UK.
    Johansson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    James, Stefan K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Polymorphism of the cystatin C gene in patients with acute coronary syndromes: Results from the PLATelet Inhibition and Patient Outcomes (PLATO) Study2014In: American Heart Journal, ISSN 0002-8703, E-ISSN 1097-6744, Vol. 168, no 1, p. 96-102Article in journal (Other academic)
    Abstract [en]

    Purpose: Plasma cystatin C is independently associated with cardiovascular (CV) risk in non-ST-elevation acute coronary syndromes (NSTE-ACS). The effect of genetic variability on cystatin C concentrations and outcome is unclear.

    Methods: Plasma cystatin C concentrations were measured in blood, obtained within 24 hours of admission, in 16279 ACS patients from the PLATelet inhibition and patient Outcomes trial. 9978 patients were genome-wide genotyped with up to 2.5 million SNPs. The first occurrence of CV death or myocardial infarction (MI) within one year was evaluated by multivariable (clinical variables and biomarkers) Cox regression analysis and c-statistics both overall (all ACS) and in NSTE-ACS.

    Results: We observed SNPs association with cystatin C levels (up to p=7.82 x 10-16). The most significant SNP (rs6048952) was adjacent the CST3 gene with additive effect on cystatin C concentrations: 0.85mg/L, 0.80mg/L and 0.73mg/L for the A/A, A/G and G/G genotypes respectively. Multivariable c-statistics regarding the combined endpoint (CV death or MI) was 0.6619. Adding cystatin C concentrations or genetically adjusted cystatin C levels, exhibited c-statistics of 0.6705 and 0.6703, respectively.

    The overall hazard ratio for rs6048952 was 0.93 (95%CI 0.82-1.04) regarding the CV death or MI while 0.85 (95%CI 0.70-1.03) regarding CV death in all ACS patients. In the NSTE-ACS subgroup, the hazard ratio for rs6048952 was 0.72 (95%CI 0.54-0.95).

    Conclusions: Genetic polymorphism, independently of kidney function, affects cystatin C concentrations, but does not appear to influence ischemic outcome in an overall ACS population. However, genetic variation appears to affect cardiovascular mortality in moderate-to-high risk NSTE-ACS patients.

  • 38.
    Åkerblom, Axel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Becker, Richard C.
    Budaj, Andrzej
    Himmelmann, Anders
    Husted, Steen
    Storey, Robert F.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Johansson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    James, Stefan K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Genetic Polymorphism and Relationship to Cystatin C Concentrations and Outcome - Results From the Platelet Inhibition and Patient Outcomes Study2013In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 128, no 22Article in journal (Other academic)
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