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  • 1051. Ueda, Yasutaka
    et al.
    Calado, Rodrigo T.
    Norberg, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Kajigaya, Sachiko
    Roos, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Hellstrom-Lindberg, Eva
    Young, Neal S.
    A mutation in the H/ACA box of telomerase RNA component gene (TERC) in a young patient with myelodysplastic syndrome2014Inngår i: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 15, s. 68-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Telomeres are repeated sequences (the hexanucleotide TTAGGG in vertebrates) located at chromosome ends of eukaryotes, protecting DNA from end joining or degradation. Telomeres become shorter with each cell cycle, but telomerase, a ribonucleoprotein complex, alleviates this attrition. The telomerase RNA component (TERC) is an essential element of telomerase, serving as a template for telomere elongation. The H/ACA domain of TERC is indispensable for telomere biogenesis. Mutations in the telomerase components allow accelerated telomere loss, resulting in various disease manifestations, including bone marrow failure. To date, this is the first detailed report of an H-box mutation in TERC that is related to human disease. Case presentation: A 26-year-old man with myelodysplastic syndrome (MDS) had very short telomeres. Sequencing identified a single heterozygous mutation in the H box of the patient's TERC gene. The same mutation was also present in his father and his son, demonstrating that it was germline in origin. The telomere length in the father's blood was shorter compared to age-matched healthy controls, while it was normal in the son and also in the sperm cells of the patient. In vitro experiments suggested that the mutation was responsible for the telomere shortening in the patient's leukocytes and contributed to the pathogenesis of bone marrow failure in our patient. Conclusion: We analyzed a mutation (A377G) in the H box of TERC in a young MDS patient who had significantly short-for-age telomeres. As telomeres protect chromosomes from instability, it is highly plausible that this genetic lesion was responsible for the patient's hematological manifestations, including marrow failure and aneuploidy in the hematopoietic stem cell compartment.

  • 1052.
    Ugalde-Morales, Emilio
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Li, Jingmei
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Human Genetics, Genome Institute of Singapore, Singapore, Singapore.
    Humphreys, Keith
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Ludvigsson, Jonas F.
    Örebro universitet, Institutionen för medicinska vetenskaper. Region Örebro län. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Pediatrics, Örebro University Hospital, Örebro, Sweden.
    Yang, Haomin
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Hall, Per
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Czene, Kamila
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Common shared genetic variation behind decreased risk of breast cancer in celiac disease2017Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, artikkel-id 5942Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    There is epidemiologic evidence showing that women with celiac disease have reduced risk of later developing breast cancer, however, the etiology of this association is unclear. Here, we assess the extent of genetic overlap between the two diseases. Through analyses of summary statistics on densely genotyped immunogenic regions, we show a significant genetic correlation (r = -0.17, s.e. 0.05, P < 0.001) and overlap (Ppermuted < 0.001) between celiac disease and breast cancer. Using individuallevel genotype data from a Swedish cohort, we find higher genetic susceptibility to celiac disease summarized by polygenic risk scores to be associated with lower breast cancer risk (ORper-SD, 0.94, 95% CI 0.91 to 0.98). Common single nucleotide polymorphisms between the two diseases, with low P-values (P-CD < 1.00E-05, P-BC <= 0.05), mapped onto genes enriched for immunoregulatory and apoptotic processes. Our results suggest that the link between breast cancer and celiac disease is due to a shared polygenic variation of immune related regions, uncovering pathways which might be important for their development.

  • 1053. Uhlén, Mathias
    et al.
    Fagerberg, Linn
    Hallström, Bjoern M.
    Lindskog, Cecilia
    Oksvold, Per
    Mardinoglu, Adil
    Sivertsson, Asa
    Kampf, Caroline
    Sjöstedt, Evelina
    Asplund, Anna
    Olsson, IngMarie
    Edlund, Karolina
    Lundberg, Emma
    Navani, Sanjay
    Szigyarto, Cristina Al-Khalili
    Odeberg, Jacob
    Djureinovic, Dijana
    Ottosson Takanen, Jenny
    Hober, Sophia
    Alm, Tove
    Edqvist, Per-Henrik
    Berling, Holger
    Tegel, Hanna
    Mulder, Jan
    Rockberg, Johan
    Nilsson, Peter
    Schwenk, Jochen M.
    Hamsten, Marica
    von Feilitzen, Kalle
    Forsberg, Mattias
    Persson, Lukas
    Johansson, Fredric
    Zwahlen, Martin
    von Heijne, Gunnar
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Nielsen, Jens
    Pontén, Fredrik
    Tissue-based map of the human proteome2015Inngår i: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 347, nr 6220, artikkel-id 1260419Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Resolving the molecular details of proteome variation in the different tissues and organs of the human body will greatly increase our knowledge of human biology and disease. Here, we present a map of the human tissue proteome based on an integrated omics approach that involves quantitative transcriptomics at the tissue and organ level, combined with tissue microarray-based immunohistochemistry, to achieve spatial localization of proteins down to the single-cell level. Our tissue-based analysis detected more than 90% of the putative protein-coding genes. We used this approach to explore the human secretome, the membrane proteome, the druggable proteome, the cancer proteome, and the metabolic functions in 32 different tissues and organs. All the data are integrated in an interactive Web-based database that allows exploration of individual proteins, as well as navigation of global expression patterns, in all major tissues and organs in the human body.

  • 1054.
    Uhrbom, Lene
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Roles of p16INk a and PDGF-B in glioma1999Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Gliomas are diffuse astrocytic tumors of the central nervous system (CNS) which usually affect adults. This thesis work has focused on molecular mechanisms of altered growth control in glioma, and the significance of two gene products belonging to pathways commonly affected in glioma, p16INK4a and PDGF-B, has been investigated in vitro and in vivo.

    The INK4a locus is one of the most frequently lossed tumor suppressor gene of human gliomas. It encodes a G1 specific cell cycle inhibitor, p16INK4a, which was ectopically expressed in the human malignant glioma cell line U-1242 MG. Forced expression caused a G1 arrest and senescence in the cells, defined by an inability to induce DNA replication at subconfluency in the presence of serum, an enlarged cell morphology and expression of a senescence marker, senescence-associated β-galactosidase (SA-β-gal).

    Many studies have implicated a role for platelet-derived growth factor (PDGF) in human glioma. We established a mouse brain tumor model by injecting a murine retrovirus containing the PDGP-B cDNA together with wild-type virus, intracranially in neonatal mice. The induced malignant brain tumors displayed features of human gliomas. Tumor cells were nestin positive and expressed PDGP-B and PDGF-Rα mRNA, suggesting an autocrine stimulation of a neuroepithelial progenitor cell as the mechanism of tumor induction. A cell line was established from one PDGF-B induced tumor. Cultured tumor cells expressed PDGF-B causing autophosphorylation of endogenous PDGF receptors. A specific PDGF tyrosine kinase inhibitor caused a striking inhibition of PDGF receptor tyrosine phosphorylation and cell proliferation, showing a dependence of PDGF stimulation in initiation as well as progression of these tumors. Furthermore, the contribution of insertional mutagenesis in tumor development was analysed. Retroviral insertions in genomic DNA from 15 tumors were investigated with inverse polymerase chain reaction (IPCR) and sequencing. Preliminary data indicate the presence of a common integration site in a sequence mapped to a defined region of human chromosome 22, corresponding to mouse chromosome 15.

  • 1055.
    Ulvmar, Maria H
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Martinez-Corral, Ines
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Stanczuk, Lukas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Mäkinen, Taija
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Pdgfrb-Cre targets lymphatic endothelial cells of both venous and non-venous origins2016Inngår i: Genesis, ISSN 1526-954X, E-ISSN 1526-968X, Vol. 54, nr 6, s. 350-358Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The Pdgfrb-Cre line has been used as a tool to specifically target pericytes and vascular smooth muscle cells. Recent studies showed additional targeting of cardiac and mesenteric lymphatic endothelial cells (LECs) by the Pdgfrb-Cre transgene. In the heart, this was suggested to provide evidence for a previously unknown non-venous source of LECs originating from yolk sac (YS) hemogenic endothelium (HemEC). Here we show that Pdgfrb-Cre does not, however, target YS HemEC or YS-derived erythro-myeloid progenitors (EMPs). Instead, a high proportion of ECs in embryonic blood vessels of multiple organs, as well as venous derived LECs were targeted. Assessment of temporal Cre activity using the R26-mTmG double reporter suggested recent occurrence of Pdgfrb-Cre recombination in both blood and lymphatic ECs. It thus cannot be excluded that Pdgfrb-Cre mediated targeting of LECs is due to de novo expression of the Pdgfrb-Cre transgene or their previously established venous endothelial origin. Importantly, Pdgfrb-Cre targeting of LECs does not provide evidence for YS HemEC origin of the lymphatic vasculature. Our results highlight the need for careful interpretation of lineage tracing using constitutive Cre lines that cannot discriminate active from historical expression. The early vascular targeting by the Pdgfrb-Cre also warrants consideration for its use in studies of mural cells.

  • 1056.
    Umer, Husen M.
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräkningsbiologi och bioinformatik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Komorowski, Jan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräkningsbiologi och bioinformatik. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Institute of Computer Science, Polish Academy of Sciences, Warsaw, Poland.
    Wadelius, Claes
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    the PCAWG Drivers and Functional Interpretation Group, the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Network
    Functional annotation of noncoding mutations identifies candidate regulatory aberrations in cancerManuskript (preprint) (Annet vitenskapelig)
  • 1057.
    Uusimaa, Johanna
    et al.
    Department of Paediatrics, University of Oulu, Oulu; Clinical Research Center, Oulu University Hospital, Oulu.
    Moilanen, Jukka S
    Department of Clinical Genetics, University of Oulu, Oulu; Institute of Medical Technology, University of Tampere, Tampere.
    Vainionpää, Leena
    Department of Paediatrics, University of Oulu, Oulu.
    Tapanainen, Päivi
    Department of Paediatrics, University of Oulu, Oulu.
    Lindholm, Päivi
    Department of Otorhinolaryngology, University of Oulu, Oulu; Department of Child Psychiatry, University of Oulu, Oulu.
    Nuutinen, Matti
    Department of Paediatrics, University of Oulu, Oulu.
    Löppönen, Tuija
    Department of Clinical Genetics, University of Oulu, Oulu; Department of Paediatrics, University of Kuopio, Kuopio, Finland.
    Mäki-Torkko, Elina
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Otorhinolaryngology, University of Oulu, Oulu; Department of Otorhinolaryngology, Linköping University Hospital, Linköping, Sweden.
    Rantala, Heikki
    Department of Paediatrics, University of Oulu, Oulu.
    Majamaa, Kari
    Clinical Research Center, Oulu University Hospital, Oulu; Department of Neurology, University of Oulu, Oulu; Department of Neurology, University of Turku, Turku, Finland.
    Prevalence, segregation, and phenotype of the mitochondrial DNA 3243A>G mutation in children2007Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 62, nr 3, s. 278-287Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: We studied the prevalence, segregation, and phenotype of the mitochondrial DNA 3243A>G mutation in children in a defined population in Northern Ostrobothnia, Finland.

    METHODS: Children with diagnoses commonly associated with mitochondrial diseases were ascertained. Blood DNA from 522 selected children was analyzed for 3243A>G. Children with the mutation were clinically examined. Information on health history before the age of 18 years was collected from previously identified adult patients with 3243A>G. Mutation segregation analysis in buccal epithelial cells was performed in mothers with 3243A>G and their children whose samples were analyzed anonymously.

    RESULTS: Eighteen children were found to harbor 3243A>G in a population of 97,609. A minimum estimate for the prevalence of 3243A>G was 18.4 in 100,000 (95% confidence interval, 10.9-29.1/100,000). Information on health in childhood was obtained from 37 adult patients with 3243A>G. The first clinical manifestations appearing in childhood were sensorineural hearing impairment, short stature or delayed maturation, migraine, learning difficulties, and exercise intolerance. Mutation analysis from 13 mothers with 3243A>G and their 41 children gave a segregation rate of 0.80. The mothers with heteroplasmy greater than 50% tended to have offspring with lower or equal heteroplasmy, whereas the opposite was true for mothers with heteroplasmy less than or equal to 50% (p = 0.0016).

    INTERPRETATION: The prevalence of 3243A>G is relatively high in the pediatric population, but the morbidity in children is relatively low. The random genetic drift model may be inappropriate for the transmission of the 3243A>G mutation.

  • 1058. Valencia, Liliana
    et al.
    Randazzo, Andres
    Engfeldt, Peter
    Olsson, Lovisa A.
    Chavez, Adolfo
    Buckland, Robert J.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Nilsson, Torbjörn K.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Almon, Ricardo
    Identification of novel genetic variants in the mutational hotspot region 14kb upstream of the LCT gene in a Mexican population2017Inngår i: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 77, nr 5, s. 311-314Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Several polymorphic loci linked to lactase persistence (LP) have been described, all located in a small mutational hotspot region far upstream (approximate to 14kb) of the lactase (LCT) gene. One is typically found in Europeans, LCT -13910C>T, several others are found in East Africans and Arabs, e.g. LCT -13907C>G and LCT -13915T>G. The possibility of similar loci, specific to populations in South and Central America, has not received much attention so far. To identify possible novel polymorphisms in the mutational hotspot region, we sampled 158 subjects from a rural area in South-Central Mexico. DNA was isolated from serum, and Sanger sequencing of a 501bp region spanning the LCT -13910C>T hotspot was successfully performed in 150 samples. The frequency of the European-type LCT -13910T-allele was q=0.202, and 35% of the population was thus lactase-persistent (CT or TT). Sixteen novel genetic variants were found amongst 11 of the subjects, all were heterozygotes: seven of the subjects were also carriers of at least one LCT -13910T-allele. Thus, the mutational hotspot region is also a hotspot in the rural Mexican population: 11/150 subjects carried a total of 16 previously unknown private mutations but no novel polymorphism was found. The relationship between such novel genetic variants in Mexicans and lactase persistence is worthy of more investigation.

  • 1059.
    Valencia, Liliana
    et al.
    Departamento de Nutrición Aplicada y Educación Nutricional, Instituto Nacional de Ciencias Médicas y Nutrición 'Salvador Zubiran’ , Mexico City, Mexico.
    Randazzo, Andres
    Departamento de Nutrición Aplicada y Educación Nutricional, Instituto Nacional de Ciencias Médicas y Nutrición 'Salvador Zubiran’ , Mexico City, Mexico.
    Engfeldt, Peter
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Olsson, Lovisa A.
    Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Chavez, Adolfo
    Departamento de Nutrición Aplicada y Educación Nutricional, Instituto Nacional de Ciencias Médicas y Nutrición 'Salvador Zubiran’ , Mexico City, Mexico.
    Buckland, Robert J.
    Department of Medical Biosciences/Clinical Chemistry, Faculty of Medicine, Umeå University, Umeå, Sweden.
    Nilsson, Torbjörn K.
    Department of Medical Biosciences/Clinical Chemistry, Faculty of Medicine, Umeå University, Umeå, Sweden.
    Almon, Ricardo
    Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Identification of novel genetic variants in the mutational hotspot region 14kb upstream of the LCT gene in a Mexican population2017Inngår i: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 77, nr 5, s. 311-314Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Several polymorphic loci linked to lactase persistence (LP) have been described, all located in a small mutational hotspot region far upstream (approximate to 14kb) of the lactase (LCT) gene. One is typically found in Europeans, LCT -13910C>T, several others are found in East Africans and Arabs, e.g. LCT -13907C>G and LCT -13915T>G. The possibility of similar loci, specific to populations in South and Central America, has not received much attention so far. To identify possible novel polymorphisms in the mutational hotspot region, we sampled 158 subjects from a rural area in South-Central Mexico. DNA was isolated from serum, and Sanger sequencing of a 501bp region spanning the LCT -13910C>T hotspot was successfully performed in 150 samples. The frequency of the European-type LCT -13910T-allele was q=0.202, and 35% of the population was thus lactase-persistent (CT or TT). Sixteen novel genetic variants were found amongst 11 of the subjects, all were heterozygotes: seven of the subjects were also carriers of at least one LCT -13910T-allele. Thus, the mutational hotspot region is also a hotspot in the rural Mexican population: 11/150 subjects carried a total of 16 previously unknown private mutations but no novel polymorphism was found. The relationship between such novel genetic variants in Mexicans and lactase persistence is worthy of more investigation.

  • 1060. Van de Veire, Sara
    et al.
    Stalmans, Ingeborg
    Heindryckx, Femke
    Oura, Hajimu
    Tijeras-Raballand, Annemilaï
    Schmidt, Thomas
    Loges, Sonja
    Albrecht, Imke
    Jonckx, Bart
    Vinckier, Stefan
    Van Steenkiste, Christophe
    Tugues, Sònia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Rolny, Charlotte
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    De Mol, Maria
    Dettori, Daniela
    Hainaud, Patricia
    Coenegrachts, Lieve
    Contreres, Jean-Olivier
    Van Bergen, Tine
    Cuervo, Henar
    Xiao, Wei-Hong
    Le Henaff, Carole
    Buysschaert, Ian
    Kharabi Masouleh, Behzad
    Geerts, Anja
    Schomber, Tibor
    Bonnin, Philippe
    Lambert, Vincent
    Haustraete, Jurgen
    Zacchigna, Serena
    Rakic, Jean-Marie
    Jiménez, Wladimiro
    Noël, Agnes
    Giacca, Mauro
    Colle, Isabelle
    Foidart, Jean-Michel
    Tobelem, Gerard
    Morales-Ruiz, Manuel
    Vilar, José
    Maxwell, Patrick
    Vinores, Stanley A.
    Carmeliet, Geert
    Dewerchin, Mieke
    Claesson-Welsh, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Dupuy, Evelyne
    Van Vlierberghe, Hans
    Christofori, Gerhard
    Mazzone, Massimiliano
    Detmar, Michael
    Collen, Désiré
    Carmeliet, Peter
    Further pharmacological and genetic evidence for the efficacy of PlGF inhibition in cancer and eye disease2010Inngår i: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 141, nr 1, s. 178-190Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Our findings that PlGF is a cancer target and anti-PlGF is useful for anticancer treatment have been challenged by Bais et al. Here we take advantage of carcinogen-induced and transgenic tumor models as well as ocular neovascularization to report further evidence in support of our original findings of PlGF as a promising target for anticancer therapies. We present evidence for the efficacy of additional anti-PlGF antibodies and their ability to phenocopy genetic deficiency or silencing of PlGF in cancer and ocular disease but also show that not all anti-PlGF antibodies are effective. We also provide additional evidence for the specificity of our anti-PlGF antibody and experiments to suggest that anti-PlGF treatment will not be effective for all tumors and why. Further, we show that PlGF blockage inhibits vessel abnormalization rather than density in certain tumors while enhancing VEGF-targeted inhibition in ocular disease. Our findings warrant further testing of anti-PlGF therapies.

  • 1061. Van Deerlin, Vivian M
    et al.
    Sleiman, Patrick M. A.
    Martinez-Lage, Maria
    Chen-Plotkin, Alice
    Wang, Li-San
    Graff-Radford, Neill R.
    Dickson, Dennis W.
    Rademakers, Rosa
    Boeve, Bradley F.
    Grossman, Murray
    Arnold, Steven E.
    Mann, David M. A.
    Pickering-Brown, Stuart M.
    Seelaar, Harro
    Heutink, Peter
    van Swieten, John C.
    Murrell, Jill R.
    Ghetti, Bernardino
    Spina, Salvatore
    Grafman, Jordan
    Hodges, John
    Spillantini, Maria Grazia
    Gilman, Sid
    Lieberman, Andrew P.
    Kaye, Jeffrey A.
    Woltjer, Randall L.
    Bigio, Eileen H.
    Mesulam, Marsel
    Al-Sarraj, Safa
    Troakes, Claire
    Rosenberg, Roger N.
    White, Charles L.
    Ferrer, Isidro
    Lladó, Albert
    Neumann, Manuela
    Kretzschmar, Hans A.
    Hulette, Christine Marie
    Welsh-Bohmer, Kathleen A.
    Miller, Bruce L.
    Alzualde, Ainhoa
    de Munain, Adolfo Lopez
    McKee, Ann C.
    Gearing, Marla
    Levey, Allan I.
    Lah, James J.
    Hardy, John
    Rohrer, Jonathan D.
    Lashley, Tammaryn
    Mackenzie, Ian R. A.
    Feldman, Howard H.
    Hamilton, Ronald L.
    Dekosky, Steven T.
    van der Zee, Julie
    Kumar-Singh, Samir
    Van Broeckhoven, Christine
    Mayeux, Richard
    Vonsattel, Jean Paul G.
    Troncoso, Juan C.
    Kril, Jillian J.
    Kwok, John B. J.
    Halliday, Glenda M.
    Bird, Thomas D.
    Ince, Paul G.
    Shaw, Pamela J.
    Cairns, Nigel J.
    Morris, John C.
    McLean, Catriona Ann
    DeCarli, Charles
    Ellis, William G.
    Freeman, Stefanie H.
    Frosch, Matthew P.
    Growdon, John H.
    Perl, Daniel P.
    Sano, Mary
    Bennett, David A.
    Schneider, Julie A.
    Beach, Thomas G.
    Reiman, Eric M.
    Woodruff, Bryan K.
    Cummings, Jeffrey
    Vinters, Harry V.
    Miller, Carol A.
    Chui, Helena C.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Hartikainen, Päivi
    Seilhean, Danielle
    Galasko, Douglas
    Masliah, Eliezer
    Cotman, Carl W.
    Tuñón, M. Teresa
    Martínez, M. Cristina Caballero
    Munoz, David G.
    Carroll, Steven L.
    Marson, Daniel
    Riederer, Peter F.
    Bogdanovic, Nenad
    Schellenberg, Gerard D.
    Hakonarson, Hakon
    Trojanowski, John Q.
    Lee, Virginia M-Y.
    Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions2010Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 42, nr 3, s. 234-239Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA-binding protein (TDP-43) inclusions (FTLD-TDP). FTLD-TDP is frequently familial, resulting from mutations in GRN (which encodes progranulin). We assembled an international collaboration to identify susceptibility loci for FTLD-TDP through a genome-wide association study of 515 individuals with FTLD-TDP. We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium block on 7p21 that contains TMEM106B. Three SNPs retained genome-wide significance following Bonferroni correction (top SNP rs1990622, P = 1.08 x 10(-11); odds ratio, minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 x 10(-4)). TMEM106B variants may confer risk of FTLD-TDP by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in individuals with mutations in GRN. Our data implicate variants in TMEM106B as a strong risk factor for FTLD-TDP, suggesting an underlying pathogenic mechanism.

  • 1062. Van Den Bogaert, Ann
    et al.
    Sleegers, Kristel
    De Zutter, Sonia
    Heyrman, Lien
    Norrback, Karl-Fredrik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Adolfsson, Rolf
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Van Broeckhoven, Christine
    Del-Favero, Jurgen
    No allelic association or interaction of three known functional polymorphisms with bipolar disorder in a northern Swedish isolated population2006Inngår i: Psychiatric Genetics, ISSN 0955-8829, E-ISSN 1473-5873, Vol. 16, nr 5, s. 209-212Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Most genetic association studies in bipolar disorder have focussed on genes involved in major neurotransmitter systems or brain development. Functional polymorphisms in the serotonin transporter (5-HTTLPR), catechol-O-methyltransferase (Val158Met) and dopamine D3 receptor (Ser9Gly) genes have all been associated with bipolar disorder. We aimed at investigating whether these functional variants contribute to the genetic etiology of bipolar disorder in a northern Swedish isolated population. Moreover, we wanted to gain information about the synergistic contribution of these functional variants. Neither of these functional polymorphisms was associated with bipolar disorder in the northern Swedish patient-control sample nor did we find evidence of gene-gene interaction. Together, our data suggest that these functional variants are not involved in the etiology of bipolar disorder in the northern Swedish population nor did gene-gene interaction analysis support a central role of these variants in bipolar disorder.

  • 1063.
    Van Den Eede, Filip
    et al.
    Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology ; Collaborative Antwerp Psychiatric Research Institute, University of Antwerp, Antwerp ; Department of Psychiatry, University Hospital Antwerp, Edegem.
    Venken, Tine
    Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology.
    Van Den Bogaert, Ann
    Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology.
    Del-Favero, Jurgen
    Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology.
    Norrback, Karl-Fredrik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Nilsson, Lars Göran
    Department of Psychology, Stockholm University, Stockholm, Sweden.
    Adolfsson, Rolf
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri. Department of Psychology, Stockholm University, Stockholm, Sweden.
    Van Broeckhoven, Christine
    Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology.
    Claes, Stephan J
    Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology ; Department of Psychiatry, University Hospital Gasthuisberg, Leuven, Belgium.
    Single nucleotide polymorphism analysis of corticotropin-releasing factor-binding protein gene in bipolar disorder2007Inngår i: Psychiatric Genetics, ISSN 0955-8829, E-ISSN 1473-5873, Vol. 17, nr 5, s. 304-307Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Corticotropin-releasing factor-binding protein regulates the availability of free corticotropin-releasing factor and is a functional candidate gene for affective disorders. The aim of this study was to examine the association between polymorphisms in CRF-BP gene and bipolar disorder in an isolated Swedish population. One hundred and eighty-two patients with bipolar I disorder and 333 controls from Northern Sweden were included in the study. Five single nucleotide polymorphisms and a deletion polymorphism in the CRF-BP gene were genotyped. The haplotype block structure of the gene was considered and the expectation maximization algorithm was adopted to estimate the haplotype frequencies. As a result, there were no significant associations of the different polymorphisms in the CRF-BP gene with bipolar disorder. In conclusion, this study in an isolated Swedish population does not support a role for the CRF-BP gene in the vulnerability for bipolar disorder.

  • 1064. van der Valk, Ralf J P
    et al.
    Kreiner-Møller, Eskil
    Kooijman, Marjolein N
    Guxens, Mònica
    Stergiakouli, Evangelia
    Sääf, Annika
    Bradfield, Jonathan P
    Geller, Frank
    Hayes, M Geoffrey
    Cousminer, Diana L
    Körner, Antje
    Thiering, Elisabeth
    Curtin, John A
    Myhre, Ronny
    Huikari, Ville
    Joro, Raimo
    Kerkhof, Marjan
    Warrington, Nicole M
    Pitkänen, Niina
    Ntalla, Ioanna
    Horikoshi, Momoko
    Veijola, Riitta
    Freathy, Rachel M
    Teo, Yik-Ying
    Barton, Sheila J
    Evans, David M
    Kemp, John P
    St Pourcain, Beate
    Ring, Susan M
    Davey Smith, George
    Bergström, Anna
    Kull, Inger
    Hakonarson, Hakon
    Mentch, Frank D
    Bisgaard, Hans
    Chawes, Bo
    Stokholm, Jakob
    Waage, Johannes
    Eriksen, Patrick
    Sevelsted, Astrid
    Melbye, Mads
    van Duijn, Cornelia M
    Medina-Gomez, Carolina
    Hofman, Albert
    de Jongste, Johan C
    Taal, H Rob
    Uitterlinden, André G
    Armstrong, Loren L
    Eriksson, Johan
    Palotie, Aarno
    Bustamante, Mariona
    Estivill, Xavier
    Gonzalez, Juan R
    Llop, Sabrina
    Kiess, Wieland
    Mahajan, Anubha
    Flexeder, Claudia
    Tiesler, Carla M T
    Murray, Clare S
    Simpson, Angela
    Magnus, Per
    Sengpiel, Verena
    Hartikainen, Anna-Liisa
    Keinanen-Kiukaanniemi, Sirkka
    Lewin, Alexandra
    Da Silva Couto Alves, Alexessander
    Blakemore, Alexandra I
    Buxton, Jessica L
    Kaakinen, Marika
    Rodriguez, Alina
    Mittuniversitetet, Fakulteten för humanvetenskap, Avdelningen för psykologi.
    Sebert, Sylvain
    Vaarasmaki, Marja
    Lakka, Timo
    Lindi, Virpi
    Gehring, Ulrike
    Postma, Dirkje S
    Ang, Wei
    Newnham, John P
    Lyytikäinen, Leo-Pekka
    Pahkala, Katja
    Raitakari, Olli T
    Panoutsopoulou, Kalliope
    Zeggini, Eleftheria
    Boomsma, Dorret I
    Groen-Blokhuis, Maria
    Ilonen, Jorma
    Franke, Lude
    Hirschhorn, Joel N
    Pers, Tune H
    Liang, Liming
    Huang, Jinyan
    Hocher, Berthold
    Knip, Mikael
    Saw, Seang-Mei
    Holloway, John W
    Melén, Erik
    Grant, Struan F A
    Feenstra, Bjarke
    Lowe, William L
    Widén, Elisabeth
    Sergeyev, Elena
    Grallert, Harald
    Custovic, Adnan
    Jacobsson, Bo
    Jarvelin, Marjo-Riitta
    Atalay, Mustafa
    Koppelman, Gerard H
    Pennell, Craig E
    Niinikoski, Harri
    Dedoussis, George V
    Mccarthy, Mark I
    Frayling, Timothy M
    Sunyer, Jordi
    Timpson, Nicholas J
    Rivadeneira, Fernando
    Bønnelykke, Klaus
    Jaddoe, Vincent W V
    A novel common variant in DCST2 is associated with length in early life and height in adulthood2015Inngår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, nr 4, s. 1155-68, artikkel-id ddu510Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 × 10(-6)) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; β = 0.046, SE = 0.008, P = 2.46 × 10(-8), explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 × 10(-4)) and adult height (N = 127 513; P = 1.45 × 10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.

  • 1065.
    van Dijk-Härd, Iris
    et al.
    Division for Clinical Immunology, Karolinska Institute, Huddinge Hospital, Sweden..
    Söderström, Ingegerd
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Feld, Sari
    ivision for Clinical Immunology, Karolinska Institute, Huddinge Hospital, Sweden..
    Holmberg, Dan
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Lundkvist, Inger
    Division for Clinical Immunology, Karolinska Institute, Huddinge Hospital, Sweden..
    Age-related impaired affinity maturation and differential D-JH gene usage in human VH6-expressing B lymphocytes from healthy individuals1997Inngår i: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 27, nr 6, s. 1381-1386Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To elucidate the basic molecular events underlying humoral immunity during ontogeny and senescence, we analyzed a panel of 179 polymerase chain reaction-derived VH6-D-JH rearrangements from cord blood, peripheral blood, and spleen. Nucleotide sequence analysis of the CDR3 region shows that there is a difference in D and JH gene usage in functional rearrangements between lymphocytes from peripheral blood and spleen. Analysis of the VH6 gene shows that the mutational frequencies rise from 0.81% in cord blood to 1.96% in peripheral blood lymphocytes derived from young adults, and decrease to 0.80% in samples from individuals older than 50 years. The number of rearrangements carrying mutations follows a similar pattern: 22% in cord blood, 73% in the age group 20-49 years, and 57% in the age group over 50 years. The mutational frequencies among the mutated genes are, however, similar for cord blood and young adults, 2.76% and 2.51%, respectively, and 1.3% in older adults. These data show an age-related impaired affinity maturation which might relate to the decrease in immunological responsiveness among the elderly.

  • 1066. van Doormaal, Perry T. C.
    et al.
    Ticozzi, Nicola
    Weishaupt, Jochen H.
    Kenna, Kevin
    Diekstra, Frank P.
    Verde, Federico
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Dekker, Annelot M.
    Tiloca, Cinzia
    Marroquin, Nicolai
    Overste, Daniel J.
    Pensato, Viviana
    Nuernberg, Peter
    Pulit, Sara L.
    Schellevis, Raymond D.
    Calini, Daniela
    Altmueller, Janine
    Francioli, Laurent C.
    Muller, Bernard
    Castellotti, Barbara
    Motameny, Susanne
    Ratti, Antonia
    Wolf, Joachim
    Gellera, Cinzia
    Ludolph, Albert C.
    van den Berg, Leonard H.
    Kubisch, Christian
    Landers, John E.
    Veldink, Jan H.
    Silani, Vincenzo
    Volk, Alexander E.
    The role of de novo mutations in the development of amyotrophic lateral sclerosis2017Inngår i: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 38, nr 11, s. 1534-1541Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The genetic basis combined with the sporadic occurrence of amyotrophic lateral sclerosis (ALS) suggests a role of de novo mutations in disease pathogenesis. Previous studies provided some evidence for this hypothesis; however, results were conflicting: no genes with recurrent occurring de novo mutations were identified and different pathways were postulated. In this study, we analyzed whole-exome data from 82 new patient-parents trios and combined it with the datasets of all previously published ALS trios (173 trios in total). The per patient de novo rate was not higher than expected based on the general population (P = 0.40). We showed that these mutations are not part of the previously postulated pathways, and gene-gene interaction analysis found no enrichment of interacting genes in this group (P = 0.57). Also, we were able to show that the de novo mutations in ALS patients are located in genes already prone for de novo mutations (P < 1 x 10(-15)). Although the individual effect of rare de novo mutations in specific genes could not be assessed, our results indicate that, in contrast to previous hypothesis, de novo mutations in general do not impose a major burden on ALS risk.

  • 1067.
    Van Eyken, Els
    et al.
    Department of Medical Genetics, University of Antwerp (UA), Antwerp, Belgium.
    Van Camp, Guy V.
    Department of Medical Genetics, University of Antwerp (UA), Antwerp, Belgium.
    Fransen, Erik
    Department of Medical Genetics, University of Antwerp (UA), Antwerp, Belgium.
    Topsakal, Vedat V.
    Department of Otorhinolaryngology, University Hospital of Antwerp (UZA), Antwerp, Belgium.
    Hendrickx, Jan Jaap
    Department of Otorhinolaryngology, University Hospital of Antwerp (UZA), Antwerp, Belgium.
    Demeester, Kelly
    Department of Otorhinolaryngology, University Hospital of Antwerp (UZA), Antwerp, Belgium.
    Van de Heyning, Paul
    Department of Otorhinolaryngology, University Hospital of Antwerp (UZA), Antwerp, Belgium.
    Mäki-Torkko, Elina
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Otorhinolaryngology, University of Oulu, Oulu, Finland.
    Hannula, Samuli
    Department of Otorhinolaryngology, University of Oulu, Oulu, Finland.
    Sorri, Martti J.
    Department of Otorhinolaryngology, University of Oulu, Oulu, Finland.
    Jensen, Mona
    Department of Audiology, Bispebjerg Hospital (BBH), Copenhagen, Denmark.
    Parving, Agnete
    Department of Audiology, Bispebjerg Hospital (BBH), Copenhagen, Denmark.
    Bille, Michael
    Department of Audiology, Bispebjerg Hospital (BBH), Copenhagen, Denmark.
    Baur, Manuela
    Department of Otorhinolaryngology, University of Tuebingen, Tuebingen, Germany.
    Pfister, Markus H.F.
    Department of Otorhinolaryngology, University of Tuebingen, Tuebingen, Germany.
    Bonaconsa, Amanda
    Department of Oto-surgery, University Hospital Padova, Padova, Italy.
    Mazzoli, Manuela
    Department of Oto-surgery, University Hospital Padova, Padova, Italy.
    Orzan, Eva
    Department of Oto-surgery, University Hospital Padova, Padova, Italy.
    Espeso, Angeles
    Welsh hearing Institute, University Hospital of Wales, Cardiff, UK.
    Stephens, Dafydd
    Welsh hearing Institute, University Hospital of Wales, Cardiff, UK.
    Verbruggen, Katia
    Department of Otorhinolaryngology, University Hospital of Gent (UZ), Gent, Belgium.
    Huyghe, Joke
    Department of Otorhinolaryngology, University Hospital of Gent (UZ), Gent, Belgium.
    Dhooge, Ingeborg
    Department of Otorhinolaryngology, University Hospital of Gent (UZ), Gent, Belgium.
    Huygen, Patrick L.M.
    Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
    Kremer, Hannie Ph .
    Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
    Cremers, Cor Wrj R.J.
    Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
    Kunst, Sylvia J.W.
    Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
    Manninen, Minna
    Department of Otorhinolaryngology, University of Tampere, Tampere, Finland.
    Pyykkö, Ilmari V.
    Department of Otorhinolaryngology, University of Tampere, Tampere, Finland.
    Lacava, Amalia Diaz
    Institute of Medical Biometry, Informatics and Epidemiology, University of Bonn, Germany.
    Steffens, Michael
    Institute of Medical Biometry, Informatics and Epidemiology, University of Bonn, Germany.
    Wienker, Thomas F.
    Institute of Medical Biometry, Informatics and Epidemiology, University of Bonn, Germany.
    Van Laer, Lut
    Department of Medical Genetics, University of Antwerp (UA), Antwerp, Belgium.
    Contribution of the N-acetyltransferase 2 polymorphism NAT2*6A to age-related hearing impairment2007Inngår i: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 44, nr 9, s. 570-578Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Age-related hearing impairment (ARHI) is the most common sensory impairment in older people, affecting 50% of those aged 80 years. The proportion of older people is increasing in the general population, and as a consequence, the number of people affected with ARHI is growing. ARHI is a complex disorder, with both environmental and genetic factors contributing to the disease. The first studies to elucidate these genetic factors were recently performed, resulting in the identification of the first two susceptibility genes for ARHI, NAT2 and KCNQ4.

    METHODS: In the present study, the association between ARHI and polymorphisms in genes that contribute to the defence against reactive oxygen species, including GSTT1, GSTM1 and NAT2, was tested. Samples originated from seven different countries and were combined into two test population samples, the general European population and the Finnish population. Two distinct phenotypes for ARHI were studied, Z(low) and Z(high), representing hearing in the low and high frequencies, respectively. Statistical analysis was performed for single polymorphisms (GSTM1, GSTT1, NAT2*5A, NAT2*6A, and NAT2*7A), haplotypes, and gene-environment and gene-gene interactions.

    RESULTS: We found an association between ARHI and GSTT1 and GSTM1 in the Finnish population sample, and with NAT2*6A in the general European population sample. The latter finding replicates previously published data.

    CONCLUSION: As replication is considered the ultimate proof of true associations in the study of complex disorders, this study provides further support for the involvement of NAT2*6A in ARHI.

  • 1068.
    Van Eyken, Els
    et al.
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    Van Laer, Lut
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    Fransen, Erik
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    Topsakal, Vedat
    Department of Otorhinolaryngology, University Hospital of Antwerp, Antwerp, Belgium.
    Hendrickx, Jan-Jaap
    Department of Otorhinolaryngology, University Hospital of Antwerp, Antwerp, Belgium.
    Demeester, Kelly
    Department of Otorhinolaryngology, University Hospital of Antwerp, Antwerp, Belgium.
    Van de Heyning, Paul
    Department of Otorhinolaryngology, University Hospital of Antwerp, Antwerp, Belgium.
    Mäki-Torkko, Elina
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Otorhinolaryngology, University of Oulu, Oulu, Finland.
    Hannula, Samuli
    Department of Otorhinolaryngology, University of Oulu, Oulu, Finland.
    Sorri, Martti
    Department of Otorhinolaryngology, University of Oulu, Oulu, Finland.
    Jensen, Mona
    Department of Audiology, Bispebjerg Hospital (BBH) H:S, Copenhagen, Denmark.
    Parving, Agnete
    Department of Audiology, Bispebjerg Hospital (BBH) H:S, Copenhagen, Denmark.
    Bille, Michael
    Department of Audiology, Bispebjerg Hospital (BBH) H:S, Copenhagen, Denmark.
    Baur, Manuela
    Department of Otorhinolaryngology, University of Tüebingen, Tüebingen, Germany;.
    Pfister, Markus
    Department of Otorhinolaryngology, University of Tüebingen, Tüebingen, Germany.
    Bonaconsa, Amanda
    Department of Oto-surgery, University Hospital Padova, Padova, Italy.
    Mazzoli, Manuela
    Department of Oto-surgery, University Hospital Padova, Padova, Italy.
    Orzan, Eva
    Department of Oto-surgery, University Hospital Padova, Padova, Italy.
    Espeso, Angeles
    Welsh hearing Institute, University Hospital of Wales, Cardiff, U.K..
    Stephens, Dafydd
    Welsh hearing Institute, University Hospital of Wales, Cardiff, U.K..
    Verbruggen, Katia
    Department of Otorhinolaryngology, University Hospital of Gent, Gent, Belgium.
    Huyghe, Joke
    Department of Otorhinolaryngology, University Hospital of Gent, Gent, Belgium.
    Dhooge, Ingeborg
    Department of Otorhinolaryngology, University Hospital of Gent, Gent, Belgium.
    Huygen, Patrick
    Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
    Kremer, Hannie
    Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
    Cremers, Cor
    Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
    Kunst, Sylvia
    Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
    Manninen, Mina
    Department of Otorhinolaryngology, University of Tampere, Tampere, Finland.
    Pyykkö, Ilmari
    Department of Otorhinolaryngology, University of Tampere, Tampere, Finland.
    Rajkowska, Elzbieta
    Department of Audiology and Phoniatrics, Nofer Institute of Occupational Medicine, Lodz, Poland.
    Pawelczyk, Malgorzata
    Department of Audiology and Phoniatrics, Nofer Institute of Occupational Medicine, Lodz, Poland.
    Sliwinska-Kowalska, Mariola
    Department of Audiology and Phoniatrics, Nofer Institute of Occupational Medicine, Lodz, Poland.
    Steffens, Michael
    Institute of Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.
    Wienker, Thomas
    Institute of Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.
    Van Camp, Guy
    Department of Medical Genetics, University of Antwerp, the Netherlands.
    The contribution of GJB2 (Connexin 26) 35delG to age-related hearing impairment and noise-induced hearing loss2007Inngår i: Otology and Neurotology, ISSN 1531-7129, E-ISSN 1537-4505, Vol. 28, nr 7, s. 970-975Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    HYPOTHESIS: The common GJB2 (Connexin 26) 35delG mutation might contribute to the development of age-related hearing impairment (ARHI) and noise-induced hearing loss (NIHL).

    BACKGROUND: GJB2, a gene encoding a gap junction protein expressed in the inner ear, has been suggested to be involved in the potassium recycling pathway in the cochlea. GJB2 mutations account for a large number of individuals with nonsyndromic recessive hearing loss, with 35delG being the most frequent mutation in populations of European origin. Other genes involved in potassium homeostasis have been suggested to be associated with ARHI and NIHL, and distortion product otoacoustic emission distortions indicative of hearing loss alterations have been found in 35delG carriers.

    METHOD: We genotyped 35delG in two distinct sample sets: an ARHI sample set, composed of 2,311 Caucasian samples from nine different centers originating from seven different countries with an age range between 53 and 67 years, and an NIHL sample set consisting of 702 samples from the two extremes of a noise-exposed Polish sample.

    RESULTS: After statistical analysis, we were unable to detect an association between 35delG and ARHI, nor between 35delG and NIHL.

    CONCLUSION: Our findings indicate that there is no increased susceptibility in 35delG carriers for the development of ARHI or NIHL.

  • 1069. van Kuilenburg, A B P
    et al.
    Meijer, J
    Dobritzsch, Doreen
    Karolinska Institutet.
    Lohkamp, B
    Ruitenbeek, W
    Roelofsen, J
    Abeling, N G G M
    Duran, M
    Buzing, C
    Identification of two novel mutations C79X and R235Q in the dihydropyrimidine dehydrogenase gene in a patient presenting with hematuria2008Inngår i: Nucleosides, Nucleotides & Nucleic Acids, ISSN 1525-7770, E-ISSN 1532-2335, Vol. 27, nr 6-7, s. 809-815Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A patient with hematuria was shown to have thymine-uraciluria. The dihydropyrimidine dehydrogenase (DPD) activity in peripheral blood mononuclear cells was 0.16 nmol/mg/h; controls: 9.9 +/- 2.8 nmol/mg/h. Analysis of DPYD showed that the patient was compound heterozygous for the novel mutations 237C > A (C79X) in exon 4 and 704G > A (R235Q) in exon 7. The nonsense mutation (C79X) leads to premature termination of translation and thus to a non-functional protein. Analysis of the crystal structure of pig DPD suggested that the R235Q mutation might interfere with the binding of FAD and the electron flow between the NADPH and the pyrimidine substrate site of DPD.

  • 1070. van Kuilenburg, André B P
    et al.
    Dobritzsch, Doreen
    Karolinska Institutet.
    Meijer, Judith
    Krumpel, Michael
    Selim, Laila A
    Rashed, Mohamed S
    Assmann, Birgit
    Meinsma, Rutger
    Lohkamp, Bernhard
    Ito, Tetsuya
    Abeling, Nico G G M
    Saito, Kayoko
    Eto, Kaoru
    Smitka, Martin
    Engvall, Martin
    Zhang, Chunhua
    Xu, Wang
    Zoetekouw, Lida
    Hennekam, Raoul C M
    ß-ureidopropionase deficiency: phenotype, genotype and protein structural consequences in 16 patients2012Inngår i: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1822, nr 7, s. 1096-108Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    ß-ureidopropionase is the third enzyme of the pyrimidine degradation pathway and catalyzes the conversion of N-carbamyl-ß-alanine and N-carbamyl-ß-aminoisobutyric acid to ß-alanine and ß-aminoisobutyric acid, ammonia and CO(2). To date, only five genetically confirmed patients with a complete ß-ureidopropionase deficiency have been reported. Here, we report on the clinical, biochemical and molecular findings of 11 newly identified ß-ureidopropionase deficient patients as well as the analysis of the mutations in a three-dimensional framework. Patients presented mainly with neurological abnormalities (intellectual disabilities, seizures, abnormal tonus regulation, microcephaly, and malformations on neuro-imaging) and markedly elevated levels of N-carbamyl-ß-alanine and N-carbamyl-ß-aminoisobutyric acid in urine and plasma. Analysis of UPB1, encoding ß-ureidopropionase, showed 6 novel missense mutations and one novel splice-site mutation. Heterologous expression of the 6 mutant enzymes in Escherichia coli showed that all mutations yielded mutant ß-ureidopropionase proteins with significantly decreased activity. Analysis of a homology model of human ß-ureidopropionase generated using the crystal structure of the enzyme from Drosophila melanogaster indicated that the point mutations p.G235R, p.R236W and p.S264R lead to amino acid exchanges in the active site and therefore affect substrate binding and catalysis. The mutations L13S, R326Q and T359M resulted most likely in folding defects and oligomer assembly impairment. Two mutations were identified in several unrelated ß-ureidopropionase patients, indicating that ß-ureidopropionase deficiency may be more common than anticipated.

  • 1071. van Kuilenburg, André B P
    et al.
    Dobritzsch, Doreen
    Karolinska Institutet.
    Meijer, Judith
    Meinsma, Rutger
    Benoist, Jean-François
    Assmann, Birgit
    Schubert, Susanne
    Hoffmann, Georg F
    Duran, Marinus
    de Vries, Maaike C
    Kurlemann, Gerd
    Eyskens, François J M
    Greed, Lawrence
    Sass, Jörn Oliver
    Schwab, K Otfried
    Sewell, Adrian C
    Walter, John
    Hahn, Andreas
    Zoetekouw, Lida
    Ribes, Antonia
    Lind, Suzanne
    Hennekam, Raoul C M
    Dihydropyrimidinase deficiency: Phenotype, genotype and structural consequences in 17 patients2010Inngår i: Biochimica et Biophysica Acta - Molecular Basis of Disease, ISSN 0925-4439, E-ISSN 1879-260X, Vol. 1802, nr 7-8, s. 639-648Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Dihydropyrimidinase (DHP) is the second enzyme of the pyrimidine degradation pathway and catalyses the ring opening of 5,6-dihydrouracil and 5,6-dihydrothymine. To date, only 11 individuals have been reported suffering from a complete DHP deficiency. Here, we report on the clinical, biochemical and molecular findings of 17 newly identified DHP deficient patients as well as the analysis of the mutations in a three-dimensional framework. Patients presented mainly with neurological and gastrointestinal abnormalities and markedly elevated levels of 5,6-dihydrouracil and 5,6-dihydrothymine in plasma, cerebrospinal fluid and urine. Analysis of DPYS, encoding DHP, showed nine missense mutations, two nonsense mutations, two deletions and one splice-site mutation. Seventy-one percent of the mutations were located at exons 5-8, representing 41% of the coding sequence. Heterologous expression of 11 mutant enzymes in Escherichia coli showed that all but two missense mutations yielded mutant DHP proteins without significant activity. Only DHP enzymes containing the mutations p.R302Q and p.T343A possessed a residual activity of 3.9% and 49%, respectively. The crystal structure of human DHP indicated that the point mutations p.R490C, p.R302Q and p.V364M affect the oligomerization of the enzyme. In contrast, p.M70T, p.D81G, p.L337P and p.T343A affect regions near the di-zinc centre and the substrate binding site. The p.S379R and p.L7V mutations were likely to cause structural destabilization and protein misfolding. Four mutations were identified in multiple unrelated DHP patients, indicating that DHP deficiency may be more common than anticipated.

  • 1072. van Kuilenburg, André B P
    et al.
    Dobritzsch, Doreen
    Karolinska Institutet.
    Meinsma, Rutger
    Haasjes, Janet
    Waterham, Hans R
    Nowaczyk, Malgorzata J M
    Maropoulos, George D
    Hein, Guido
    Kalhoff, Hermann
    Kirk, Jean M
    Baaske, Holger
    Aukett, Anne
    Duley, John A
    Ward, Kate P
    Lindqvist, Ylva
    van Gennip, Albert H
    Novel disease-causing mutations in the dihydropyrimidine dehydrogenase gene interpreted by analysis of the three-dimensional protein structure2002Inngår i: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 364, nr Pt 1, s. 157-163Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive disease characterized by thymine-uraciluria in homozygous deficient patients. Cancer patients with a partial deficiency of DPD are at risk of developing severe life-threatening toxicities after the administration of 5-fluorouracil. Thus, identification of novel disease-causing mutations is of the utmost importance to allow screening of patients at risk. In eight patients presenting with a complete DPD deficiency, a considerable variation in the clinical presentation was noted. Whereas motor retardation was observed in all patients, no patients presented with convulsive disorders. In this group of patients, nine novel mutations were identified including one deletion of two nucleotides [1039-1042delTG] and eight missense mutations. Analysis of the crystal structure of pig DPD suggested that five out of eight amino acid exchanges present in these patients with a complete DPD deficiency, Pro86Leu, Ser201Arg, Ser492Leu, Asp949Val and His978Arg, interfered directly or indirectly with cofactor binding or electron transport. Furthermore, the mutations Ile560Ser and Tyr211Cys most likely affected the structural integrity of the DPD protein. Only the effect of the Ile370Val and a previously identified Cys29Arg mutation could not be readily explained by analysis of the three-dimensional structure of the DPD enzyme, suggesting that at least the latter might be a common polymorphism. Our data demonstrate for the first time the possible consequences of missense mutations in the DPD gene on the function and stability of the DPD enzyme.

  • 1073. van Kuilenburg, André B P
    et al.
    Meijer, Judith
    Dobritzsch, Doreen
    Karolinska Institutet.
    Meinsma, Rutger
    Duran, Marinus
    Lohkamp, Bernhard
    Zoetekouw, Lida
    Abeling, Nico G G M
    van Tinteren, Herman L G
    Bosch, Annet M
    Clinical, biochemical and genetic findings in two siblings with a dihydropyrimidinase deficiency2007Inngår i: Molecular Genetics and Metabolism, ISSN 1096-7192, E-ISSN 1096-7206, Vol. 91, nr 2, s. 157-164Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Dihydropyrimidinase (DHP) is the second enzyme of the pyrimidine degradation pathway and it catalyses the ring opening of 5,6-dihydrouracil and 5,6-dihydrothymine to N-carbamyl-beta-alanine and N-carbamyl-beta-aminoisobutyric acid, respectively. To date, only nine individuals have been reported suffering from a complete DHP deficiency. We report two siblings presenting with strongly elevated levels of 5,6-dihydrouracil and 5,6-dihydrothymine in plasma, cerebrospinal fluid and urine. One of the siblings had a severe delay in speech development and white matter abnormalities, whereas the other one was free of symptoms. Analysis of the DHP gene (DPYS) showed that both patients were compound heterozygous for the missense mutation 1078T>C (W360R) in exon 6 and a novel missense mutation 1235G>T (R412M) in exon 7. Heterologous expression of the mutant enzymes in Escherichia coli showed that both missense mutations resulted in a mutant DHP enzyme without residual activity. Analysis of the crystal structure of eukaryotic DHP from the yeast Saccharomyces kluyveri and the slime mold Dictyostelium discoideum suggests that the W360R and R412M mutations lead to structural instability of the enzyme which could potentially impair the assembly of the tetramer.

  • 1074. van Kuilenburg, André B P
    et al.
    Meijer, Judith
    Maurer, Dirk
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    Dobritzsch, Doreen
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    Meinsma, Rutger
    Los, Maartje
    Knegt, Lia C
    Zoetekouw, Lida
    Jansen, Rob L H
    Dezentjé, Vincent
    van Huis-Tanja, Lieke H
    van Kampen, Roel J W
    Hertz, Jens Michael
    Hennekam, Raoul C M
    Severe fluoropyrimidine toxicity due to novel and rare DPYD missense mutations, deletion and genomic amplification affecting DPD activity and mRNA splicing2017Inngår i: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1863, nr 3, s. 721-730Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5FU). Genetic variations in DPD have emerged as predictive risk factors for severe fluoropyrimidine toxicity. Here, we report novel and rare genetic variants underlying DPD deficiency in 9 cancer patients presenting with severe fluoropyrimidine-associated toxicity. All patients possessed a strongly reduced DPD activity, ranging from 9 to 53% of controls. Analysis of the DPD gene (DPYD) showed the presence of 21 variable sites including 4 novel and 4 very rare aberrations: 3 missense mutations, 2 splice-site mutations, 1 intronic mutation, a deletion of 21 nucleotides and a genomic amplification of exons 9-12. Two novel/rare variants (c.2843T>C, c.321+1G>A) were present in multiple, unrelated patients. Functional analysis of recombinantly-expressed DPD mutants carrying the p.I948T and p.G284V mutation showed residual DPD activities of 30% and 0.5%, respectively. Analysis of a DPD homology model indicated that the p.I948T and p.G284V mutations may affect electron transfer and the binding of FAD, respectively. cDNA analysis showed that the c.321+1G>A mutation in DPYD leads to skipping of exon 4 immediately upstream of the mutated splice-donor site in the process of DPD pre-mRNA splicing. A lethal toxicity in two DPD patients suggests that fluoropyrimidines combined with other therapies such as radiotherapy might be particularly toxic for DPD deficient patients. Our study advocates a more comprehensive genotyping approach combined with phenotyping strategies for upfront screening for DPD deficiency to ensure the safe administration of fluoropyrimidines.

  • 1075. van Kuilenburg, André B P
    et al.
    Meijer, Judith
    Mul, Adri N P M
    Meinsma, Rutger
    Schmid, Veronika
    Dobritzsch, Doreen
    Karolinska Institutet.
    Hennekam, Raoul C M
    Mannens, Marcel M A M
    Kiechle, Marion
    Etienne-Grimaldi, Marie-Christine
    Klümpen, Heinz-Josef
    Maring, Jan Gerard
    Derleyn, Veerle A
    Maartense, Ed
    Milano, Gérard
    Vijzelaar, Raymon
    Gross, Eva
    Intragenic deletions and a deep intronic mutation affecting pre-mRNA splicing in the dihydropyrimidine dehydrogenase gene as novel mechanisms causing 5-fluorouracil toxicity2010Inngår i: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 128, nr 5, s. 529-538Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Dihydropyrimidine dehydrogenase (DPD) is the initial enzyme acting in the catabolism of the widely used antineoplastic agent 5-fluorouracil (5FU). DPD deficiency is known to cause a potentially lethal toxicity following administration of 5FU. Here, we report novel genetic mechanisms underlying DPD deficiency in patients presenting with grade III/IV 5FU-associated toxicity. In one patient a genomic DPYD deletion of exons 21-23 was observed. In five patients a deep intronic mutation c.1129-5923C>G was identified creating a cryptic splice donor site. As a consequence, a 44 bp fragment corresponding to nucleotides c.1129-5967 to c.1129-5924 of intron 10 was inserted in the mature DPD mRNA. The deleterious c.1129-5923C>G mutation proved to be in cis with three intronic polymorphisms (c.483 + 18G>A, c.959-51T>G, c.680 + 139G>A) and the synonymous mutation c.1236G>A of a previously identified haplotype. Retrospective analysis of 203 cancer patients showed that the c.1129-5923C>G mutation was significantly enriched in patients with severe 5FU-associated toxicity (9.1%) compared to patients without toxicity (2.2%). In addition, a high prevalence was observed for the c.1129-5923C>G mutation in the normal Dutch (2.6%) and German (3.3%) population. Our study demonstrates that a genomic deletion affecting DPYD and a deep intronic mutation affecting pre-mRNA splicing can cause severe 5FU-associated toxicity. We conclude that screening for DPD deficiency should include a search for genomic rearrangements and aberrant splicing.

  • 1076. Van Kuilenburg, André B P
    et al.
    Meinsma, Rutger
    Beke, Eva
    Bobba, Barbara
    Boffi, Patrizia
    Enns, Gregory M
    Witt, David R
    Dobritzsch, Doreen
    Karolinska Institutet.
    Identification of three novel mutations in the dihydropyrimidine dehydrogenase gene associated with altered pre-mRNA splicing or protein function2005Inngår i: Biological chemistry (Print), ISSN 1431-6730, E-ISSN 1437-4315, Vol. 386, nr 4, s. 319-324Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of the pyrimidine bases uracil and thymine, as well as of the widely used chemotherapeutic drug 5-fluorouracil (5FU). Analysis of the DPD gene ( DPYD ) in two patients presenting with complete DPD deficiency and the parents of an affected child showed the presence of three novel mutations, including one splice site mutation IVS11 + 1G-->T and the missense mutations 731A-->C (E244V) and 1651G-->A (A551T). The G-->T mutation in the invariant GT splice donor site flanking exon 11 (IVS11 + 1G-->T) created a cryptic splice site within exon 11. As a consequence, a 141-bp fragment encoding the aminoacid residues 400-446 of the primary sequence of the DPD protein was missing in the mature DPD mRNA. Analysis of the crystal structure of pig DPD suggested that the E244V mutation might interfere with the electron flow between NADPH and the pyrimidine binding site of DPD. The A551T point mutation might prevent binding of the prosthetic group FMN and affect folding of the DPD protein. The identification of these novel mutations in DPYD will allow the identification of patients with an increased risk of developing severe 5FU-associated toxicity.

  • 1077.
    Van Laer, Lut
    et al.
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    Huyghe, Jeroen R.
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    Hannula, Samuli
    Department of Otorhinolaryngology, University of Oulu, Oulu, Finland.
    Van Eyken, Els
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    Stephan, Dietrich A.
    Neurogenomics Division, Translational Genomics Research Institute, Phoenix AZ, United States.
    Mäki-Torkko, Elina
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Otorhinolaryngology, University of Oulu, Oulu, Finland.
    Aikio, Pekka
    Thule Institute, University of Oulu, Oulu, Finland.
    Fransen, Erik
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    Lysholm-Bernacchi, Alana
    Neurogenomics Division, Translational Genomics Research Institute, Phoenix AZ, United States.
    Sorri, Martti
    Department of Otorhinolaryngology, University of Oulu, Oulu, Finland.
    Huentelman, Matthew J.
    Neurogenomics Division, Translational Genomics Research Institute, Phoenix AZ, United States.
    Van Camp, Guy
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    A genome-wide association study for age-related hearing impairment in the Saami2010Inngår i: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 18, nr 6, s. 685-693Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    This study aimed at contributing to the elucidation of the genetic basis of age-related hearing impairment (ARHI), a common multifactorial disease with an important genetic contribution as demonstrated by heritability studies. We conducted a genome-wide association study (GWAS) in the Finnish Saami, a small, ancient, genetically isolated population without evidence of demographic expansion. The choice of this study population was motivated by its anticipated higher extent of LD, potentially offering a substantial power advantage for association mapping. DNA samples and audiometric measurements were collected from 352 Finnish Saami individuals, aged between 50 and 75 years. To reduce the burden of multiple testing, we applied principal component (PC) analysis to the multivariate audiometric phenotype. The first three PCs captured 80% of the variation in hearing thresholds, while maintaining biologically important audiometric features. All subjects were genotyped with the Affymetrix 100 K chip. To account for multiple levels of relatedness among subjects, as well as for population stratification, association testing was performed using a mixed model. We summarised the top-ranking association signals for the three traits under study. The top-ranked SNP, rs457717 (P-value 3.55 x 10(-7)), was associated with PC3 and was localised in an intron of the IQ motif-containing GTPase-activating-like protein (IQGAP2). Intriguingly, the SNP rs161927 (P-value 0.000149), seventh-ranked for PC1, was positioned immediately downstream from the metabotropic glutamate receptor-7 gene (GRM7). As a previous GWAS of a European and Finnish sample set already suggested a role for GRM7 in ARHI, this study provides further evidence for the involvement of this gene.

  • 1078.
    Van Laer, Lut
    et al.
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    Van Eyken, Els
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    Fransen, Erik
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    Huyghe, Jeroen R.
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    Topsakal, Vedat
    Department of Otorhinolaryngology, University Hospital of Antwerp, Antwerp, Belgium.
    Hendrickx, Jan-Jaap
    Department of Otorhinolaryngology, University Hospital of Antwerp, Antwerp, Belgium; Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands.
    Hannula, Samuli
    Department of Otorhinolaryngology, University of Oulu, Oulu, Finland.
    Mäki-Torkko, Elina
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Otorhinolaryngology, University of Oulu, Oulu, Finland.
    Jensen, Mona
    Department of Audiology, Bispebjerg Hospital, Copenhagen, Denmark.
    Demeester, Kelly
    Department of Otorhinolaryngology, University Hospital of Antwerp, Antwerp, Belgium.
    Baur, Manuela
    Department of Otorhinolaryngology, University of Tübingen, Tübingen, Germany.
    Bonaconsa, Amanda
    Department of Oto-Surgery, University Hospital Padova, Padova, Italy.
    Mazzoli, Manuela
    Department of Oto-Surgery, University Hospital Padova, Padova, Italy.
    Espeso, Angeles
    Welsh Hearing Institute, Cardiff University, Cardiff, United Kingdom.
    Verbruggen, Katia
    Department of Otorhinolaryngology, University Hospital of Ghent, Ghent, Belgium.
    Huyghe, Joke
    Department of Otorhinolaryngology, University Hospital of Ghent, Ghent, Belgium.
    Huygen, Patrick
    Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands.
    Kunst, Sylvia
    Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands.
    Manninen, Minna
    Department of Otorhinolaryngology, University of Tampere, Tampere, Finland.
    Konings, Annelies
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    Diaz-Lacava, Amalia N.
    Institute of Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.
    Steffens, Michael
    Institute of Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.
    Wienker, Thomas F.
    Institute of Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.
    Pyykkö, Ilmari
    Department of Otorhinolaryngology, University of Tampere, Tampere, Finland.
    Cremers, Cor W. R. J.
    Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands.
    Kremer, Hannie
    Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands.
    Dhooge, Ingeborg
    Department of Otorhinolaryngology, University Hospital of Ghent, Ghent, Belgium.
    Stephens, Dafydd
    Welsh Hearing Institute, Cardiff University, Cardiff, United Kingdom.
    Orzan, Eva
    Department of Oto-Surgery, University Hospital Padova, Padova, Italy.
    Pfister, Markus
    Department of Otorhinolaryngology, University of Tübingen, Tübingen, Germany.
    Bille, Michael
    Department of Audiology, Bispebjerg Hospital, Copenhagen, Denmark.
    Parving, Agnete
    Department of Audiology, Bispebjerg Hospital, Copenhagen, Denmark.
    Sorri, Martti
    Department of Otorhinolaryngology, University of Oulu, Oulu, Finland.
    Van de Heyning, Paul H.
    Department of Otorhinolaryngology, University Hospital of Antwerp, Antwerp, Belgium.
    Van Camp, Guy
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    The grainyhead like 2 gene (GRHL2), alias TFCP2L3, is associated with age-related hearing impairment2008Inngår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 17, nr 2, s. 159-169Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Age-related hearing impairment (ARHI) is the most prevalent sensory impairment in the elderly. ARHI is a complex disease caused by an interaction between environmental and genetic factors. The contribution of various environmental factors has been relatively extensively studied. In contrast, investigations to identify the genetic risk factors have only recently been initiated. In this paper we describe the results of an association study performed on 2418 ARHI samples derived from nine centers from seven European countries. In 70 candidate genes, a total of 768 tag single nucleotide polymorphisms (SNPs) were selected based on HAPMAP data. These genes were chosen among the monogenic hearing loss genes identified in mice and men in addition to several strong functional candidates. After genotyping and data polishing, statistical analysis of all samples combined resulted in a P-value that survived correction for multiple testing for one SNP in the GRHL2 gene. Other SNPs in this gene were also associated, albeit to a lesser degree. Subsequently, an analysis of the most significant GRHL2 SNP was performed separately for each center. The direction of the association was identical in all nine centers. Two centers showed significant associations and a third center showed a trend towards significance. Subsequent fine mapping of this locus demonstrated that the majority of the associated SNPs reside in intron 1. We hypothesize that the causative variant may change the expression levels of a GRHL2 isoform.

  • 1079. van Ommen, Gert-Jan B
    et al.
    Törnwall, Outi
    Bréchot, Christian
    Dagher, Georges
    Galli, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hveem, Kristian
    Landegren, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Luchinat, Claudio
    Metspalu, Andres
    Nilsson, Cecilia
    Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Solesvik, Ove V
    Perola, Markus
    Litton, Jan-Eric
    Zatloukal, Kurt
    BBMRI-ERIC as a resource for pharmaceutical and life science industries: the development of biobank-based Expert Centres2015Inngår i: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 23, nr 7, s. 893-900Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Biological resources (cells, tissues, bodily fluids or biomolecules) are considered essential raw material for the advancement of health-related biotechnology, for research and development in life sciences, and for ultimately improving human health. Stored in local biobanks, access to the human biological samples and related medical data for transnational research is often limited, in particular for the international life science industry. The recently established pan-European Biobanking and BioMolecular resources Research Infrastructure-European Research Infrastructure Consortium (BBMRI-ERIC) aims to improve accessibility and interoperability between academic and industrial parties to benefit personalized medicine, disease prevention to promote development of new diagnostics, devices and medicines. BBMRI-ERIC is developing the concept of Expert Centre as public-private partnerships in the precompetitive, not-for-profit field to provide a new structure to perform research projects that would face difficulties under currently established models of academic-industry collaboration. By definition, Expert Centres are key intermediaries between public and private sectors performing the analysis of biological samples under internationally standardized conditions. This paper presents the rationale behind the Expert Centres and illustrates the novel concept with model examples.

  • 1080. van Rheenen, Wouter
    et al.
    Shatunov, Aleksey
    Dekker, Annelot M.
    McLaughlin, Russell L.
    Diekstra, Frank P.
    Pulit, Sara L.
    van der Spek, Rick A. A.
    Vosa, Urmo
    de Jong, Simone
    Robinson, Matthew R.
    Yang, Jian
    Fogh, Isabella
    van Doormaal, Perry T. C.
    Tazelaar, Gijs H. P.
    Koppers, Max
    Blokhuis, Anna M.
    Sproviero, William
    Jones, Ashley R.
    Kenna, Kevin P.
    van Eijk, Kristel R.
    Harschnitz, Oliver
    Schellevis, Raymond D.
    Brands, William J.
    Medic, Jelena
    Menelaou, Androniki
    Vajda, Alice
    Ticozzi, Nicola
    Lin, Kuang
    Rogelj, Boris
    Vrabec, Katarina
    Ravnik-Glavac, Metka
    Koritnik, Blazi
    Zidar, Janez
    Leonardis, Lea
    Groselj, Leja Dolenc
    Millecamps, Stephanie
    Salachas, Francois
    Meininger, Vincent
    de Carvalho, Mamede
    Pinto, Susana
    Mora, Jesus S.
    Rojas-Garcia, Ricardo
    Polak, Meraida
    Chandran, Siddharthan
    Colville, Shuna
    Swingler, Robert
    Morrison, Karen E.
    Shaw, Pamela J.
    Hardy, John
    Orrell, Richard W.
    Pittman, Alan
    Sidle, Katie
    Fratta, Pietro
    Malaspina, Andrea
    Topp, Simon
    Petri, Susanne
    Abdulla, Susanne
    Drepper, Carsten
    Sendtner, Michael
    Meyer, Thomas
    Ophoff, Roel A.
    Staats, Kim A.
    Wiedau-Pazos, Martina
    Lomen-Hoerth, Catherine
    Van Deerlin, Vivianna M.
    Trojanowski, John Q.
    Elman, Lauren
    McCluskey, Leo
    Basak, A. Nazli
    Tunca, Ceren
    Hamzeiy, Hamid
    Parman, Yesim
    Meitinger, Thomas
    Lichtner, Peter
    Radivojkov-Blagojevic, Milena
    Andres, Christian R.
    Maurel, Cindy
    Bensimon, Gilbert
    Landwehrmeyer, Bernhard
    Brice, Alexis
    Payan, Christine A. M.
    Saker-Delye, Safaa
    Duerr, Alexandra
    Wood, Nicholas W.
    Tittmann, Lukas
    Lieb, Wolfgang
    Franke, Andre
    Rietschel, Marcella
    Cichon, Sven
    Noethen, Markus M.
    Amouyel, Philippe
    Tzourio, Christophe
    Dartigues, Jean-Francois
    Uitterlinden, Andre G.
    Rivadeneira, Fernando
    Estrada, Karol
    Hofman, Albert
    Curtis, Charles
    Blauw, Hylke M.
    van der Kooi, Anneke J.
    de Visser, Marianne
    Goris, An
    Weber, Markus
    Shaw, Christopher E.
    Smith, Bradley N.
    Pansarasa, Orietta
    Cereda, Cristina
    Del Bo, Roberto
    Comi, Giacomo P.
    D'Alfonso, Sandra
    Bertolin, Cinzia
    Soraru, Gianni
    Mazzini, Letizia
    Pensato, Viviana
    Gellera, Cinzia
    Tiloca, Cinzia
    Ratti, Antonia
    Calvo, Andrea
    Moglia, Cristina
    Brunetti, Maura
    Arcuti, Simona
    Capozzo, Rosa
    Zecca, Chiara
    Lunetta, Christian
    Penco, Silvana
    Riva, Nilo
    Padovani, Alessandro
    Filosto, Massimiliano
    Muller, Bernard
    Stuit, Robbert Jan
    Blair, Ian
    Zhang, Katharine
    McCann, Emily P.
    Fifita, Jennifer A.
    Nicholson, Garth A.
    Rowe, Dominic B.
    Pamphlett, Roger
    Kiernan, Matthew C.
    Grosskreutz, Julian
    Witte, Otto W.
    Ringer, Thomas
    Prell, Tino
    Stubendorff, Beatrice
    Kurth, Ingo
    Huebner, Christian A.
    Leigh, P. Nigel
    Casale, Federico
    Chio, Adrian
    Beghi, Ettore
    Pupillo, Elisabetta
    Tortelli, Rosanna
    Logroscino, Giancarlo
    Powell, John
    Ludolph, Albert C.
    Weishaupt, Jochen H.
    Robberecht, Wim
    Van Damme, Philip
    Franke, Lude
    Pers, Tune H.
    Brown, Robert H.
    Glass, Jonathan D.
    Landers, John E.
    Hardiman, Orla
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap. Department of Neurology, Ulm University, Ulm, Germany.
    Corcia, Philippe
    Vourc'h, Patrick
    Silani, Vincenzo
    Wray, Naomi R.
    Visscher, Peter M.
    de Bakker, Paul I. W.
    van Es, Michael A.
    Pasterkamp, R. Jeroen
    Lewis, Cathryn M.
    Breen, Gerome
    Al-Chalabi, Ammar
    van den Berg, Leonard H.
    Veldink, Jan H.
    Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis2016Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 48, nr 9, s. 1043-1048Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.

  • 1081.
    van Thuijl, Hinke F.
    et al.
    University of Calif San Francisco, CA 94143 USA; Vrije University of Amsterdam Medical Centre, Netherlands; Vrije University of Amsterdam Medical Centre, Netherlands.
    Mazor, Tali
    University of Calif San Francisco, CA 94143 USA.
    Johnson, Brett E.
    University of Calif San Francisco, CA 94143 USA.
    Fouse, Shaun D.
    University of Calif San Francisco, CA 94143 USA.
    Aihara, Koki
    University of Tokyo, Japan; University of Tokyo, Japan.
    Hong, Chibo
    University of Calif San Francisco, CA 94143 USA.
    Malmström, Annika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, LAH Linköping.
    Hallbeck, Martin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Heimans, Jan J.
    Vrije University of Amsterdam Medical Centre, Netherlands.
    Kloezeman, Jenneke J.
    Erasmus MC, Netherlands.
    Stenmark Askmalm, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Lamfers, Martine L. M.
    Erasmus MC, Netherlands.
    Saito, Nobuhito
    University of Tokyo, Japan.
    Aburatani, Hiroyuki
    University of Tokyo, Japan.
    Mukasa, Akitake
    University of Tokyo, Japan.
    Berger, Mitchell S.
    University of Calif San Francisco, CA 94143 USA.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Taylor, Barry S.
    Mem Sloan Kettering Cancer Centre, NY 10021 USA; Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Molinaro, Annette M.
    University of Calif San Francisco, CA 94143 USA; University of Calif San Francisco, CA 94143 USA.
    Wesseling, Pieter
    Vrije University of Amsterdam Medical Centre, Netherlands; Radboud University of Nijmegen, Netherlands.
    Reijneveld, Jaap C.
    Vrije University of Amsterdam Medical Centre, Netherlands; University of Amsterdam, Netherlands.
    Chang, Susan M.
    University of Calif San Francisco, CA 94143 USA.
    Ylstra, Bauke
    Vrije University of Amsterdam Medical Centre, Netherlands.
    Costello, Joseph F.
    University of Calif San Francisco, CA 94143 USA.
    Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment2015Inngår i: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 129, nr 4, s. 597-607Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Temozolomide (TMZ) increases the overall survival of patients with glioblastoma (GBM), but its role in the clinical management of diffuse low-grade gliomas (LGG) is still being defined. DNA hypermethylation of the O (6) -methylguanine-DNA methyltransferase (MGMT) promoter is associated with an improved response to TMZ treatment, while inactivation of the DNA mismatch repair (MMR) pathway is associated with therapeutic resistance and TMZ-induced mutagenesis. We previously demonstrated that TMZ treatment of LGG induces driver mutations in the RB and AKT-mTOR pathways, which may drive malignant progression to secondary GBM. To better understand the mechanisms underlying TMZ-induced mutagenesis and malignant progression, we explored the evolution of MGMT methylation and genetic alterations affecting MMR genes in a cohort of 34 treatment-na less than ve LGGs and their recurrences. Recurrences with TMZ-associated hypermutation had increased MGMT methylation compared to their untreated initial tumors and higher overall MGMT methylation compared to TMZ-treated non-hypermutated recurrences. A TMZ-associated mutation in one or more MMR genes was observed in five out of six TMZ-treated hypermutated recurrences. In two cases, pre-existing heterozygous deletions encompassing MGMT, or an MMR gene, were followed by TMZ-associated mutations in one of the genes of interest. These results suggest that tumor cells with methylated MGMT may undergo positive selection during TMZ treatment in the context of MMR deficiency.

  • 1082.
    van Zuydam, Natalie R.
    et al.
    Univ Oxford, Wellcome Trust Ctr Human Genet, London, England.;Univ Dundee, Med Res Inst, Dundee, Scotland..
    Voight, Benjamin F.
    Univ Penn, Philadelphia, PA 19104 USA..
    Ladenvall, Claes
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Fernandez, Juan
    Univ Oxford, Wellcome Trust Ctr Human Genet, London, England..
    Strawbridge, Rona J.
    Karolinska Inst, Stockholm, Sweden..
    A Gene-by-Environment Analysis of 184,428 Subjects Reveals a Role for Adaptive and Innate Immunity in Coronary Artery Disease in Subjects with Type 2 Diabetes2016Inngår i: Genetic Epidemiology, ISSN 0741-0395, E-ISSN 1098-2272, Vol. 40, nr 7, s. 668-668Artikkel i tidsskrift (Annet vitenskapelig)
  • 1083. Varga, M G
    et al.
    Shaffer, C L
    Sierra, J C
    Suarez, G
    Piazuelo, M B
    Whitaker, M E
    Romero-Gallo, J
    Krishna, U S
    Delgado, A
    Gomez, M A
    Good, James A D
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Skaar, E P
    Correa, P
    Wilson, K T
    Hadjifrangiskou, M
    Peek, R M
    Pathogenic Helicobacter pylori strains translocate DNA and activate TLR9 via the cancer-associated cag type IV secretion system2016Inngår i: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 35, nr 48, s. 6262-6269Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Helicobacter pylori (H. pylori) is the strongest identified risk factor for gastric cancer, the third most common cause of cancer-related death worldwide. An H. pylori constituent that augments cancer risk is the strain-specific cag pathogenicity island, which encodes a type IV secretion system (T4SS) that translocates a pro-inflammatory and oncogenic protein, CagA, into epithelial cells. However, the majority of persons colonized with CagA+ H. pylori strains do not develop cancer, suggesting that other microbial effectors also have a role in carcinogenesis. Toll-like receptor 9 (TLR9) is an endosome bound, innate immune receptor that detects and responds to hypo-methylated CpG DNA motifs that are most commonly found in microbial genomes. High-expression tlr9 polymorphisms have been linked to the development of premalignant lesions in the stomach. We now demonstrate that levels of H. pylori-mediated TLR9 activation and expression are directly related to gastric cancer risk in human populations. Mechanistically, we show for the first time that the H. pylori cancer-associated cag T4SS is required for TLR9 activation and that H. pylori DNA is actively translocated by the cag T4SS to engage this host receptor. Activation of TLR9 occurs through a contact-dependent mechanism between pathogen and host, and involves transfer of microbial DNA that is both protected as well as exposed during transport. These results indicate that TLR9 activation via the cag island may modify the risk for malignancy within the context of H. pylori infection and provide an important framework for future studies investigating the microbial-epithelial interface in gastric carcinogenesis.

  • 1084. Varga, Tibor V.
    et al.
    Sonestedt, Emily
    Shungin, Dmitry
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital Malmö, Malmö, Sweden.
    Koivula, Robert W.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Andersson Escher, Stefan
    Barroso, Ines
    Nilsson, Peter
    Melander, Olle
    Orho-Melander, Marju
    Renström, Frida
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital Malmö, Malmö, Sweden.
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital Malmö, Malmö, Sweden ; Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.
    Genetic determinants of long-term changes in blood lipid concentrations: 10-year follow-up of the GLACIER study2014Inngår i: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, nr 6, s. e1004388-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Recent genome-wide meta-analyses identified 157 loci associated with cross-sectional lipid traits. Here we tested whether these loci associate (singly and in trait-specific genetic risk scores [GRS]) with longitudinal changes in total cholesterol (TC) and triglyceride (TG) levels in a population-based prospective cohort from Northern Sweden (the GLACIER Study). We sought replication in a southern Swedish cohort (the MDC Study; N = 2,943). GLACIER Study participants (N = 6,064) were genotyped with the MetaboChip array. Up to 3,495 participants had 10-yr follow-up data available in the GLACIER Study. The TC- and TG-specific GRSs were strongly associated with change in lipid levels (beta = 0.02 mmol/l per effect allele per decade follow-up, P = 2.0x10(-11) for TC; beta = 0.02 mmol/l per effect allele per decade follow-up, P = 5.0x10(-5) for TG). In individual SNP analysis, one TC locus, apolipoprotein E (APOE) rs4420638 (beta = 0.12 mmol/l per effect allele per decade follow-up, P = 2.0x10(-5)), and two TG loci, tribbles pseudokinase 1 (TRIB1) rs2954029 (beta = 0.09 mmol/l per effect allele per decade follow-up, P = 5.1x10(-4)) and apolipoprotein A-I (APOA1) rs6589564 (beta = 0.31 mmol/l per effect allele per decade follow-up, P = 1.4x10(-8)), remained significantly associated with longitudinal changes for the respective traits after correction for multiple testing. An additional 12 loci were nominally associated with TC or TG changes. In replication analyses, the APOE rs4420638, TRIB1 rs2954029, and APOA1 rs6589564 associations were confirmed (P <= 0.001). In summary, trait-specific GRSs are robustly associated with 10-yr changes in lipid levels and three individual SNPs were strongly associated with 10-yr changes in lipid levels.

  • 1085. Varga, Tibor V.
    et al.
    Winters, Alexandra H.
    Jablonski, Kathleen A.
    Horton, Edward S.
    Khare-Ranade, Prajakta
    Knowler, William C.
    Marcovina, Santica M.
    Renström, Frida
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden.
    Watson, Karol E.
    Goldberg, Ronald
    Florez, José C.
    Pollin, Toni I.
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA.
    Comprehensive Analysis of Established Dyslipidemia-Associated Loci in the Diabetes Prevention Program2016Inngår i: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 9, nr 6, s. 495-503Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: We assessed whether 234 established dyslipidemia-associated loci modify the effects of metformin treatment and lifestyle intervention (versus placebo control) on lipid and lipid subfraction levels in the Diabetes Prevention Program randomized controlled trial. Methods and Results: We tested gene treatment interactions in relation to baseline-adjusted follow-up blood lipid concentrations (high-density lipoprotein [HDL] and low-density lipoprotein-cholesterol, total cholesterol, and triglycerides) and lipoprotein subfraction particle concentrations and size in 2993 participants with pre-diabetes. Of the previously reported single-nucleotide polymorphism associations, 32.5% replicated at P<0.05 with baseline lipid traits. Trait-specific genetic risk scores were robustly associated (3x10(-4)>P>1.1x10(-16)) with their respective baseline traits for all but 2 traits. Lifestyle modified the effect of the genetic risk score for large HDL particle numbers, such that each risk allele of the genetic risk scores was associated with lower concentrations of large HDL particles at follow-up in the lifestyle arm (beta=-0.11 mu mol/L per genetic risk scores risk allele; 95% confidence interval, -0.188 to -0.033; P=5x10(-3); P-interaction=1x10(-3) for lifestyle versus placebo), but not in the metformin or placebo arms (P>0.05). In the lifestyle arm, participants with high genetic risk had more favorable or similar trait levels at 1-year compared with participants at lower genetic risk at baseline for 17 of the 20 traits. Conclusions: Improvements in large HDL particle concentrations conferred by lifestyle may be diminished by genetic factors. Lifestyle intervention, however, was successful in offsetting unfavorable genetic loading for most lipid traits.

  • 1086.
    Vears, Danya F.
    et al.
    Katholieke Univ Leuven, Dept Publ Hlth & Primary Care, Ctr Biomed Eth & Law, Kapucijnenvoer 35 Box 7001, B-3000 Leuven, Belgium;Leuven Inst Human Genom & Soc, B-3000 Leuven, Belgium.
    Niemiec, Emilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Centrum för forsknings- och bioetik. Univ Bologna, Erasmus Mundus Joint Int Doctoral PhD Degree Prog, Via Galliera 3, I-40121 Bologna, Italy;Univ Turin, Dept Law, Lungo Dora Siena 100A, I-10153 Turin, Italy;Leibniz Univ Hannover, Ctr Eth & Law Life Sci, Klagesmarkt 14-17, D-30159 Hannover, Germany.
    Howard, Heidi Carmen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Centrum för forsknings- och bioetik.
    Borry, Pascal
    Katholieke Univ Leuven, Dept Publ Hlth & Primary Care, Ctr Biomed Eth & Law, Kapucijnenvoer 35 Box 7001, B-3000 Leuven, Belgium;Leuven Inst Human Genom & Soc, B-3000 Leuven, Belgium.
    Analysis of VUS reporting, variant reinterpretation and recontact policies in clinical genomic sequencing consent forms2018Inngår i: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 26, nr 12, s. 1743-1751Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    There are several key unsolved issues relating to the clinical use of next generation sequencing, such as: should laboratories report variants of uncertain significance (VUS) to clinicians and/or patients ? Should they reinterpret VUS in response to growing knowledge in the field ? And should patients be recontacted regarding such results ? We systematically analyzed 58 consent forms in English used in the diagnostic context to investigate their policies for (a) reporting VUS, (b) reinterpreting variants, including who should initiate this, and (c) recontacting patients and the mechanisms for undertaking any recontact. One-third (20/58) of the forms did not mention VUS in any way. Of the 38 forms that mentioned VUS, only half provided some description of what a VUS is. Approximately one-third of forms explicitly stated that reinterpretation of variants for clinical purposes may occur. Less than half mentioned recontact for clinical purposes, with variation as to whether laboratories, patients, or clinicians should initiate this. We suggest that the variability in variant reporting, reinterpretation, and recontact policies and practices revealed by our analysis may lead to diffused responsibility, which could result in missed opportunities for patients or family members to receive a diagnosis in response to updated variant classifications. Finally, we provide some suggestions for ethically appropriate inclusion of policies for reporting VUS, reinterpretation, and recontact on consent forms.

  • 1087. Velie, Brandon D.
    et al.
    Jaederkvist, Kim
    Imsland, Freyja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Viluma, Agnese
    Andersson, Lisa S.
    Mikko, Sofia
    Eriksson, Susanne
    Lindgren, Gabriella
    Frequencies of polymorphisms in myostatin vary in Icelandic horses according to the use of the horses2015Inngår i: Animal Genetics, ISSN 0268-9146, E-ISSN 1365-2052, Vol. 46, nr 4, s. 467-468Artikkel i tidsskrift (Fagfellevurdert)
  • 1088. Venken, Tine
    et al.
    Alaerts, Maaike
    Adolfsson, Rolf
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Van Broeckhoven, Christine
    Del-Favero, Jurgen
    No association of the trace amine-associated receptor 6 with bipolar disorder in a northern Swedish population2006Inngår i: Psychiatric Genetics, ISSN 0955-8829, E-ISSN 1473-5873, Vol. 16, nr 1, s. 1-2Artikkel i tidsskrift (Fagfellevurdert)
  • 1089. Venken, Tine
    et al.
    Claes, Stephan
    Sluijs, Samuël
    Paterson, Andrew D
    van Duijn, Cornelia
    Adolfsson, Rolf
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Del-Favero, Jurgen
    Van Broeckhoven, Christine
    Genomewide scan for affective disorder susceptibility loci in families of a northern Swedish isolated population2005Inngår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 76, nr 2, s. 237-248Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We analyzed nine multigenerational families with ascertained affective spectrum disorders in northern Sweden's geographically isolated population of Vasterbotten. This northern Swedish population, which originated from a limited number of early settlers similar to8,000 years ago, is genetically more homogeneous than outbred populations. In a genomewide linkage analysis, we identified three chromosomal loci with multipoint LOD scores (MPLOD) greater than or equal to2 at 9q31.1-q34.1 (MPLOD 3.24), 6q22.2-q24.2 (MPLOD 2.48), and 2q33-q36 (MPLOD 2.26) under a recessive affected-only model. Follow-up genotyping with application of a 2-cM density simple-tandem-repeat (STR) map confirmed linkage at 9q31.1-q34.1 (MPLOD 3.22), 6q23-q24 (MPLOD 3.25), and 2q33-q36 (MPLOD 2.2). In an initial analysis aimed at identification of the underlying susceptibility genes, we focused our attention on the 9q locus. We fine mapped this region at a 200-kb STR density, with the result of an MPLOD of 3.70. Genealogical studies showed that three families linked to chromosome 9q descended from common founder couples similar to10 generations ago. In this similar to10-generation pedigree, a common ancestral haplotype was inherited by the patients, which reduced the 9q candidate region to 1.6 Mb. Further, the shared haplotype was observed in 4.2% of patients with bipolar disorder with alternating episodes of depression and mania, but it was not observed in control individuals in a patient-control sample from the Vasterbotten isolate. These results suggest a susceptibility locus on 9q31-q33 for affective disorder in this common ancestral region.

  • 1090.
    Verma, Deepti
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Genetic variations in the NALP3 inflammasome: a susceptibility factor for inflammatory diseases2009Licentiatavhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Innate immunity has received impressive attention in the past decade owing to the discovery of the Toll like receptors (TLRs) and the NOD-like receptors (NLRs). While the TLRs specialize in fighting microbes at the cell surface, the NLRs complement by detecting and responding to intracellular microbes. Recently, the non-microbe sensing NLR called inflammasomes, have been identified, which senses metabolic stress as well as certain pathogenic microbes and elicits host’s inflammatory response.

    The NLR, NALP3 (formerly known as cryopyrin) forms a large cytoplasmic complex called the ‘inflammasome’ when NALP3, activated by a stimuli, associates with the adaptor proteins ASC and CARD-8. This interaction leads to the activation of pro-inflammatory caspase-1 which subsequently results in the formation of Interleukin (IL)-1β and IL-18. Mutations in the gene encoding NALP3, termed NLRP3 can lead to its constitutive activation resulting in an uncontrolled production of IL-1β. These mutations have been implicated in hereditary inflammatory diseases, often grouped under cryopyrin associated periodic syndromes (CAPS).

    This thesis describes a patient with a long history of arthritis and antibiotic resistant fever, but without the typical symptoms of CAPS. The patient was found to be a heterozygous carrier of two common polymorphisms Q705K in NLRP3 and C10X in the CARD-8. Experimental studies showed elevated levels of caspase-1 and IL-1β in the patient, and a total clinical remission was achieved by IL-1β blockade. These two polymorphisms combined, were found to occur in approximately 4% of the control population, suggesting the possibility of a genetic predisposition for inflammation in these individuals. Therefore, a cohort of rheumatoid arthritis (RA) patients, where elevated IL-1β could be one of the reasons behind chronic inflammation, was investigated. We found that carrying the combined polymorphisms resulted in increased RA susceptibility and a more severe disease course. Hypothetically, this subgroup of patients might benefit from IL-1β blockade. Additional studies are warranted to elucidate the functional effects of the two polymorphisms and to determine whether they identify a subgroup of patients that could benefit from IL-1 targeted therapy. Given the structural similarity of NALP3 to other NALPs, the possibility of involvement of the alternative, homologous genes cannot be eliminated.

  • 1091. Verweij, Karin J. H.
    et al.
    Mosing, Miriam A.
    Ullén, Fredrik
    Madison, Guy
    Umeå universitet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Individual differences in personality masculinity-femininity: examining the effects of genes, environment, and prenatal hormone transfer2016Inngår i: Twin Research and Human Genetics, ISSN 1832-4274, E-ISSN 1839-2628, Vol. 19, nr 2, s. 87-96Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Males and females score differently on some personality traits, but the underlying etiology of these differences is not well understood. This study examined genetic, environmental, and prenatal hormonal influences on individual differences in personality masculinity-femininity (M-F). We used Big-Five personality inventory data of 9,520 Swedish twins (aged 27 to 54) to create a bipolar M-F personality scale. Using biometrical twin modeling, we estimated the influence of genetic and environmental factors on individual differences in a M-F personality score. Furthermore, we tested whether prenatal hormone transfer may influence individuals' M-F scores by comparing the scores of twins with a same-sex versus those with an opposite-sex co-twin. On average, males scored 1.09 standard deviations higher than females on the created M-F scale. Around a third of the variation in M-F personality score was attributable to genetic factors, while family environmental factors had no influence. Males and females from opposite-sex pairs scored significantly more masculine (both approximately 0.1 SD) than those from same-sex pairs. In conclusion, genetic influences explain part of the individual differences in personality M-F, and hormone transfer from the male to the female twin during pregnancy may increase the level of masculinization in females. Additional well-powered studies are needed to clarify this association and determine the underlying mechanisms in both sexes.

  • 1092.
    Viberg, Jennifer
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Centrum för forsknings- och bioetik.
    Hansson, Mats G.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Centrum för forsknings- och bioetik.
    Langenskiöld, Sophie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Hälsoekonomi.
    Segerdahl, Pär
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Centrum för forsknings- och bioetik.
    Incidental findings: the time is not yet ripe for a policy for biobanks2014Inngår i: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 22, nr 4, s. 437-441Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Incidental findings (IFs) are acknowledged to be among the most important ethical issues to consider in biobank research. Genome-wide association studies and disease-specific genetic research might reveal information about individual participants that are not related to the research purpose, but may be relevant to those participants' future health. In this article, we provide a synopsis of arguments for and against the disclosure of IFs in biobank research. We argue that arguments that do not distinguish between communications about pathogenic conditions and complex genetic risk for diseases fail, as preferences and decisions may be far more complex in the latter case. The principle of beneficence, for example, often supports the communication of incidentally discovered diseases, but if communication of risk is different, the beneficence of such communication is not equally evident. By conflating the latter form of communication with the former, the application of ethical principles to IFs in biobank research sometimes becomes too easy and frictionless. Current empirical surveys of people's desire to be informed about IFs do not provide sufficient guidance because they rely on the same notion of risk communication as a form of communication about actual health and disease. Differently designed empirical research and more reflection on biobank research and genetic risk information is required before ethical principles can be applied to support the adoption of a reasonable and comprehensive policy for handling IFs.

  • 1093.
    Viberg, Jennifer
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Centrum för forsknings- och bioetik.
    Segerdahl, Pär
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Centrum för forsknings- och bioetik.
    Hösterey Ugander, Ulrika
    Clinical Genetics, Sahlgrenska University Hospital.
    Hansson, Mats G.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Centrum för forsknings- och bioetik.
    Langenskiöld, Sophie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Hälsoekonomi. Department of Learning, Informatics, Management and Ethics, Medical Management Centre, Karolinska Institutet..
    Making sense of genetic risk: A qualitative focus-group study of healthy participants in genomic research2018Inngår i: Patient Education and Counseling, ISSN 0738-3991, E-ISSN 1873-5134, Vol. 101, nr 3, s. 422-427Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective

    It is well known that research participants want to receive genetic risk information that is about high risks, serious diseases and potential preventive measures. The aim of this study was to explore, by qualitative means, something less well known: how do healthy research participants themselves make sense of genetic risk information?

    Method

    A phenomenographic approach was chosen to explore research participants’ understanding and assessment of genetic risk. We conducted four focus-group (N = 16) interviews with participants in a research programme designed to identify biomarkers for cardiopulmonary disease.

    Results

    Among the research participants, we found four ways of understanding genetic risk: as a binary concept, as an explanation, as revealing who I am (knowledge of oneself) and as affecting life ahead.

    Conclusion

    Research participants tend to understand genetic risk as a binary concept. This does not necessarily imply a misunderstanding of, or an irrational approach to, genetic risk. Rather, it may have a heuristic function in decision-making.

    Practical implications

    Risk communication may be enhanced by tailoring the communication to the participants’ own lay conceptions. For example, researchers and counselors should address risk in binary terms, maybe looking out for how individual participants search for threshold figures.

  • 1094.
    Vigorito, Elena
    et al.
    Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England..
    Kuchenbaecker, Karoline B.
    Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England..
    Beesley, Jonathan
    QIMR Berghofer Med Res Inst, Dept Genet, Herston Rd, Brisbane, Qld 4029, Australia..
    Adlard, Julian
    Chapel Allerton Hosp, Yorkshire Reg Genet Serv, Leeds, W Yorkshire, England..
    Agnarsson, Bjarni A.
    Univ Hosp Landspitali, Dept Pathol, IS-101 Reykjavik, Iceland.;Univ Iceland, Sch Med, IS-101 Reykjavik, Iceland..
    Andrulis, Irene L.
    Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada..
    Arun, Banu K.
    Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, 1515 Pressler St,CBP 5, Houston, TX USA.;Univ Texas MD Anderson Canc Ctr, Clin Canc Genet Program, 1515 Pressler St,CBP 5, Houston, TX USA..
    Barjhoux, Laure
    Ctr Leon Berard, Batiment Cheney D,28 Rue Laennec, Lyon, France..
    Belotti, Muriel
    Inst Curie, Serv Geneit Oncol, 26 Rue Ulm, Paris 05, France..
    Benitez, Javier
    Spanish Natl Canc Ctr CNIO, Human Genet Grp, Madrid, Spain.;Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Program, Human Genotyping CEGEN Unit, Madrid, Spain..
    Berger, Andreas
    Med Univ Vienna, Dept OB GYN, Vienna, Austria..
    Bojesen, Anders
    Vejle Hosp, Dept Clin Genet, Kabbeltoft 25, Vejle, Denmark..
    Bonanni, Bernardo
    IEO, Div Canc Prevent & Genet, Via Ripamonti 435, I-20141 Milan, Italy..
    Brewer, Carole
    Royal Devon & Exeter Hosp, Dept Clin Genet, Exeter, Devon, England..
    Caldes, Trinidad
    Hosp Clin San Carlos, IdISSC Inst Invest Sanitaria, Mol Oncol Lab, Martin Lagos S-N, Madrid, Spain..
    Caligo, Maria A.
    Univ Pisa, Dept Lab Med, Sect Genet Oncol, Pisa, Italy.;Univ Hosp Pisa, Pisa, Italy..
    Campbell, Ian
    Peter MacCallum Canc Ctr, Div Res, Locked Bag 1,ABeckett St, Melbourne, Vic 8006, Australia..
    Chan, Salina B.
    1600 Div St,C415, San Francisco, CA 94143 USA..
    Claes, Kathleen B. M.
    Univ Ghent, Ctr Med Genet, De Pintelaan 185, B-9000 Ghent, Belgium..
    Cohn, David E.
    Ohio State Univ, Columbus Canc Council GYN Oncol, 3651 Ridge Mill Dr, Columbus, OH 43026 USA..
    Cook, Jackie
    Sheffield Childrens Hosp, Sheffield Clin Genet Serv, Sheffield, S Yorkshire, England..
    Daly, Mary B.
    Fox Chase Canc Ctr, Dept Clin Oncol, 333 Cottman Ave, Philadelphia, PA USA..
    Damiola, Francesca
    Ctr Leon Berard, Batiment Cheney D,28 Rue Laennec, Lyon, France..
    Davidson, Rosemarie
    South Glasgow Univ Hosp, Dept Clin Genet, Glasgow, Lanark, Scotland..
    de Pauw, Antoine
    Inst Curie, Serv Geneit Oncol, 26 Rue Ulm, Paris 05, France..
    Delnatte, Capucine
    ICO Ctr Rene Gauducheau, Unite Oncogenet, Blvd Jacques Monod, F-44805 St Herblain, France..
    Diez, Orland
    Vall Hebron Univ Hosp, VHIO, Oncogenet Grp, Passeig Vall Hebron 119-129, Barcelona, Spain.;Univ Autonoma Barcelona, Passeig Vall Hebron 119-129, Barcelona, Spain..
    Domchek, Susan M.
    Univ Penn, Dept Med, Abramson Canc Ctr, Perelman Sch Med, 3400 Civic Ctr Blvd, Philadelphia, PA 19104 USA..
    Dumont, Martine
    CHU, Quebec Res Ctr, Genom Ctr, 2705 Laurier Blvd, Quebec City, PQ, Canada.;Univ Laval, 2705 Laurier Blvd, Quebec City, PQ, Canada..
    Durda, Katarzyna
    Pomeranian Med Univ, Dept Genet & Pathol, Polabska 4, Szczecin, Poland..
    Dworniczak, Bernd
    Univ Munster, Inst Human Genet, Munster, Germany..
    Easton, Douglas F.
    Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England..
    Eccles, Diana
    Southampton Univ Hosp NHS Trust, Fac Med, Southampton, Hants, England..
    Ardnor, Christina Edwinsdotter
    Umea Univ, Dept Radiat Sci, Oncol, Umea, Sweden..
    Eeles, Ros
    Inst Canc Res, Oncogenet Team, Sutton, Surrey, England.;Royal Marsden NHS Fdn Trust, Sutton, Surrey, England..
    Ejlertsen, Bent
    Univ Copenhagen Hosp, Dept Oncol, Rigshosp, Blegdamsvej 9, DK-2100 Copenhagen, Denmark..
    Ellis, Steve
    Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Strangeways Res Lab, Cambridge, England..
    Evans, D. Gareth
    Univ Manchester, Cent Manchester Univ Hosp NHS Fdn Trust, Inst Human Dev, Genom Med,Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England..
    Feliubadalo, Lidia
    Catalan Inst Oncol, Hereditary Canc Program, Mol Diagnost Unit, IDIBELL Bellvitge Biomed Res Inst, Gran Via lHospitalet,199-203, Barcelona 08908, Spain..
    Fostira, Florentia
    Natl Ctr Sci Res Demokritos, INRASTES Inst Nucl & Radiol Sci & Technol, Mol Diagnost Lab, Patriarchou Gregoriou & Neapoleos Str, Athens, Greece..
    Foulkes, William D.
    McGill Univ, Dept Human Genet, Program Canc Genet, Montreal, PQ, Canada.;McGill Univ, Dept Oncol, Montreal, PQ, Canada..
    Friedman, Eitan
    Chaim Sheba Med Ctr, Inst Human Genet, Susanne Levy Gertner Oncogenet Unit, IL-52621 Ramat Gan, Israel.;Tel Aviv Univ, Sackler Fac Med, IL-69978 Ramat Aviv, Israel..
    Frost, Debra
    Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Strangeways Res Lab, Cambridge, England..
    Gaddam, Pragna
    Mem Sloane Kettering Canc Ctr, Clin Canc Genet Lab, New York, NY USA..
    Ganz, Patricia A.
    Jonsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, UCLA Sch Med, 650 Charles Young Dr South,Room A2-125 HS, Los Angeles, CA 90095 USA.;Jonsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, UCLA Sch Publ Hlth, 650 Charles Young Dr South,Room A2-125 HS, Los Angeles, CA 90095 USA..
    Garber, Judy
    Dana Farber Canc Inst, Canc Risk & Prevent Clin, 450 Brookline Ave, Boston, MA 02115 USA..
    Garcia-Barberan, Vanesa
    Hosp Clin San Carlos, IdISSC Inst Invest Sanitaria, Mol Oncol Lab, Martin Lagos S-N, Madrid, Spain..
    Gauthier-Villars, Marion
    Inst Curie, Serv Geneit Oncol, 26 Rue Ulm, Paris 05, France..
    Gehrig, Andrea
    Univ Wurzburg, Inst Human Genet, Dept Med Genet, Ctr Familial Breast & Ovarian Canc, Wurzburg, Germany..
    Gerdes, Anne-Marie
    Rigshosp 4062, Dept Clin Genet, Blegdamsvej 9, Copenhagen O, Denmark..
    Giraud, Sophie
    Hospices Civils Lyon, Serv Genet Mol & Clin, Lyon 04, France..
    Godwin, Andrew K.
    Univ Kansas, Med Ctr, Dept Pathol & Lab Med, 3901 Rainbow Blvd,4019 Wahl Hall East,MS 3040, Kansas City, KS USA..
    Goldgar, David E.
    Univ Utah, Sch Med, Dept Dermatol, 30 North 1900 East,SOM 4B454, Salt Lake City, UT 84132 USA..
    Hake, Christopher R.
    City Hope Natl Med Ctr, Clin Canc Genet Community Res Network, 1500 East Duarte Rd, Duarte, CA 91010 USA..
    Hansen, Thomas V. O.
    Univ Copenhagen Hosp, Ctr Genom Med, Rigshosp, Blegdamsvej 9, DK-2100 Copenhagen, Denmark..
    Healey, Sue
    QIMR Berghofer Med Res Inst, Dept Genet, Herston Rd, Brisbane, Qld 4029, Australia..
    Hodgson, Shirley
    St Georges Univ London, Med Genet Unit, London, England..
    Hogervorst, Frans B. L.
    Netherlands Canc Inst, Family Canc Clin, POB 90203, NL-1000 BE Amsterdam, Netherlands..
    Houdayer, Claude
    Inst Curie, Serv Geneit Oncol, 26 Rue Ulm, Paris 05, France..
    Hulick, Peter J.
    Univ Chicago, Pritzker Sch Med, Ctr Med Genet, NorthShore Univ Hlth Syst, 1000 Cent St,Suite 620, Evanston, IL 60201 USA..
    Imyanitov, Evgeny N.
    NN Petrov Inst Oncol, St Petersburg 197758, Russia..
    Isaacs, Claudine
    Georgetown Univ, Lombardi Comprehens Canc Ctr, 3800 Reservoir Rd NW, Washington, DC USA..
    Izatt, Louise
    Guys & St Thomas NHS Fdn Trust, Clin Genet, London, England..
    Izquierdo, Angel
    Catalan Inst Oncol, Genet Counseling Unit, Hereditary Canc Program, IDIBGI Inst Invest Biomed Girona, Av Franca S-N, Girona 1707, Spain..
    Jacobs, Lauren
    Mem Sloan Kettering Canc Ctr, Dept Med, Clin Genet Res Lab, 1275 York Ave, New York, NY 10044 USA..
    Jakubowska, Anna
    Pomeranian Med Univ, Dept Genet & Pathol, Polabska 4, Szczecin, Poland..
    Janavicius, Ramunas
    Vilnius Univ Hosp Santariskiu Clin, Hematol Oncol & Transfus Med Ctr, Dept Mol & Regenerat Med, State Res Inst Ctr Innovat Med, Santariskiu St,Zygymantu St 9, Vilnius, Lithuania..
    Jaworska-Bieniek, Katarzyna
    Pomeranian Med Univ, Dept Genet & Pathol, Polabska 4, Szczecin, Poland..
    Jensen, Uffe Birk
    Aarhus Univ Hosp, Dept Clin Genet, Brendstrupgaardsvej 21C, Aarhus N, Denmark..
    John, Esther M.
    Canc Prevent Inst Calif, Dept Epidemiol, 2201 Walnut Ave,Suite 300, Fremont, CA 94538 USA..
    Vijai, Joseph
    Mem Sloan Kettering Canc Ctr, Dept Med, Clin Genet Res Lab, 1275 York Ave, New York, NY 10044 USA..
    Karlan, Beth Y.
    Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, 8700 Beverly Blvd,Suite 290W, Los Angeles, CA 90048 USA..
    Kast, Karin
    Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Dept Obstet & Gynaecol, Dresden, Germany..
    Khan, Sofia
    Univ Helsinki, Dept Obstet & Gynecol, POB 700,Haartmaninkatu 8, Helsinki 00029, Finland.;Helsinki Univ Hosp, Biomed Helsinki, POB 700,Haartmaninkatu 8, Helsinki 00029, Finland..
    Kwong, Ava
    Hong Kong Sanat & Hosp, Canc Genet Ctr, Hong Kong Hereditary Breast Canc Family Registry, Hong Kong, Hong Kong, Peoples R China..
    Laitman, Yael
    Chaim Sheba Med Ctr, Inst Human Genet, Susanne Levy Gertner Oncogenet Unit, IL-52621 Tel Hashomer, Israel. Inst Curie, Inserm U900, Genet Epidemiol Canc team, Mines ParisTech,26 Rue Ulm, F-75248 Paris 05, France..
    Lester, Jenny
    Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, 8700 Beverly Blvd,Suite 290W, Los Angeles, CA 90048 USA..
    Lesueur, Fabienne
    Liljegren, Annelie
    Karolinska Univ Hosp, Dept Oncol, Stockholm, Sweden..
    Lubinski, Jan
    Pomeranian Med Univ, Dept Genet & Pathol, Polabska 4, Szczecin, Poland..
    Mai, Phuong L.
    NCI, DCEG, Clin Genet Branch, NIH, 9609 Med Ctr Dr,Room 6E-454, Bethesda, MD 20892 USA..
    Manoukian, Siranoush
    Ist Nazl Tumori, Fdn IRCCS Ist Ricovero Cura & Caratter Sci, Dept Prevent & Predict Med, Unit Med Genet, Via Giacomo Venezian 1, I-20133 Milan, Italy..
    Mazoyer, Sylvie
    Ctr Leon Berard, Batiment Cheney D,28 Rue Laennec, Lyon, France..
    Meindl, Alfons
    Tech Univ Munich, Klinikum Rechts Isar, Div Tumor Genet, Dept Obstet & Gynaecol, Munich, Germany..
    Mensenkamp, Arjen R.
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, POB 9101, NL-6500 HB Nijmegen, Netherlands..
    Montagna, Marco
    Veneto Inst Oncol IOV IRCCS, Immunol & Mol Oncol Unit, Via Gattamelata 64, Padua, Italy..
    Nathanson, Katherine L.
    Univ Penn, Dept Med, Abramson Canc Ctr, Perelman Sch Med, 3400 Civic Ctr Blvd, Philadelphia, PA 19104 USA..
    Neuhausen, Susan L.
    City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Duarte, CA USA..
    Nevanlinna, Heli
    Univ Helsinki, Dept Obstet & Gynecol, POB 700,Haartmaninkatu 8, Helsinki 00029, Finland.;Helsinki Univ Hosp, Biomed Helsinki, POB 700,Haartmaninkatu 8, Helsinki 00029, Finland..
    Niederacher, Dieter
    Univ Dusseldorf, Univ Hosp Dusseldorf, Dept Obstet & Gynaecol, Dusseldorf, Germany..
    Olah, Edith
    Natl Inst Oncol, Dept Mol Genet, Budapest, Hungary..
    Olopade, Olufunmilayo I.
    Univ Chicago Med, 5841 South Maryland Ave,MC 2115, Chicago, IL 60637 USA..
    Ong, Kai-ren
    Birmingham Womens Hosp Healthcare NHS Trust, West Midlands Reg Genet Serv, Birmingham, W Midlands, England..
    Osorio, Ana
    Spanish Natl Canc Ctr CNIO, Human Genet Grp, Madrid, Spain..
    Park, Sue Kyung
    Seoul Natl Univ, Grad Sch, Dept Biomed Sci, Dept Prevent Med,Coll Med, 103 Daehak Ro, Seoul 110799, South Korea.;Seoul Natl Univ, Canc Res Inst, 103 Daehak Ro, Seoul 110799, South Korea..
    Paulsson-Karlsson, Ylva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Pedersen, Inge Sokilde
    Aalborg Univ Hosp, Sect Mol Diagnost, Dept Biochem, Reberbansgade 15, Aalborg, Denmark..
    Peissel, Bernard
    Ist Nazl Tumori, Fdn IRCCS Ist Ricovero Cura & Caratter Sci, Dept Prevent & Predict Med, Unit Med Genet, Via Giacomo Venezian 1, I-20133 Milan, Italy..
    Peterlongo, Paolo
    Inst Mol Oncol, IFOM, FIRC Italian Fdn Canc Res, IFOM-IEO Campus,Via Adamello 16, I-20139 Milan, Italy..
    Pfeiler, Georg
    Med Univ Vienna, Wahringer Gurtel 18-20, A-1090 Vienna, Austria..
    Phelan, Catherine M.
    H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL USA..
    Piedmonte, Marion
    Roswell Pk Canc Inst, NRG Oncol, Stat & Data Management Ctr, Elm St & Carlton St, Buffalo, NY 14263 USA..
    Poppe, Bruce
    Univ Ghent, Ctr Med Genet, De Pintelaan 185, B-9000 Ghent, Belgium..
    Angel Pujana, Miquel
    Catalan Inst Oncol, IDIBELL Bellvitge Biomed Res Inst, Translat Res Lab, Barcelona, Spain..
    Radice, Paolo
    Ist Nazl Tumori, Unit Mol Bases Genet Risk & Genet Testing, Dept Prevent & Predicted Med, Fdn IRCCS Ist Ricovero Cura Caratter Sci, Amaedeolab,Via GA Amadeo 42, I-20133 Milan, Italy..
    Rennert, Gad
    Clalit Natl Israeli Canc Control Ctr, 7 Michal St, IL-34362 Haifa, Israel.;Carmel Hosp, Dept Community Med & Epidemiol, 7 Michal St, IL-34362 Haifa, Israel.;B Rappaport Fac Med, 7 Michal St, IL-34362 Haifa, Israel..
    Rodriguez, Gustavo C.
    Univ Chicago, NorthShore Univ HealthSyst, Div Gynecol Oncol, 2650 Ridge Ave Suite 1507 Walgreens, Evanston, IL 60201 USA..
    Rookus, Matti A.
    Netherlands Canc Inst, Dept Epidemiol, POB 90203, NL-1000 BE Amsterdam, Netherlands..
    Ross, Eric A.
    Fox Chase Canc Ctr, Biostat & Bioinformat Facil, 333 Coltman Ave, Philadelphia, PA 19111 USA..
    Schmutzler, Rita Katharina
    Univ Hosp Cologne, Fac Med, Ctr Hereditary Breast & Ovarian Canc, Cologne, Germany..
    Simard, Jacques
    CHU, Quebec Res Ctr, Genom Ctr, 2705 Laurier Blvd, Quebec City, PQ, Canada.;Univ Laval, 2705 Laurier Blvd, Quebec City, PQ, Canada..
    Singer, Christian F.
    Med Univ Vienna, Dept OB GYN, A-1090 Vienna, Austria.;Waehringer Guertel 18-20, A-1090 Vienna, Austria..
    Slavin, Thomas P.
    City Hope Natl Med Ctr, Clin Canc Genet, 1500 East Duarte Rd, Duarte, CA 91010 USA..
    Soucy, Penny
    CHU, Quebec Res Ctr, Genom Ctr, 2705 Laurier Blvd, Quebec City, PQ, Canada.;Univ Laval, 2705 Laurier Blvd, Quebec City, PQ, Canada..
    Southey, Melissa
    Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Parkville, Vic, Australia..
    Steinemann, Doris
    Hannover Med Sch, Inst Cell & Mol Pathol, Hannover, Germany..
    Stoppa-Lyonnet, Dominique
    Inst Curie, Serv Geneit Oncol, 26 Rue Ulm, Paris 05, France..
    Sukiennicki, Grzegorz
    Pomeranian Med Univ, Dept Genet & Pathol, Polabska 4, Szczecin, Poland..
    Sutter, Christian
    Univ Heidelberg Hosp, Dept Human Genet, Inst Human Genet, Heidelberg, Germany..
    Szabo, Csilla I.
    NHGRI, NIH, Bldg 50,Room 5312,50 South Dr,MSC 004, Bethesda, MD 20892 USA..
    Tea, Muy-Kheng
    Med Univ Vienna, Dept OB GYN, A-1090 Vienna, Austria.;Waehringer Guertel 18-20, A-1090 Vienna, Austria..
    Teixeira, Manuel R.
    Portuguese Oncol Inst, Dept Genet, Rua Dr Antonio Bernardino de Almeida, P-4200072 Oporto, Portugal..
    Teo, Soo-Hwang
    Sime Darby Med Ctr, Canc Res Initiat Fdn, 1 Jalan SS12-1A, Subang Jaya 47500, Malaysia..
    Terry, Mary Beth
    Columbia Univ, Dept Epidemiol, New York, NY USA..
    Thomassen, Mads
    Odense Univ Hosp, Dept Clin Genet, Sonder Blvd 29, Odense C, Denmark..
    Tibiletti, Maria Grazia
    Osped Circolo Univ Insubria, UO Anat Patol, Via O Rossi 9, I-21100 Varese, Italy..
    Tihomirova, Laima
    Latvian Biomed Res & Study Ctr, Ratsupites Str 1, Riga, Latvia..
    Tognazzo, Silvia
    Veneto Inst Oncol IOV IRCCS, Immunol & Mol Oncol Unit, Via Gattamelata 64, Padua, Italy..
    van Rensburg, Elizabeth J.
    Univ Pretoria, Dept Genet, Canc Genet Lab, Private Bag X323, ZA-0007 Arcadia, South Africa..
    Varesco, Liliana
    AOU San Martino IST Ist Nazl Ric Cancro, IRCCS, Dept Epidemiol Prevent & Special Funct, Unit Hereditary Canc, Largo Rosanna Benzi 10, I-16132 Genoa, Italy..
    Varon-Mateeva, Raymonda
    Charite, Inst Human Genet, Campus Virchov Klinikum, Berlin, Germany..
    Vratimos, Athanassios
    Natl Ctr Sci Res Demokritos, INRASTES Inst Nucl & Radiol Sci & Technol, Mol Diagnost Lab, Patriarchou Gregoriou & Neapoleos Str, Athens, Greece..
    Weitzel, Jeffrey N.
    City Hope Natl Med Ctr, Clin Canc Genet, 1500 East Duarte Rd, Duarte, CA 91010 USA..
    McGuffog, Lesley
    Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England..
    Kirk, Judy
    Westmead Hosp, Familial Canc Serv, Hawkesbury Rd,POB 533, Wentworthville, NSW 2145, Australia..
    Toland, Amanda Ewart
    Ohio State Univ, Dept Internal Med, Div Human Canc Genet, 998 Biomed Res Tower, Columbus, OH 43210 USA.;Ohio State Univ, Ctr Comprehens Canc, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA..
    Hamann, Ute
    German Canc Res Ctr, Mol Genet Breast Canc, Neuenheimer Feld 580, D-69120 Heidelberg, Germany..
    Lindor, Noralane
    Mayo Clin, Dept Hlth Sci Res, 13400 E Scottsdale Blvd, Scottsdale, AZ USA..
    Ramus, Susan J.
    Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA..
    Greene, Mark H.
    NCI, DCEG, Clin Genet Branch, NIH, 9609 Med Ctr Dr,Room 6E-454, Bethesda, MD 20892 USA..
    Couch, Fergus J.
    Mayo Clin, Dept Lab Med & Pathol, 200 First St SW, Rochester, MN USA.;Mayo Clin, Hlth Sci Res, 200 First St SW, Rochester, MN USA..
    Offit, Kenneth
    Mem Sloan Kettering Canc Ctr, Clin Genet Res Lab, Dept Med Canc Biol & Genet, 1275 York Ave, New York, NY 10044 USA..
    Pharoah, Paul D. P.
    Univ Cambridge, Dept Oncol, Cambridge, England..
    Chenevix-Trench, Georgia
    QIMR Berghofer Med Res Inst, Dept Genet, Herston Rd, Brisbane, Qld 4029, Australia..
    Antoniou, Antonis C.
    Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England..
    Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers2016Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 7, artikkel-id e0158801Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95% CI: 0.68 to 0.79, p-value 2x 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95% CI: 0.59 to 0.80, p-value 1.0 x 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.

  • 1095.
    Vikberg, Ann-Louise
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Vooder, Tonu
    Lokk, Kaie
    Annilo, Tarmo
    Golovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Mutation analysis and copy number alterations of KIF23 in non-small-cell lung cancer exhibiting KIF23 over-expression2017Inngår i: OncoTargets and Therapy, ISSN 1178-6930, Vol. 10, s. 4969-4979Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    KIF23 was recently suggested to be a potential molecular target for the treatment of lung cancer. This proposal is based on elevated expression of KIF23 in several tumors affecting breast, lung, brain, and liver, and also on the presence of KIF23 mutations in melanoma and colorectal cancer. Recently, we identified a mutation in the KIF23 gene causing a rare hereditary form of dyserythropoietic anemia (CDA III) with predisposition to blood cancer. We suggested that KIF23 overexpression in tumors might be due to the presence of activating somatic mutations, and therefore, mutation screening of the KIF23 in 15 non-small-cell lung cancer (NSCLC) cases with elevated expression level of KIF23 was undertaken. Eight sequence variants were found in all samples. Furthermore, one variant was present in two cases, and one variant was case specific. Nine variants were previously reported while one variant lacks frequency information. Nine of ten cases available for single nucleotide polymorphism-array analysis demonstrated aberrant karyotypes with additional copy of entire chromosome 15. Thus, no activating somatic mutations in coding regions of the KIF23 were found. Furthermore, no mutations were detected in cell cycle genes homology region in KIF23 promoter responsible for p53-dependent repression of KIF23 expression. We showed that the elevated level of KIF23 could be due to additional copy of chromosome 15 demonstrated in 90% of NSCLC cases analyzed in this study. Considering the crucial role of KIF23 in the final step of mitosis, the gene is a potential molecular marker, and for better understanding of its role in cancer development, more tumors should be analyzed.

  • 1096.
    Villesen P, Gertsch PJ, Boomsma JJ
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för evolutionsbiologi. CONSERVATION BIOLOGY AND GENETICS.
    Microsatellite primers for fungus-growing ants.2002Inngår i: Molecular Ecology Notes, Vol. 2, s. 320-322Artikkel i tidsskrift (Fagfellevurdert)
  • 1097. Vizoso, Miguel
    et al.
    Ferreira, Humberto J.
    Lopez-Serra, Paula
    Javier Carmona, F.
    Martinez-Cardus, Anna
    Girotti, Maria Romina
    Villanueva, Alberto
    Guil, Sonia
    Moutinho, Catia
    Liz, Julia
    Portela, Anna
    Heyn, Holger
    Moran, Sebastian
    Vidal, August
    Martinez-Iniesta, Maria
    Manzano, Jose L.
    Teresa Fernandez-Figueras, Maria
    Elez, Elena
    Munoz-Couselo, Eva
    Botella-Estrada, Rafael
    Berrocal, Alfonso
    Pontén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    van den Oord, Joost
    Gallagher, William M.
    Frederick, Dennie T.
    Flaherty, Keith T.
    McDermott, Ultan
    Lorigan, Paul
    Marais, Richard
    Esteller, Manel
    Epigenetic activation of a cryptic TBC1D16 transcript enhances melanoma progression by targeting EGFR2015Inngår i: Nature Medicine, ISSN 1078-8956, E-ISSN 1546-170X, Vol. 21, nr 7, s. 741-+Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Metastasis is responsible for most cancer-related deaths, and, among common tumor types, melanoma is one with great potential to metastasize. Here we study the contribution of epigenetic changes to the dissemination process by analyzing the changes that occur at the DNA methylation level between primary cancer cells and metastases. We found a hypomethylation event that reactivates a cryptic transcript of the Rab GTPase activating protein TBC1D16 (TBC1D16-47 kDa; referred to hereafter as TBC1D16-47KD) to be a characteristic feature of the metastatic cascade. This short isoform of TBC1D16 exacerbates melanoma growth and metastasis both in vitro and in vivo. By combining immunoprecipitation and mass spectrometry, we identified RAB5C as a new TBC1D16 target and showed that it regulates EGFR in melanoma cells. We also found that epigenetic reactivation of TBC1D16-47KD is associated with poor clinical outcome in melanoma, while conferring greater sensitivity to BRAF and MEK inhibitors.

  • 1098.
    Voisin, Sarah
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap. Biologie du Developpement et Reproduction, INRA, Jouy-en-Josas.
    Bioinformatic and Biostatistic Analysis of Epigenetic Data from Humans and Mice in the Context of Obesity and its Complications2016Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Worldwide obesity has more than doubled since 1980 and at least 2.8 million people die each year as a result of being overweight or obese. An elevated body weight is the result of the interplay between susceptibility gene variants and an obesogenic environment, and recent evidence shows that epigenetic processes are likely involved. The growing availability of high-throughput technologies has made it possible to assess quickly the entire epigenome of large samples at a relatively low cost. As a result, vast amounts of data have been generated and researchers are now confronted to both bioinformatic and biostatistic challenges to make sense of such data in the context of obesity and its complications. In this doctoral thesis, we explored associations between the human blood methylome and obesity-associated gene variants as well as dietary fat quality and quantity. We used well described preprocessing techniques and statistical methods, along with publicly available data from consortiums and other research groups, as well as tools for pathway enrichment and chromatin state inference. We found associations between obesityassociated SNPs and methylation levels at proximal promoters and enhancers, and some of these associations were replicated in multiple tissues. We also found that contrary to dietary fat quantity, dietary fat quality associates with methylation levels in the promoter of genes involved in metabolic pathways. Then, using a gene-targeted approach, we looked at the impact of an acute environmental stress (sleep loss) on the methylation and transcription levels of circadian clock genes in skeletal muscle and adipose tissue of healthy men. We found that a single night of wakefulness can alter the epigenetic and transcriptional profile of core circadian clock genes in a tissue-specific manner. Finally, we looked at the effects of chronic maternal obesity and subsequent weight loss on the transcription of epigenetic machinery genes in the fetus and placenta of mice. We found that the transcription of epigenetic machinery genes is highly sensitive to maternal weight trajectories, and particularly those of the histone acetylation pathway. Overall, this thesis demonstrated that genetics, obesogenic environment stimuli and maternal programming impact epigenetic marks at genomic locations relevant in the pathogenesis of obesity.

  • 1099.
    Voisin, Sarah
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Almén, Markus S
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Moschonis, George
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Chrousos, George P
    Manios, Yannis
    Schiöth, Helgi B
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Dietary fat quality impacts genome-wide DNA methylation patterns in a cross-sectional study of Greek preadolescents2015Inngår i: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 23, s. 654-662Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The type and the amount of dietary fat have a significant influence on the metabolic pathways involved in the development of obesity, metabolic syndrome, diabetes type 2 and cardiovascular diseases. However, it is unknown to what extent this modulation is achieved through DNA methylation. We assessed the effects of cholesterol intake, the proportion of energy intake derived from fat, the ratio of polyunsaturated fatty acids (PUFA) to saturated fatty acids (SFA), the ratio of monounsaturated fatty acids (MUFA) to SFA, and the ratio of MUFA+PUFA to SFA on genome-wide DNA methylation patterns in normal-weight and obese children. We determined the genome-wide methylation profile in the blood of 69 Greek preadolescents (∼10 years old) as well as their dietary intake for two consecutive weekdays and one weekend day. The methylation levels of one CpG island shore and four sites were significantly correlated with total fat intake. The methylation levels of 2 islands, 11 island shores and 16 sites were significantly correlated with PUFA/SFA; of 9 islands, 26 island shores and 158 sites with MUFA/SFA; and of 10 islands, 40 island shores and 130 sites with (MUFA+PUFA)/SFA. We found significant gene enrichment in 34 pathways for PUFA/SFA, including the leptin pathway, and a significant enrichment in 5 pathways for (MUFA+PUFA)/SFA. Our results suggest that specific changes in DNA methylation may have an important role in the mechanisms involved in the physiological responses to different types of dietary fat.European Journal of Human Genetics advance online publication, 30 July 2014; doi:10.1038/ejhg.2014.139.

  • 1100.
    von der Heyde, Benedikt
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Emmanouilidou, Anastasia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Klingström, Tiffany
    Mazzaferro, Eugenia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Vicenzi, Silvia
    Jumaa, Sitaf
    Dethlefsen, Olga
    Snieder, Harold
    de Geus, Eco
    Ingelsson, Erik
    Allalou, Amin
    Brooke, Hannah
    den Hoed, Marcel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Translating GWAS-identified loci for cardiac rhythm and rate using an in vivo, image-based, large-scale genetic screen in zebrafishInngår i: Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A meta-analysis of genome-wide association studies (GWAS) identified eight loci that are associated with heart rate variability (HRV) in data from 53,174 individuals. However, functional follow-up experiments - aiming to identify and characterize causal genes in these loci - have not yet been performed. We developed an image- and CRISPR-Cas9-based pipeline to systematically characterize candidate genes for HRV in live zebrafish embryos and larvae. Nine zebrafish orthologues of six human candidate genes were targeted simultaneously in fertilized eggs from fish that transgenically express GFP on smooth muscle cells (Tg(acta2:GFP)), to visualize the beating heart using a fluorescence microscope. An automated analysis of repeated 30s recordings of 381 live zebrafish atria at 2 and 5 days post-fertilization highlighted genes that influence HRV (hcn4 and kiaa1755); heart rate (rgs6 and hcn4) and the risk of sinoatrial pauses and arrests (hcn4). Hence, our screen confirmed the role of established genes for heart rate (rgs6 and hcn4), and highlighted a novel gene implicated in HRV (kiaa1755).

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