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  • 1.
    Ghaneh, Paula
    et al.
    Univ Liverpool, Liverpool Canc Res, UK Canc Trials Unit, Liverpool, Merseyside, England;Royal Liverpool & Broadgreen Univ Hosp NHS Trust, Dept Surg, Liverpool, Merseyside, England.
    Kleeff, Jorg
    Royal Liverpool & Broadgreen Univ Hosp NHS Trust, Dept Surg, Liverpool, Merseyside, England;Martin Luther Univ Halle Wittenberg, Univ Hosp Halle, Dept Surg, Halle, Germany.
    Halloran, Christopher M.
    Royal Liverpool & Broadgreen Univ Hosp NHS Trust, Dept Surg, Liverpool, Merseyside, England.
    Raraty, Michael
    Royal Liverpool & Broadgreen Univ Hosp NHS Trust, Dept Surg, Liverpool, Merseyside, England.
    Jackson, Richard
    Univ Liverpool, Liverpool Canc Res, UK Canc Trials Unit, Liverpool, Merseyside, England.
    Melling, James
    Royal Liverpool & Broadgreen Univ Hosp NHS Trust, Dept Surg, Liverpool, Merseyside, England.
    Jones, Owain
    Royal Liverpool & Broadgreen Univ Hosp NHS Trust, Dept Surg, Liverpool, Merseyside, England.
    Palmer, Daniel H.
    Univ Liverpool, Liverpool Canc Res, UK Canc Trials Unit, Liverpool, Merseyside, England.
    Cox, Trevor F.
    Univ Liverpool, Liverpool Canc Res, UK Canc Trials Unit, Liverpool, Merseyside, England.
    Smith, Chloe J.
    Univ Liverpool, Liverpool Canc Res, UK Canc Trials Unit, Liverpool, Merseyside, England.
    O'Reilly, Derek A.
    Manchester Royal Infirm, Dept Surg, Manchester, Lancs, England.
    Izbicki, Jakob R.
    Univ Hamburg, Dept Surg, Med Inst UKE, Hamburg, Germany.
    Scarfe, Andrew G.
    Univ Alberta, Dept Oncol, Div Med Oncol, Cross Canc Inst 2228, Edmonton, AB, Canada.
    Valle, Juan W.
    The Christie, Dept Med Oncol, Manchester, Lancs, England.
    McDonald, Alexander C.
    Beatson West Scotland Canc Ctr, Dept Med Oncol, Glasgow, Lanark, Scotland.
    Carter, Ross
    Glasgow Royal Infirm, Dept Surg, Glasgow, Lanark, Scotland.
    Tebbutt, Niall C.
    Austin Hlth, Dept Med Oncol, Melbourne, Vic, Australia.
    Goldstein, David
    Univ New South Wales, Prince Wales Hosp, Dept Med Oncol, Sydney, NSW, Australia;Univ New South Wales, Sch Clin, Sydney, NSW, Australia.
    Padbury, Robert
    Flinders Med Ctr, Dept Surg, Adelaide, SA, Australia.
    Shannon, Jennifer
    Nepean Canc Ctr, Dept Med Oncol, Nepean, ON, Australia;Univ Sydney, Sydney, NSW, Australia.
    Dervenis, Christos
    Agia Olga Hosp, Dept Surg, Athens, Greece.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Deakin, Mark
    Univ Hosp North Staffordshire, Dept Surg, Stoke On Trent, Staffs, England.
    Anthoney, Alan
    Univ Leeds, St Jamess Univ Hosp, Div Oncol, Leeds, W Yorkshire, England.
    Lerch, Markus M.
    Univ Med Greifswald, Dept Med A, Greifswald, Germany.
    Mayerle, Julia
    Univ Med Greifswald, Dept Med A, Greifswald, Germany.
    Olah, Attila
    Petz Aladar Hosp, Dept Surg, Gyor, Hungary.
    Rawcliffe, Charlotte L.
    Univ Liverpool, Liverpool Canc Res, UK Canc Trials Unit, Liverpool, Merseyside, England.
    Campbell, Fiona
    Heidelberg Univ, Dept Surg, Heidelberg, Germany.
    Strobel, Oliver
    Royal Liverpool & Broadgreen Univ Hosp NHS Trust, Dept Pathol, Liverpool, Merseyside, England.
    Buechler, Markus W.
    Royal Liverpool & Broadgreen Univ Hosp NHS Trust, Dept Pathol, Liverpool, Merseyside, England.
    Neoptolemos, John P.
    Univ Liverpool, Liverpool Canc Res, UK Canc Trials Unit, Liverpool, Merseyside, England;Royal Liverpool & Broadgreen Univ Hosp NHS Trust, Dept Surg, Liverpool, Merseyside, England;Heidelberg Univ, Dept Surg, Heidelberg, Germany.
    The Impact of Positive Resection Margins on Survival and Recurrence Following Resection and Adjuvant Chemotherapy for Pancreatic Ductal Adenocarcinoma2019In: Annals of Surgery, ISSN 0003-4932, E-ISSN 1528-1140, Vol. 269, no 3, p. 520-529Article in journal (Refereed)
    Abstract [en]

    Objective and Background: Local and distant disease recurrence are frequently observed following pancreatic cancer resection, but an improved understanding of resection margin assessment is required to aid tailored therapies

    Methods: Analyses were carried out to assess the association between clinical characteristics and margin involvement as well as the effects of individual margin involvement on site of recurrence and overall and recurrence-free survival using individual patient data from the European Study Group for Pancreatic Cancer (ESPAC)-3 randomized controlled trial.

    Results: There were 1151 patients, of whom 505 (43.9%) had an RI resection. The median and 95% confidence interval (CI) overall survival was 24.9 (22.9-27.2) months for 646 (56.1%) patients with resection margin negative R0 >1 mm) tumors, 25.4 (21.6 30.4) months for 146 (12.7%) patients with RI <1 mm positive resection margins, and 18.7 (17.2-21.1) months for 359 (31.2%) patients with R1-direct positive margins (P < 0.001). In multivariable analysis, overall R 1-direct tumor margins, poor tumor differentiation, positive lymph node status, WHO performance status ≥ 1, maximum tumor size, and RI-direct posterior resection margin were all independently significantly associated with reduced overall and recurrence-free survival. Competing risks analysis showed that overall R1-direct positive resection margin status, positive lymph node status. WHO performance status 1, and R1-direct positive superior mesenteric/medial margin resection status were all significantly associated with local recurrence.

    Conclusions: RI-direct resections were associated with significantly reduced overall and recurrence-free survival following pancreatic cancer resection. Resection margin involvement was also associated with an increased risk for local recurrence.

  • 2.
    Jones, Robert P.
    et al.
    Royal Liverpool Univ Hosp, Liverpool, Merseyside, England.
    Psarelli, Eftychia-Eirini
    Univ Liverpool, Liverpool, Merseyside, England.
    Jackson, Richard
    Univ Liverpool, Liverpool, Merseyside, England.
    Ghaneh, Paula
    Royal Liverpool Univ Hosp, Liverpool, Merseyside, England;Univ Liverpool, Liverpool, Merseyside, England.
    Halloran, Christopher M.
    Royal Liverpool Univ Hosp, Liverpool, Merseyside, England;Univ Liverpool, Liverpool, Merseyside, England.
    Palmer, Daniel H.
    Univ Liverpool, Liverpool, Merseyside, England;Clatterbridge Canc Ctr, Wirral, Merseyside, England.
    Campbell, Fiona
    Royal Liverpool Univ Hosp, Liverpool, Merseyside, England.
    Valle, Juan W.
    Univ Manchester Christie, Manchester, Lancs, England.
    Faluyi, Olusola
    Clatterbridge Canc Ctr, Wirral, Merseyside, England.
    O'Reilly, Derek A.
    Manchester Univ Fdn Trust, Manchester, Lancs, England.
    Cunningham, David
    Royal Marsden Hosp, London, England.
    Wadsley, Jonathan
    Weston Pk Hosp, Sheffield, S Yorkshire, England.
    Darby, Suzanne
    Weston Pk Hosp, Sheffield, S Yorkshire, England.
    Meyer, Tim
    Royal Free Hosp, London, England.
    Gillmore, Roopinder
    Royal Free Hosp, London, England.
    Anthoney, Alan
    St James Univ Hosp, Leeds, W Yorkshire, England.
    Lind, Pehr
    Karolinska Inst, Clin Res Sormland, Stockholm, Sweden;Malarsjukhuset Hosp, Eskilstuna, Sweden.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Falk, Stephen
    Bristol Haematol & Oncol Ctr, Bristol, Avon, England.
    Izbicki, Jakob R.
    Univ Hamburg, Med Inst UKE, Hamburg, Germany.
    Middleton, Gary William
    Royal Surrey Cty Hosp, Guildford, Surrey, England.
    Cummins, Sebastian
    Royal Surrey Cty Hosp, Guildford, Surrey, England.
    Ross, Paul J.
    Guys Hosp, London, England.
    Wasan, Harpreet
    Hammersmith Hosp, London, England.
    McDonald, Alec
    Beatson West Scotland Canc Ctr, Glasgow, Lanark, Scotland.
    Crosby, Tom
    Velindre Hosp, Cardiff, S Glam, Wales.
    Ting, Yuk
    Queen Elizabeth Hosp, Birmingham, W Midlands, England.
    Patel, Kinnari
    Churchill Hosp, Oxford, England.
    Sherriff, David
    Derriford Hosp, Plymouth, Devon, England.
    Soomal, Rubin
    Jersey Gen Hosp, Jersey, England.
    Borg, David
    Skane Univ Hosp, Lund, Sweden;Skane Univ Hosp, Malmo, Sweden.
    Sothi, Sharmila
    Univ Hosp Coventry, Coventry, W Midlands, England.
    Hammel, Pascal
    Hop Beaujon, Clichy, France.
    Lerch, Markus M.
    Greifswald Univ, Med, Greifswald, Germany.
    Mayerle, Julia
    Greifswald Univ, Med, Greifswald, Germany;Ludwig Maximilians Univ Munchen, Univ Hosp Munich, Munich, Germany.
    Tjaden, Christine
    Heidelberg Univ, Heidelberg, Germany.
    Strobel, Oliver
    Heidelberg Univ, Heidelberg, Germany.
    Hackert, Thilo
    Heidelberg Univ, Heidelberg, Germany.
    Buchler, Markus W.
    Heidelberg Univ, Heidelberg, Germany.
    Neoptolemos, John P.
    Heidelberg Univ, Heidelberg, Germany.
    Hill, Mark
    Kent Oncol Ctr, Maidstone, Kent, England.
    Corrie, Pippa
    Addenbrookes Hosp, Cambridge, England.
    Hickish, Tamas
    Royal Bournemouth Hosp, Bournemouth, Dorset, England.
    Napier, Mark
    North Devon Dist Hosp Barnstaple, Barnstaple, England.
    Slater, Sarah
    St Bartholomews Hosp, London, England.
    Valle, Juan
    North Manchester Gen Hosp, Manchester, Lancs, England.
    Shablak, Alaaeldin
    Salisbury Dist Hosp, Salisbury, Wilts, England.
    Cunnell, Michelle
    Nottingham City Hosp, Nottingham, England.
    Guimbaud, Rosine
    CHU Purpan, Toulouse, France.
    Roques, Tom
    Norfolk & Norwich Univ Hosp, Norwich, Norfolk, England.
    Iveson, Tim
    Southampton Gen Hosp, Southampton, Hants, England.
    Jamil, Arshad
    Univ Hosp North Staffordshire, Stoke, England;Leighton Hosp, Crewe, England.
    Robinson, Angus
    Conquest Hosp, Hastings, England.
    Garcia-Alonso, Angel
    Glan Clwyd Gen Hosp, Rhyl, Wales.
    Chang, David
    Royal Blackburn Hosp, Blackburn, Lancs, England.
    Tsang, David
    Southend Hosp, Westcliff On Sea, England.
    Wadd, Nick
    James Cook Univ Hosp, Middlesbrough, Cleveland, England.
    Wall, Lucy
    Western Gen Hosp, Edinburgh, Midlothian, Scotland.
    Nielsen, Niels Hilmer
    Norrlands Univ Sjukhus, Umea, Sweden.
    Lerch, Markus
    Ernst Moritz Arndt Univ Greifswald, Greifswald, Germany.
    Mehta, Ajay
    Royal Preston Hosp, Preston, Lancs, England.
    Sivaramalingam, Muthiah
    Blackpool Victoria Hosp, Blackpool, England.
    Fyfe, David
    Royal Lancaster Infirm, Lancaster, England.
    Osborne, Richard
    Poole Hosp, Poole, Dorset, England.
    Blesing, Claire
    Great Western Hosp, Swindon, Wilts, England.
    Bulusu, Venkata Ramesh
    Bedford Hosp, Bedford, England.
    Rathbone, Emma
    Huddersfield Royal Infirm, Huddersfield, W Yorkshire, England.
    Seitz, Jean-Francois
    CHU La Timone, Marseille, France.
    Beaumont, Erica
    Yeovil Dist Hosp, Yeovil, England.
    Dernedde, Ulrike
    James Paget Hosp, Great Yarmouth, England.
    McAdam, Karen
    Peterborough City Hosp, Peterborough, Cambs, England.
    Dimopoulos, Prokopios
    St Marys Hosp, Newport, Wight, England.
    Cominos, Mathilda
    Queen Elizabeth Queen Mother Hosp, Margate, England;William Harvey Hosp, Ashford, Kent, England.
    Askill, Colin
    Singleton Hosp, Swansea, England.
    Piwowar, Andrzej
    Vastmanlands Sjukhus, Vasteras, Sweden.
    Bachet, Jean-Baptiste
    Grp Hosp Pitie Salpetriere, Paris, France.
    Sumpter, Kate
    Freeman Rd Hosp, Newcastle, England.
    Raouf, Sherif
    Queens Hosp, Romford, Essex, England.
    Nicoll, Jonathan
    Cumberland Infirm, Carlisle, England.
    Rees, Charlotte
    Basingstoke & North Hampshire Hosp, Basingstoke, Hants, England.
    Dhinakaran, Kathirvelu
    Royal Shrewsbury Hosp, Shrewsbury, Salop, England.
    Haux, Johan
    Univ Sjukhuset Linkoping, Linkoping, Sweden.
    Bengrine-Lefevre, Leila
    Hop St Antoine, Paris, France.
    Terrebonne, Eric
    Hop Haut Leveque, Pessac, France.
    Shankland, Catherine
    Royal Derby Hosp, Derby, England.
    Palmer, Cheryl
    Hinchingbrooke Hosp, Huntingdon, England.
    Medley, Louise
    Torbay Hosp, Torquay, England.
    Toy, Elizabeth
    Royal Devon & Exeter Hosp, Exeter, Devon, England.
    Kaur, Jasvinder
    Darent Valley Hosp, Dartford, England.
    Gupta, Kamalnayan
    Alexandra Hosp, Redditch, England.
    Cheeseman, Sue
    Bradford Royal Infirm, Bradford, W Yorkshire, England.
    Patterson, Daniel
    West Suffolk Hosp, Bury St Edmunds, Suffolk, England.
    Candish, Charles
    Cheltenham Gen Hosp, Cheltenham, Glos, England.
    Thompson, Joyce
    Heartlands Hosp, Birmingham, W Midlands, England.
    Coxon, Fareeda
    Bishop Auckland Gen Hosp, Bishop Auckland, England;Darlington Mem Hosp, Darlington, Durham, England.
    Connolly, Caroline
    Stafford Hosp, Stafford, England.
    McPhail, Neil
    Raigmore Hosp, Inverness, Scotland.
    Williams, Rachel
    Ysbyty Gwynedd, Bangor, Gwynedd, Wales.
    Flygare, Petra
    Lanssjukhuset Sundsvall, Sundsvall, Sweden.
    Elmlund, Mattias
    Cent Sjukhuset Karlstad, Karlstad, Sweden.
    Artru, Pascal
    Hop Prive Jean Mermoz, Lyon, France.
    Millat, Bertrand
    Hop St Eloi, Montpellier, France.
    Patterns of Recurrence After Resection of Pancreatic Ductal Adenocarcinoma: A Secondary Analysis of the ESPAC-4 Randomized Adjuvant Chemotherapy Trial2019In: JAMA Surgery, ISSN 2168-6254, E-ISSN 2168-6262, Vol. 154, no 11, p. 1038-1048Article in journal (Refereed)
    Abstract [en]

    Importance: The patterns of disease recurrence after resection of pancreatic ductal adenocarcinoma with adjuvant chemotherapy remain unclear.

    Objective: To define patterns of recurrence after adjuvant chemotherapy and the association with survival.

    Design, Setting, and Participants: Prospectively collected data from the phase 3 European Study Group for Pancreatic Cancer 4 adjuvant clinical trial, an international multicenter study. The study included 730 patients who had resection and adjuvant chemotherapy for pancreatic cancer. Data were analyzed between July 2017 and May 2019.

    Interventions: Randomization to adjuvant gemcitabine or gemcitabine plus capecitabine.

    Main Outcomes and Measures: Overall survival, recurrence, and sites of recurrence.

    Results: Of the 730 patients, median age was 65 years (range 37-81 years), 414 were men (57%), and 316 were women (43%). The median follow-up time from randomization was 43.2 months (95% CI, 39.7-45.5 months), with overall survival from time of surgery of 27.9 months (95% CI, 24.8-29.9 months) with gemcitabine and 30.2 months (95% CI, 25.8-33.5 months) with the combination (HR, 0.81; 95% CI, 0.68-0.98; P=.03). The 5-year survival estimates were 17.1% (95% CI, 11.6%-23.5%) and 28.0% (22.0%-34.3%), respectively. Recurrence occurred in 479 patients (65.6%); another 78 patients (10.7%) died without recurrence. Local recurrence occurred at a median of 11.63 months (95% CI, 10.05-12.19 months), significantly different from those with distant recurrence with a median of 9.49 months (95% CI, 8.44-10.71 months) (HR, 1.21; 95% CI, 1.01-1.45; P=.04). Following recurrence, the median survival was 9.36 months (95% CI, 8.08-10.48 months) for local recurrence and 8.94 months (95% CI, 7.82-11.17 months) with distant recurrence (HR, 0.89; 95% CI, 0.73-1.09; P=.27). The median overall survival of patients with distant-only recurrence (23.03 months; 95% CI, 19.55-25.85 months) or local with distant recurrence (23.82 months; 95% CI, 17.48-28.32 months) was not significantly different from those with only local recurrence (24.83 months; 95% CI, 22.96-27.63 months) (P=.85 and P=.35, respectively). Gemcitabine plus capecitabine had a 21% reduction of death following recurrence compared with monotherapy (HR, 0.79; 95% CI, 0.64-0.98; P=.03).

    Conclusions and Relevance: There were no significant differences between the time to recurrence and subsequent and overall survival between local and distant recurrence. Pancreatic cancer behaves as a systemic disease requiring effective systemic therapy after resection.

    Trial Registration: ClinicalTrials.gov identifier: NCT00058201, EudraCT 2007-004299-38, and ISRCTN 96397434. This secondary analysis of a randomized clinical trial investigates patterns of recurrence after adjuvant chemotherapy in pancreatic cancer and the association with survival.

  • 3.
    Karasik, David
    et al.
    Hebrew Senior Life Inst Aging Res, Boston, MA USA;Harvard Med Sch, Boston, MA 02115 USA;Bar Ilan Univ, Azrieli Fac Med, Safed, Israel.
    Zillikens, M. Carola
    Erasmus MC, Dept Internal Med, Rotterdam, Netherlands;Netherlands Genom Initiat, Leiden, Netherlands.
    Hsu, Yi-Hsiang
    Hebrew Senior Life Inst Aging Res, Boston, MA USA;Harvard Med Sch, Boston, MA 02115 USA;Harvard Med Sch, Dept Med, Boston, MA 02115 USA;Harvard Sch Publ Hlth, Mol & Integrat Physiol Sci Program, Boston, MA USA.
    Aghdassi, Ali
    Ernst Moritz Arndt Univ Greifswald, Dept Med A, Greifswald, Germany.
    Akesson, Kristina
    Lund Univ, Dept Clin Sci Malmo, Malmo, Sweden;Skane Univ Hosp, Dept Orthoped, Malmo, Sweden.
    Amin, Najaf
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.
    Barroso, Ines
    Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton, England;NIHR Cambridge Biomed Res Ctr, Cambridge, England;Univ Cambridge, Metab Res Labs, Inst Metab Sci, Addenbrookes Hosp, Cambridge, England.
    Bennett, David A.
    Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA.
    Bertram, Lars
    Univ Lubeck, Lubeck Interdisciplinary Platform Genome Analyt, Lubeck, Germany.
    Bochud, Murielle
    Lausanne Univ Hosp, Univ Inst Social & Prevent Med, Lausanne, Switzerland.
    Borecki, Ingrid B.
    Washington Univ, Dept Genet, Div Stat Gen, Sch Med, St Louis, MO 63110 USA;Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA.
    Broer, Linda
    Erasmus MC, Dept Internal Med, Rotterdam, Netherlands;Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.
    Buchman, Aron S.
    Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA.
    Byberg, Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Campbell, Harry
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Teviot Pl, Edinburgh, Midlothian, Scotland.
    Campos-Obando, Natalia
    Erasmus MC, Dept Internal Med, Rotterdam, Netherlands.
    Cauley, Jane A.
    Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA.
    Cawthon, Peggy M.
    Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA.
    Chambers, John C.
    Ealing Hosp NHS Trust, Cardiol, London, England;Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England;Imperial Coll Healthcare NHS Trust, London, England;Royal Brompton & Harefield NHS Fdn Trust, NIHR Cardiovasc Biomed Res Unit, London, England;Imperial Coll London, London, England.
    Chen, Zhao
    Univ Arizona, Mel & Enid Zuckerman Coll Publ Hlth, Tucson, AZ USA.
    Cho, Nam H.
    Ajou Univ, Sch Med, Dept Prevent Med, Suwon, South Korea.
    Choi, Hyung Jin
    Seoul Natl Univ, Coll Med, Dept Internal Med, Seoul, South Korea;Seoul Natl Univ, Coll Med, Neurosci Res Inst, Dept Anat & Cell Biol, Seoul, South Korea;Seoul Natl Univ, Wide River Inst Immunol, Hongcheon, South Korea.
    Chou, Wen-Chi
    Hebrew Senior Life Inst Aging Res, Boston, MA USA;Harvard Med Sch, Boston, MA 02115 USA;Broad Inst, Cambridge, MA USA.
    Cummings, Steven R.
    Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA.
    de Groot, Lisette C. P. G. M.
    Columbia Univ, Med Ctr, Ctr Translat & Computat Neuroimmunol Neurol, New York, NY USA.
    De Jager, Phillip L.
    Broad Inst, Cell Circuits Program, Cambridge, MA USA;Free Univ Berlin, Humboldt Univ Berlin, Charite Univ Med Berlin, Berlin, Germany.
    Demuth, Ilja
    Berlin Inst Hlth, Berlin, Germany;Wageningen Univ, Div Human Nutr, AFSG, Wageningen, Netherlands.
    Diatchenko, Luda
    Univ North Carolina Chapel Hill, Sch Dent, Reg Ctr Neurosensory Disorders, Chapel Hill, NC USA;McGill Univ, Alan Edwards Ctr Res Pain, Montreal, PQ, Canada.
    Econs, Michael J.
    Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA;Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA.
    Eiriksdottir, Gudny
    Iceland Heart Assoc Holtasmari, Kopavogur, Iceland.
    Enneman, Anke W.
    Erasmus MC, Dept Internal Med, Rotterdam, Netherlands.
    Eriksson, Joel
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Internal Med & Clin Nutr, Gothenburg, Sweden.
    Eriksson, Johan G.
    Natl Inst Hlth & Welfare, Helsinki, Finland;Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland;Helsinki Univ Cent Hosp, Unit Gen Practice, Helsinki, Finland;Folkhalsan Res Ctr, Helsinki, Finland.
    Estrada, Karol
    Erasmus MC, Dept Internal Med, Rotterdam, Netherlands;Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands;Biogen Inc, Translat Biol, 14 Cambridge Ctr, Cambridge, MA 02142 USA.
    Evans, Daniel S.
    Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA.
    Feitosa, Mary F.
    Washington Univ, Dept Genet, Div Stat Gen, Sch Med, St Louis, MO 63110 USA.
    Fu, Mao
    Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Program Personalized & Genom Med, Baltimore, MD 21201 USA;Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Dept Med, Baltimore, MD 21201 USA.
    Gieger, Christian
    Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Neuherberg, Germany;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Genet Epidemiol, Neuherberg, Germany.
    Grallert, Harald
    Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Neuherberg, Germany;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany;Helmholtz Zentrum Munchen, CCG Type 2 Diabet, Neuherberg, Germany;German Ctr Diabet Res, Neuherberg, Germany.
    Gudnason, Vilmundur
    Iceland Heart Assoc Holtasmari, Kopavogur, Iceland;Univ Iceland, Fac Med, Reykjavik, Iceland.
    Lenore, Launer J.
    NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, Bethesda, MD 20892 USA.
    Hayward, Caroline
    Univ Edinburgh, MRC Human Genet Unit, IGMM, Edinburgh, Midlothian, Scotland.
    Hofman, Albert
    Erasmus MC, Dept Internal Med, Rotterdam, Netherlands;Netherlands Genom Initiat, Leiden, Netherlands.
    Homuth, Georg
    Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Gen, Greifswald, Germany.
    Huffman, Kim M.
    Duke Univ, Sch Med, Dept Med, Duke Mol Physiol Inst, Durham, NC 27706 USA;Duke Univ, Sch Med, Dept Med, Div Rheumatol, Durham, NC 27706 USA.
    Husted, Lise B.
    Aarhus Univ Hosp, Endocrinol & Internal Med, Aarhus, Denmark.
    Illig, Thomas
    Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Neuherberg, Germany;Hannover Med Sch, Dept Human Genet, Hannover, Germany.
    Ingelsson, Erik
    Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Stanford, CA USA.
    Ittermann, Till
    Ernst Moritz Arndt Univ Greifswald, Inst Community Med, Greifswald, Germany.
    Jansson, John-Olov
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Physiol, Gothenburg, Sweden.
    Johnson, Toby
    Lausanne Univ Hosp, Univ Inst Social & Prevent Med, Lausanne, Switzerland;Univ Lausanne, Dept Med Genet, Lausanne, Switzerland;Swiss Inst Bioinformat, Lausanne, Switzerland.
    Biffar, Reiner
    Ernst Moritz Arndt Univ Greifswald, Dept Prosthet Dent Gerodontol & Biomat, Ctr Oral Hlth, Greifswald, Germany.
    Jordan, Joanne M.
    Univ North Carolina Chapel Hill, Thurston Arthrit Res Ctr, Chapel Hill, NC USA.
    Jula, Antti
    Natl Inst Hlth & Welfare, Helsinki, Finland.
    Karlsson, Magnus
    Skane Univ Hosp, Dept Orthoped, Malmo, Sweden.
    Khaw, Kay-Tee
    Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England.
    Kilpelainen, Tuomas O.
    Univ Cambridge, MRC Epidemiol Unit, Sch Clin Med, Cambridge Biomed Campus, Cambridge, England;Univ Copenhagen, Fac Hlth & Med Sci, Sect Metabol Genet, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark;Icahn Sch Med Mt Sinai, Dept Environm Med & Publ Hlth, New York, NY USA.
    Klopp, Norman
    Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Neuherberg, Germany;Hannover Med Sch, Hannover Unified Biobank, Hannover, Germany.
    Kloth, Jacqueline S. L.
    Erasmus MC, Dept Internal Med, Rotterdam, Netherlands.
    Koller, Daniel L.
    Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA;Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA.
    Kooner, Jaspal S.
    Ealing Hosp NHS Trust, Cardiol, London, England;Imperial Coll Healthcare NHS Trust, London, England;Imperial Coll London, Hammersmith Hosp, Natl Heart & Lung Inst Cardiovasc Sci, Fac Med, Hammersmith Campus, London, England.
    Kraus, William E.
    Duke Univ, Sch Med, Dept Med, Duke Mol Physiol Inst, Durham, NC USA;Duke Univ, Sch Med, Dept Med, Div Cardiol, Durham, NC USA.
    Kritchevsky, Stephen
    Wake Forest Sch Med, Sticht Ctr Hlth Aging & Alzheimers Prevent, Winston Salem, NC USA.
    Kutalik, Zoltan
    Lausanne Univ Hosp, Univ Inst Social & Prevent Med, Lausanne, Switzerland;Helmholtz Zentrum Munchen, CCG Nutrigen & Type 2 Diabet, Neuherberg, Germany;Swiss Inst Bioinformat, Lausanne, Switzerland.
    Kuulasmaa, Teemu
    Univ Eastern Finland, Dept Med, Kuopio, Finland;Kuopio Univ Hosp, Kuopio, Finland.
    Kuusisto, Johanna
    Univ Eastern Finland, Dept Med, Kuopio, Finland;Kuopio Univ Hosp, Kuopio, Finland.
    Laakso, Markku
    Univ Eastern Finland, Dept Med, Kuopio, Finland;Kuopio Univ Hosp, Kuopio, Finland.
    Lahti, Jari
    Univ Helsinki, Helsinki Collegium Adv Studies, Helsinki, Finland.
    Lang, Thomas
    UC San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA USA;UC San Francisco, Sch Dent, San Francisco, CA USA.
    Langdahl, Bente L.
    Aarhus Univ Hosp, Endocrinol & Internal Med, Aarhus, Denmark.
    Lerch, Markus M.
    Ernst Moritz Arndt Univ Greifswald, Dept Med A, Greifswald, Germany.
    Lewis, Joshua R.
    Univ Western Australia, Sch Med & Pharmacol, Perth, WA, Australia;Univ Sydney, Sydney Med Sch, Sch Publ Hlth, Childrens Hosp Westmead,Ctr Kidney Res, Sydney, NSW, Australia.
    Lill, Christina
    Univ Lubeck, Inst Neurogenet, Lubeck, Germany.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Epidemiology.
    Lindgren, Cecilia
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.
    Liu, Yongmei
    Wake Forest Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC USA.
    Livshits, Gregory
    Tel Aviv Univ, Dept Anat & Anthropol, Sackler Fac Med, Tel Aviv, Israel;Kings Coll London, Dept Twin Res & Genet Epidemiol, St Thomas Campus, London, England.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Loos, Ruth J. F.
    Icahn Sch Med Mt Sinai, Dept Environm Med & Publ Hlth, New York, NY USA;Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Inst Child Hlth & Dev, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Genet Obes & Related Traits Program, New York, NY 10029 USA.
    Lorentzon, Mattias
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Internal Med, Gothenburg, Sweden.
    Luan, Jian'an
    Icahn Sch Med Mt Sinai, Dept Environm Med & Publ Hlth, New York, NY USA.
    Luben, Robert N.
    Univ Copenhagen, Fac Hlth & Med Sci, Sect Metabol Genet, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark.
    Malkin, Ida
    Tel Aviv Univ, Dept Anat & Anthropol, Sackler Fac Med, Tel Aviv, Israel.
    McGuigan, Fiona E.
    Lund Univ, Dept Clin Sci Malmo, Malmo, Sweden.
    Medina-Gomez, Carolina
    Erasmus MC, Dept Internal Med, Rotterdam, Netherlands;Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.
    Meitinger, Thomas
    Tech Univ Munich, Inst Human Genet, MRI, Munich, Germany;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Human Genet, Neuherberg, Germany.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Mellstrom, Dan
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Internal Med & Clin Nutr, Gothenburg, Sweden.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Lund Univ, Dept Clin Sci Malmo, Malmo, Sweden.
    Mitchell, Braxton D.
    Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Program Personalized & Genom Med, Baltimore, MD 21201 USA;Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Dept Med, Baltimore, MD 21201 USA;Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD 21218 USA.
    Morris, Andrew P.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England;Univ Liverpool, Inst Translat Med, Liverpool, Merseyside, England.
    Mosekilde, Leif
    Aarhus Univ Hosp, Endocrinol & Internal Med, Aarhus, Denmark.
    Nethander, Maria
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Internal Med & Clin Nutr, Gothenburg, Sweden.
    Newman, Anne B.
    Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA.
    O'Connell, Jeffery R.
    Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Program Personalized & Genom Med, Baltimore, MD 21201 USA;Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Dept Med, Baltimore, MD 21201 USA.
    Oostra, Ben A.
    Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands;Ctr Med Syst Biol & Netherlands Consortium H, Leiden, Netherlands.
    Orwoll, Eric S.
    Oregon Hlth & Sci Univ, Portland, OR USA.
    Palotie, Aarno
    Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland;Univ Helsinki, Dept Med Genet, Helsinki, Finland;Univ Cent Hosp, Helsinki, Finland.
    Peacock, Munro
    Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA;Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA.
    Perola, Markus
    Natl Inst Hlth & Welfare, Helsinki, Finland;Univ Helsinki, Inst Mol Med, Helsinki, Finland;Diabet & Obes Res Program, Helsinki, Finland;Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.
    Peters, Annette
    Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Neuherberg, Germany;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany.
    Prince, Richard L.
    Univ Western Australia, Sch Med & Pharmacol, Perth, WA, Australia;Sir Charles Gairdner Hosp, Dept Endocrinol & Diabet, Perth, WA, Australia.
    Psaty, Bruce M.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA;Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA;Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA;Kaiser Permanente, Washington Hlth Res Inst, Seattle, WA USA.
    Raikkonen, Katri
    Univ Helsinki, Dept Psychol & Logoped, Helsinki, Finland.
    Ralston, Stuart H.
    Harvard Med Sch, Boston, MA 02115 USA;Western Gen Hosp, MRC Inst Genet & Mol Med, Mol Med Ctr, Edinburgh, Midlothian, Scotland.
    Ripatti, Samuli
    Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton, England;Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland;Univ Helsinki, Hjelt Inst, Helsinki, Finland.
    Rivadeneira, Fernando
    Erasmus MC, Dept Internal Med, Rotterdam, Netherlands;Netherlands Genom Initiat, Leiden, Netherlands;Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.
    Robbins, John A.
    Univ Calif Davis, Dept Med, Sacramento, CA 95817 USA.
    Rotter, Jerome I.
    Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA;Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA.
    Rudan, Igor
    Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA.
    Salomaa, Veikko
    Natl Inst Hlth & Welfare, Helsinki, Finland.
    Satterfield, Suzanne
    Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA.
    Schipf, Sabine
    Ernst Moritz Arndt Univ Greifswald, Inst Community Med, Greifswald, Germany.
    Shin, Chan Soo
    Seoul Natl Univ, Coll Med, Dept Internal Med, Seoul, South Korea.
    Smith, Albert V.
    Iceland Heart Assoc Holtasmari, Kopavogur, Iceland;Univ Iceland, Fac Med, Reykjavik, Iceland.
    Smith, Shad B.
    Duke Univ, Dept Anesthesiol, Ctr Translat Pain Med, Durham, NC USA.
    Soranzo, Nicole
    Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton, England.
    Spector, Timothy D.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, St Thomas Campus, London, England.
    Stancakova, Alena
    Univ Eastern Finland, Dept Med, Kuopio, Finland;Kuopio Univ Hosp, Kuopio, Finland.
    Stefansson, Kari
    Univ Iceland, Fac Med, Reykjavik, Iceland;deCODE Genet, Reykjavik, Iceland.
    Steinhagen-Thiessen, Elisabeth
    Harvard Sch Publ Hlth, Mol & Integrat Physiol Sci Program, Boston, MA USA.
    Stolk, Lisette
    Erasmus MC, Dept Internal Med, Rotterdam, Netherlands;Netherlands Genom Initiat, Leiden, Netherlands.
    Streeten, Elizabeth A.
    Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Program Personalized & Genom Med, Baltimore, MD 21201 USA;Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Dept Med, Baltimore, MD 21201 USA;Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD 21218 USA.
    Styrkarsdottir, Unnur
    deCODE Genet, Reykjavik, Iceland.
    Swart, Karin M. A.
    Vrije Univ Amsterdam Med Ctr, Dept Epidemiol & Biostat, Amsterdam, Netherlands;Vrije Univ Amsterdam Med Ctr, EMGO Inst, Amsterdam, Netherlands.
    Thompson, Patricia
    Univ Arizona, Mel & Enid Zuckerman Coll Publ Hlth, Tucson, AZ USA;SUNY Stony Brook, Dept Pathol, Stony Brook, NY 11794 USA.
    Thomson, Cynthia A.
    Thorleifsson, Gudmar
    deCODE Genet, Reykjavik, Iceland.
    Thorsteinsdottir, Unnur
    Univ Iceland, Fac Med, Reykjavik, Iceland;deCODE Genet, Reykjavik, Iceland.
    Tikkanen, Emmi
    Natl Inst Hlth & Welfare, Helsinki, Finland;Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland.
    Tranah, Gregory J.
    Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA.
    Uitterlinden, Andre G.
    Erasmus MC, Dept Internal Med, Rotterdam, Netherlands;Netherlands Genom Initiat, Leiden, Netherlands;Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.
    van Duijn, Cornelia M.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands;Ctr Med Syst Biol & Netherlands Consortium H, Leiden, Netherlands.
    van Schoor, Natasja M.
    Vrije Univ Amsterdam Med Ctr, Dept Epidemiol & Biostat, Amsterdam, Netherlands;Vrije Univ Amsterdam Med Ctr, EMGO Inst, Amsterdam, Netherlands.
    Vandenput, Liesbeth
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Internal Med & Clin Nutr, Gothenburg, Sweden.
    Vollenweider, Peter
    Lausanne Univ Hosp, Dept Med Internal Med, Lausanne, Switzerland;Fac Biol & Med, Lausanne, Switzerland.
    Volzke, Henry
    Erasmus MC, Dept Internal Med, Rotterdam, Netherlands.
    Wactawski-Wende, Jean
    Univ Buffalo SUNY, Dept Epidemiol & Environm Hlth, Buffalo, NY USA.
    Walker, Mark
    Newcastle Univ, Med Sch, Inst Cellular Med Diabetes, Framlington Pl, Newcastle Upon Tyne, Tyne & Wear, England.
    Wareham, Nicholas J.
    Univ Cambridge, MRC Epidemiol Unit, Sch Clin Med, Cambridge Biomed Campus, Cambridge, England.
    Waterworth, Dawn
    GlaxoSmithKline, Genet, King Of Prussia, PA USA.
    Weedon, Michael N.
    Univ Exeter, Med Sch, Royal Devon & Exeter Hosp, Genet Complex Traits, Exeter, Devon, England.
    Wichmann, H-Erich
    Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany;Ludwig Maximilians Univ Munchen, Inst Med Informat Biometry & Epidemiol, Neuherberg, Germany;Tech Univ, Inst Med Stat & Epidemiol, Munich, Germany.
    Widen, Elisabeth
    Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland.
    Williams, Frances M. K.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, St Thomas Campus, London, England.
    Wilson, James F.
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Teviot Pl, Edinburgh, Midlothian, Scotland.
    Wright, Nicole C.
    Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA.
    Yerges-Armstrong, Laura M.
    Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Program Personalized & Genom Med, Baltimore, MD 21201 USA;Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Dept Med, Baltimore, MD 21201 USA;GlaxoSmithKline, Genet, King Of Prussia, PA USA.
    Yu, Lei
    Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA.
    Zhang, Weihua
    Ealing Hosp NHS Trust, Cardiol, London, England;Imperial Coll Healthcare NHS Trust, London, England.
    Zhao, Jing Hua
    Univ Cambridge, MRC Epidemiol Unit, Sch Clin Med, Cambridge Biomed Campus, Cambridge, England.
    Zhou, Yanhua
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA.
    Nielson, Carrie M.
    Oregon Hlth & Sci Univ, Portland, OR USA.
    Harris, Tamara B.
    NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, Bethesda, MD 20892 USA.
    Demissie, Serkalem
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA.
    Kiel, Douglas P.
    Hebrew Senior Life Inst Aging Res, Boston, MA USA;Harvard Med Sch, Boston, MA 02115 USA;Harvard Med Sch, Dept Med, Boston, MA 02115 USA.
    Ohlsson, Claes
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Internal Med & Clin Nutr, Gothenburg, Sweden.
    Disentangling the genetics of lean mass2019In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 109, no 2, p. 276-287Article in journal (Refereed)
    Abstract [en]

    Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass. Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci. Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age(2), and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms). Results: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LMwere termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection. Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.

  • 4.
    Schmidt, Amand F.
    et al.
    UCL, Inst Cardiovasc Sci, 222 Euston Rd, London NW1 2DA, England;Univ Utrecht, Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Cardiol, Utrecht, Netherlands;UCLs BHF Res Accelerator Ctr, London, England.
    Holmes, Michael V.
    Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Med Res Council Populat Hlth Res Unit, Oxford, England;Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit CTSU, Oxford, England.
    Preiss, David
    Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Med Res Council Populat Hlth Res Unit, Oxford, England;Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit CTSU, Oxford, England.
    Swerdlow, Daniel I.
    UCL, Inst Cardiovasc Sci, 222 Euston Rd, London NW1 2DA, England;Imperial Coll London, Dept Med, London, England.
    Denaxas, Spiros
    UCLs BHF Res Accelerator Ctr, London, England;UCL, Hlth Data Res UK, 222 Euston Rd, London NW1 2DA, England;UCL, Inst Hlth Informat, 222 Euston Rd, London NW1 2DA, England;British Lib, Alan Turing Inst, 96 Euston Rd, London NW1 2DB, England.
    Fatemifar, Ghazaleh
    UCLs BHF Res Accelerator Ctr, London, England;UCL, Hlth Data Res UK, 222 Euston Rd, London NW1 2DA, England;UCL, Inst Hlth Informat, 222 Euston Rd, London NW1 2DA, England.
    Faraway, Rupert
    UCL, Inst Cardiovasc Sci, 222 Euston Rd, London NW1 2DA, England.
    Finan, Chris
    UCL, Inst Cardiovasc Sci, 222 Euston Rd, London NW1 2DA, England;UCLs BHF Res Accelerator Ctr, London, England.
    Valentine, Dennis
    UCLs BHF Res Accelerator Ctr, London, England;UCL, Farr Inst Hlth Informat, London, England.
    Fairhurst-Hunter, Zammy
    Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Richard Doll Bldg,Old Rd Campus,Roosevelt Dr, Oxford OX3 7LF, England;Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit CTSU, Richard Doll Bldg,Old Rd Campus,Roosevelt Dr, Oxford OX3 7LF, England.
    Hartwig, Fernando Pires
    Univ Fed Pelotas, Postgrad Program Epidemiol, Pelotas, RS, Brazil.
    Horta, Bernardo Lessa
    Univ Fed Pelotas, Postgrad Program Epidemiol, Pelotas, RS, Brazil.
    Hypponen, Elina
    Univ South Australia, Sansom Inst Hlth Res, Ctr Populat Hlth Res, Adelaide, SA, Australia;UCL GOS Inst Child Hlth, Populat Policy & Practice, London, England;South Australian Hlth & Med Res Inst, Adelaide, SA, Australia.
    Power, Christine
    UCL GOS Inst Child Hlth, Populat Policy & Practice, London, England.
    Moldovan, Max
    South Australian Hlth & Med Res Inst, Adelaide, SA, Australia.
    van Iperen, Erik
    Netherlands Heart Inst, Durrer Ctr Cardiovasc Res, Utrecht, Netherlands;Acad Med Ctr Amsterdam, Dept Clin Epidemiol Biostat & Bioinformat, Amsterdam, Netherlands.
    Hovingh, Kees
    Acad Med Ctr Amsterdam, Dept Vasc Med, Amsterdam, Netherlands.
    Demuth, Ilja
    Charite Univ Med Berlin, Berlin, Germany;Free Univ Berlin, Berlin, Germany;Humboldt Univ, Berlin, Germany;Berlin Inst Hlth, Lipid Clin, Interdisciplinary Metab Ctr, Berlin, Germany;Charite Univ Med Berlin, BCRT Berlin Inst Hlth, Ctr Regenerat Therapies, Berlin, Germany.
    Norman, Kristina
    Univ Potsdam, Inst Nutr Sci, D-14558 Nuthetal, Germany;Charite Univ Med Berlin, Geriatr Res Grp, D-13347 Berlin, Germany;German Inst Human Nutr Potsdam Rehbrucke, Dept Nutr & Gerontol, D-14558 Nuthetal, Germany.
    Steinhagen-Thiessen, Elisabeth
    Charite Univ Med Berlin, Berlin, Germany;Free Univ Berlin, Berlin, Germany;Humboldt Univ, Berlin, Germany;Berlin Inst Hlth, Lipid Clin, Interdisciplinary Metab Ctr, Berlin, Germany.
    Demuth, Juri
    ECA Econ GmbH, Berlin, Germany.
    Bertram, Lars
    Univ Lubeck, Lubeck Interdisciplinary Platform Genome Analyt L, Inst Neurogenet & Cardiogenet, Lubeck, Germany;Univ Oslo, Dept Psychol, Ctr Lifespan Changes Brain & Cognit LCBC, Oslo, Norway.
    Lill, Christina M.
    Univ Lubeck, Inst Neurogenet & Cardiogenet, Lubeck Interdisciplinary Platform Genome Analyt L, Genet & Mol Epidemiol Grp, Lubeck, Germany;Inst Human Genet, Lubeck, Germany;Imperial Coll, Sch Publ Hlth, Ageing Epidemiol Res Unit, London, England.
    Coassin, Stefan
    Med Univ Innsbruck, Dept Genet & Pharmacol, Inst Genet Epidemiol, A-6020 Innsbruck, Austria.
    Willeit, Johann
    Med Univ Innsbruck, Dept Neurol, Innsbruck, Austria.
    Kiechl, Stefan
    Med Univ Innsbruck, Dept Neurol, Innsbruck, Austria.
    Willeit, Karin
    Med Univ Innsbruck, Dept Neurol, Innsbruck, Austria;Univ Bern, Univ Hosp Bern, Inselspital, Dept Neurol, Bern, Switzerland.
    Mason, Dan
    Bradford Royal Infirm, Bradford Inst Hlth Res, Bradford, W Yorkshire, England.
    Wright, John
    Bradford Royal Infirm, Bradford Inst Hlth Res, Bradford, W Yorkshire, England.
    Morris, Richard
    UCL, Dept Primary Care & Populat Hlth, London, England.
    Wanamethee, Goya
    UCL, Dept Primary Care & Populat Hlth, London, England.
    Whincup, Peter
    St Georges Univ London, Populat Hlth Res Inst, London, England.
    Ben-Shlomo, Yoav
    Univ Bristol, Populat Hlth Sci, Bristol, Avon, England.
    McLachlan, Stela
    Univ Edinburgh, Usher Inst, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland.
    Price, Jackie F.
    Univ Edinburgh, Usher Inst, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland.
    Kivimaki, Mika
    UCL, UCL Inst Epidemiol & Hlth Care, Dept Epidemiol & Publ Hlth, London, England.
    Welch, Catherine
    UCL, UCL Inst Epidemiol & Hlth Care, Dept Epidemiol & Publ Hlth, London, England.
    Sanchez-Galvez, Adelaida
    UCL, UCL Inst Epidemiol & Hlth Care, Dept Epidemiol & Publ Hlth, London, England.
    Marques-Vidal, Pedro
    Lausanne Univ Hosp, Dept Med, Internal Med, Lausanne, Switzerland.
    Nicolaides, Andrew
    Imperial Coll, Dept Vasc Surg, London, England;Univ Nicosia, Nicosia Med Sch, Dept Surg, Nicosia, Cyprus.
    Panayiotou, Andrie G.
    Cyprus Univ Technol, Cyprus Int Inst Environm & Publ Hlth, Limassol, Cyprus.
    Onland-Moret, N. Charlotte
    Univ Utrecht, Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands.
    van der Schouw, Yvonne T.
    Univ Utrecht, Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands.
    Matullo, Giuseppe
    IIGM, Turin, Italy;Univ Turin, Dept Med Sci, Turin, Italy.
    Fiorito, Giovanni
    IIGM, Turin, Italy;Univ Turin, Dept Med Sci, Turin, Italy.
    Guarrera, Simonetta
    IIGM, Turin, Italy;Univ Turin, Dept Med Sci, Turin, Italy.
    Sacerdote, Carlotta
    Citta Salute & Sci Univ Hosp, Unit Canc Epidemiol, Turin, Italy;Ctr Canc Prevent CPO, Turin, Italy.
    Wareham, Nicholas J.
    Univ Cambridge, Addenbrookes Hosp, Sch Clin Med, MRC Epidemiol Unit,Inst Metab Sci, Cambridge Biomed Campus, Cambridge, England.
    Langenberg, Claudia
    Univ Cambridge, Addenbrookes Hosp, Sch Clin Med, MRC Epidemiol Unit,Inst Metab Sci, Cambridge Biomed Campus, Cambridge, England.
    Scott, Robert A.
    Univ Cambridge, Addenbrookes Hosp, Sch Clin Med, MRC Epidemiol Unit,Inst Metab Sci, Cambridge Biomed Campus, Cambridge, England.
    Luan, Jian'an
    Univ Cambridge, Addenbrookes Hosp, Sch Clin Med, MRC Epidemiol Unit,Inst Metab Sci, Cambridge Biomed Campus, Cambridge, England.
    Bobak, Martin
    UCL, UCL Inst Epidemiol & Hlth Care, Dept Epidemiol & Publ Hlth, London, England.
    Malyutina, Sofia
    Novosibirsk State Med Univ, Novosibirsk, Russia;Russian Acad Med Sci, Siberian Branch, Inst Internal & Prevent Med, Novosibirsk, Russia.
    Pajak, Andrzej
    Jagiellonian Univ, Coll Med, Fac Hlth Sci, Dept Epidemiol & Populat Studies, Krakow, Poland.
    Kubinova, Ruzena
    Natl Inst Publ Hlth, Prague, Czech Republic.
    Tamosiunas, Abdonas
    Lithuanian Univ Hlth Sci, Kaunas, Lithuania.
    Pikhart, Hynek
    UCL, UCL Inst Epidemiol & Hlth Care, Dept Epidemiol & Publ Hlth, London, England.
    Grarup, Niels
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark.
    Pedersen, Oluf
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark.
    Hansen, Torben
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark.
    Linneberg, Allan
    Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark;Bispebjerg & Frederiksberg Hosp, Ctr Clin Res & Prevent, Copenhagen, Capital Region, Denmark.
    Jess, Tine
    Bispebjerg & Frederiksberg Hosp, Ctr Clin Res & Prevent, Copenhagen, Capital Region, Denmark.
    Cooper, Jackie
    UCL, Dept Med, Ctr Cardiovasc Genet, London, England.
    Humphries, Steve E.
    UCL, Dept Med, Ctr Cardiovasc Genet, London, England.
    Brilliant, Murray
    Marshfield Clin Res Inst, Ctr Human Genet, Marshfield, WI USA.
    Kitchner, Terrie
    Marshfield Clin Res Inst, Ctr Human Genet, Marshfield, WI USA.
    Hakonarson, Hakon
    Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA.
    Carrell, David S.
    Kaiser Permanente Washington Hlth Res Inst, Seattle, WA USA.
    McCarty, Catherine A.
    Univ Minnesota, Minneapolis, MN USA.
    Lester, Kirchner H.
    Geisinger, Danville, PA USA.
    Larson, Eric B.
    Kaiser Permanente Washington Hlth Res Inst, Seattle, WA USA.
    Crosslin, David R.
    Univ Washington Seattle, Dept Biomed Informat & Med Educ, Seattle, WA USA.
    de Andrade, Mariza
    Mayo Clin, Rochester, MN USA.
    Roden, Dan M.
    Vanderbilt Univ, Sch Med, Dept Med, Dept Pharmacol,Dept Biomed Informat, Nashville, TN 37212 USA.
    Denny, Joshua C.
    Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA.
    Carty, Cara
    WHI, Seattle, WA USA.
    Hancock, Stephen
    Univ Newcastle, Newcastle, NSW, Australia.
    Attia, John
    Univ Newcastle, Newcastle, NSW, Australia;Hunter Med Res Inst, Publ Hlth Program, Newcastle, NSW, Australia.
    Holliday, Elizabeth
    Univ Newcastle, Newcastle, NSW, Australia;Hunter Med Res Inst, Publ Hlth Program, Newcastle, NSW, Australia.
    Scott, Rodney
    Univ Newcastle, Newcastle, NSW, Australia.
    Schofield, Peter
    Hunter New England Local Hlth Dist, Newcastle, NSW, Australia.
    O'Donnell, Martin
    Populat Hlth Res Inst, Hamilton, ON, Canada.
    Yusuf, Salim
    Populat Hlth Res Inst, Hamilton, ON, Canada.
    Chong, Michael
    Populat Hlth Res Inst, Hamilton, ON, Canada.
    Pare, Guillaume
    Populat Hlth Res Inst, Hamilton, ON, Canada.
    van der Harst, Pim
    Netherlands Heart Inst, Durrer Ctr Cardiovasc Res, Utrecht, Netherlands;Acad Med Ctr Amsterdam, Dept Clin Epidemiol Biostat & Bioinformat, Amsterdam, Netherlands;Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands;Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands.
    Said, M. Abdullah
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands.
    Eppinga, Ruben N.
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands.
    Verweij, Niek
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands.
    Snieder, Harold
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands.
    Christen, Tim
    Leiden Univ, Med Ctr, Dept Clin Epidemiol, Leiden, Netherlands.
    Mook-Kanamori, D. O.
    Leiden Univ, Med Ctr, Dept Clin Epidemiol, Leiden, Netherlands.
    Gustafsson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Lind, Lars
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Stanford Univ, Dept Med, Sch Med, Div Cardiovasc Med, Stanford, CA 94305 USA;.
    Ingelsson, Erik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Stanford Univ, Dept Med, Sch Med, Div Cardiovasc Med, Stanford, CA 94305 USA.
    Pazoki, Raha
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands;Imperial Coll London, Dept Epidemiol & Biostat, London, England.
    Franco, Oscar
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.
    Hofman, Albert
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.
    Uitterlinden, Andre
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.
    Dehghan, Abbas
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.
    Teumer, Alexander
    Univ Med Greifswald, Inst Community Med, Greifswald, Germany;DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, Greifswald, Germany.
    Baumeister, Sebastian
    Univ Med Greifswald, Inst Community Med, Greifswald, Germany;Ludwig Maximilians Univ Munchen, Chair Epidemiol, UNIKA T Augsburg, Augsburg, Germany.
    Doerr, Marcus
    DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, Greifswald, Germany;Univ Med Greifswald, Dept Internal Med B, Greifswald, Germany.
    Lerch, Markus M.
    Univ Med Greifswald, Dept Internal Med A, Greifswald, Germany.
    Voelker, Uwe
    DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, Greifswald, Germany;Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany.
    Voelzke, Henry
    Univ Med Greifswald, Inst Community Med, Greifswald, Germany;DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, Greifswald, Germany.
    Ward, Joey
    Univ Glasgow, Inst Hlth & Wellbeing, Glasgow G12 8RZ, Lanark, Scotland.
    Pell, Jill P.
    Univ Glasgow, Inst Hlth & Wellbeing, Glasgow G12 8RZ, Lanark, Scotland.
    Meade, Tom
    London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London, England.
    Christophersen, Ingrid E.
    Vestre Viken Hosp Trust, Baerum Hosp, Dept Med Res, Gjettum, Norway.
    Maitland-van der Zee, Anke H.
    Univ Utrecht, Fac Sci, Utrecht Inst Pharmaceut Sci, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht, Netherlands;Univ Amsterdam, Acad Med Ctr, Dept Resp Med, Amsterdam, Netherlands.
    Baranova, Ekaterina V.
    Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland.
    Young, Robin
    Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland.
    Ford, Ian
    Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland.
    Campbell, Archie
    Univ Edinburgh, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland.
    Padmanabhan, Sandosh
    Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow G12 8TA, Lanark, Scotland.
    Bots, Michiel L.
    Cyprus Univ Technol, Cyprus Int Inst Environm & Publ Hlth, Limassol, Cyprus.
    Grobbee, Diederick E.
    Cyprus Univ Technol, Cyprus Int Inst Environm & Publ Hlth, Limassol, Cyprus.
    Froguel, Philippe
    Univ Lille, Inst Pasteur Lille, CNRS, UMR 8199,EGID, F-59000 Lille, France;Imperial Coll London, Dept Genom Common Dis, London W12 0NN, England.
    Thuillier, Dorothee
    Univ Lille, Inst Pasteur Lille, CNRS, UMR 8199,EGID, F-59000 Lille, France.
    Roussel, Ronan
    INSERM, Ctr Rech Cordeliers, U1138, Paris, France;Univ Paris Diderot, Sorbonne Paris Cite, UFR Med, Paris, France;Hop Bicha, AP HP, Dept Diabetol Endocrinol & Nutr, Paris, France.
    Bonnefond, Amelie
    Univ Lille, Inst Pasteur Lille, CNRS, UMR 8199,EGID, F-59000 Lille, France.
    Cariou, Bertrand
    Univ Nantes, CHU Nantes, CNRS, Inst Thorax,INSERM, Nantes, France.
    Smart, Melissa
    Univ Essex, Inst Social & Econ Res, Colchester, Essex, England.
    Bao, Yanchun
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.
    Kumari, Meena
    Boston Univ, Sch Med, Boston, MA 02118 USA.
    Mahajan, Anubha
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.
    Hopewell, Jemma C.
    Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Richard Doll Bldg,Old Rd Campus,Roosevelt Dr, Oxford OX3 7LF, England;Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit CTSU, Richard Doll Bldg,Old Rd Campus,Roosevelt Dr, Oxford OX3 7LF, England.
    Seshadri, Sudha
    Boston Univ, Sch Med, Boston, MA 02118 USA.
    Dale, Caroline
    UCL, Farr Inst Hlth Informat, London, England.
    Costa, Rui Providencia E.
    UCL, Farr Inst Hlth Informat, London, England.
    Ridker, Paul M.
    Harvard Med Sch, Ctr Cardiovasc Dis Prevent, Brigham & Womens Hosp, Boston, MA 02115 USA.
    Chasman, Daniel I.
    Harvard Med Sch, Ctr Cardiovasc Dis Prevent, Brigham & Womens Hosp, Boston, MA 02115 USA.
    Reiner, Alex P.
    UWash, Seattle, WA USA.
    Ritchie, Marylyn D.
    Penn State, State Coll, PA USA.
    Lange, Leslie A.
    Univ Colorado Denver, Denver, CO USA.
    Cornish, Alex J.
    Inst Canc Res, Div Genet & Epidemiol, London, England.
    Dobbins, Sara E.
    Inst Canc Res, Div Genet & Epidemiol, London, England.
    Hemminki, Kari
    German Canc Res Ctr, Div Mol Genet Epidemiol, Neuenheimer Feld 580, D-69120 Heidelberg, Germany;Deutsch Krebsforschungszentrum, Heidelberg, Germany.
    Kinnersley, Ben
    Inst Canc Res, Div Genet & Epidemiol, London, England.
    Sanson, Marc
    Inst Cerveau Moelle Epiniere ICM, Paris, France;UPMC Univ Paris 06, Sorbonne Univ, UMR S 1127, F-75013 Paris, France.
    Labreche, Karim
    Inst Cerveau Moelle Epiniere ICM, Paris, France;UPMC Univ Paris 06, Sorbonne Univ, UMR S 1127, F-75013 Paris, France.
    Simon, Matthias
    Bethel Clin, Dept Neurosurg, Kantensiek 11, D-33617 Bielefeld, Germany.
    Bondy, Melissa
    Baylor Coll Med, Dan L Duncan Canc Ctr, Dept Pediat, Div Hematol Oncol, Houston, TX 77030 USA.
    Law, Philip
    Inst Canc Res, Div Genet & Epidemiol, London, England.
    Speedy, Helen
    Inst Canc Res, Div Genet & Epidemiol, London, England.
    Allan, James
    Newcastle Univ, Northern Inst Canc Res, Newcastle Upon Tyne, Tyne & Wear, England.
    Li, Ni
    Inst Canc Res, Div Genet & Epidemiol, London, England.
    Went, Molly
    Inst Canc Res, Div Genet & Epidemiol, London, England.
    Weinhold, Niels
    Univ Arkansas Med Sci, Myeloma Inst Res & Therapy, Little Rock, AR 72205 USA.
    Morgan, Gareth
    Univ Arkansas Med Sci, Myeloma Inst Res & Therapy, Little Rock, AR 72205 USA.
    Sonneveld, Pieter
    Erasmus MC Canc Inst, Dept Hematol, NL-3075 EA Rotterdam, Netherlands.
    Nilsson, Bjorn
    Dept Lab Med, Hematol & Transfus Med, BMC B13, SE-22184 Lund, Sweden.
    Goldschmidt, Hartmut
    Univ Clin Heidelberg, Internal Med 5, Heidelberg, Germany;Natl Ctr Tumor Dis NCT, Heidelberg, Germany.
    Sud, Amit
    Inst Canc Res, Div Genet & Epidemiol, London, England.
    Engert, Andreas
    Univ Hosp Cologne, Dept Internal Med, Cologne, Germany.
    Hansson, Markus
    Skane Univ Hosp, Hematol Clin, Skane, Sweden;Lund Univ, Wallenberg Ctr Mol Med, Lund, Sweden.
    Hemingway, Harry
    UCLs BHF Res Accelerator Ctr, London, England;UCL, Hlth Data Res UK, 222 Euston Rd, London NW1 2DA, England;UCL, Inst Hlth Informat, 222 Euston Rd, London NW1 2DA, England;UCL, Univ Coll London Hosp, Biomed Res Ctr, Natl Inst Hlth Res, 222 Euston Rd, London NW1 2DA, England.
    Asselbergs, Folkert W.
    UCL, Inst Cardiovasc Sci, 222 Euston Rd, London NW1 2DA, England;Univ Utrecht, Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Cardiol, Utrecht, Netherlands;UCLs BHF Res Accelerator Ctr, London, England;UCL, Hlth Data Res UK, London, England;UCL, Inst Hlth Informat, London, England.
    Patel, Riyaz S.
    UCL, Inst Cardiovasc Sci, 222 Euston Rd, London NW1 2DA, England;UCLs BHF Res Accelerator Ctr, London, England;St Bartholomews Hosp, Barts Heart Ctr, London, England.
    Keating, Brendan J.
    Univ Penn, Philadelphia, PA 19104 USA.
    Sattar, Naveed
    Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow G12 8TA, Lanark, Scotland.
    Houlston, Richard
    Inst Canc Res, Div Genet & Epidemiol, London, England.
    Casas, Juan P.
    Vet Affairs Boston Healthcare Syst, Massachusetts Vet Epidemiol & Res Informat Ctr MA, Boston, MA USA.
    Hingorani, Aroon D.
    UCL, Inst Cardiovasc Sci, 222 Euston Rd, London NW1 2DA, England;UCLs BHF Res Accelerator Ctr, London, England.
    Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK92019In: BMC Cardiovascular Disorders, ISSN 1471-2261, E-ISSN 1471-2261, Vol. 19, no 1, article id 240Article in journal (Refereed)
    Abstract [en]

    Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.

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