Danish Saleheen1, Wei Zhao2, Robin Young2, Christopher P Nelson2, WeangKee Ho2, Jane F Ferguson2, Asif Rasheed2, Kristy Ou2, Sylvia T Nurnberg2, Robert C Bauer2, Anuj Goel2, Ron Do2, Alexandre F R Stewart2, Jaana Hartiala2, Weihua Zhang2, Gudmar Thorleifsson2, Rona J Strawbridge2, Juha Sinisalo2, Stavroula Kanoni2, Sanaz Sedaghat2, Eirini Marouli2, Kati Kristiansson2, Jing Hua Zhao2, Robert Scott2, Dominique Gauguier2, Svati H Shah2, Albert Vernon Smith2, Natalie van Zuydam2, Amanda J Cox2, Christina Willenborg2, Thorsten Kessler2, Lingyao Zeng2, Michael A Province2, Andrea Ganna2, Lars Lind2, Nancy L Pedersen2, Charles C White2, Anni Joensuu2, Marcus Edi Kleber2, Alistair S Hall2, Winfried März2, Veikko Salomaa2, Christopher O'Donnell2, Erik Ingelsson2, Mary F Feitosa2, Jeanette Erdmann2, Donald W Bowden2, Colin N A Palmer2, Vilmundur Gudnason2, Ulf De Faire2, Pierre Zalloua2, Nicholas Wareham2, John R Thompson2, Kari Kuulasmaa2, George Dedoussis2, Markus Perola2, Abbas Dehghan2, John C Chambers2, Jaspal Kooner2, Hooman Allayee2, Panos Deloukas2, Ruth McPherson2, Kari Stefansson2, Heribert Schunkert2, Sekar Kathiresan2, Martin Farrall2, Philippe Marcel Frossard2, Daniel J Rader2, Nilesh J Samani2, Muredach P Reilly2. 1. From Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia (D.S., W.Z.); Center for Non-Communicable Diseases, Karachi, Pakistan (D.S., A.R., P.M.F., PROMIS); Department of Public Health and Primary Care, University of Cambridge, United Kingdom (R.Y., W.K.H., EPIC-CVD); Department of Cardiovascular Sciences, University of Leicester, United Kingdom (C.P.N., N.J.S.); Cardiology Division, Department of Medicine, Vanderbilt University, Nashville, TN (J.F.F., K.O.); Division of Cardiovascular Medicine, Radcliffe Department of Medicine & Wellcome Trust Centre for Human Genetics, University of Oxford, United Kingdom (A.G., M.F.); The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY (R.D.); Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY (R.D.); Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Canada (A.F.R.S., R.M.); Institute for Genetic Medicine and Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles (J.H., H.A.); Department of Epidemiology and Biostatistics, Imperial College London, United Kingdom (W.Z., J.C.C., J.K.); Department of Cardiology, Ealing Hospital NHS Trust, Middlesex, United Kingdom (W.Z., J.C.C.); Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden (R.J.S.); Helsinki University Central Hospital HUCH Heart and Lung Center, Helsinki, Uusimaa, Finland (J.S.); Cardiology Division, Department of Medicine and the Irving Institute for Clinical and Translational Research, Columbia University Medical Center, New York, NY (R.C.B., M.P.R.); William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (S.K., E.M., P.D.); Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands (S.S., A.D.); Department of Dietetics-Nutrition, Harokopio University, Athens, Greece (E.M., G.D.); National Institute for Health and Welfare, Helsinki, Finland (K.K., A.J., V.S., K.K., M.P.); MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, United Kingdom (J.H.Z., R.S.); INSERM, UMRS1138, Centre de Recherche des Cordeliers, Paris, France (D.G., N.W.); Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC (S.H.S.); Icelandic Heart Association, Kopavogur, Iceland (A.V.S., V.G.); Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, United Kingdom (N.v.Z., C.N.A.P.); Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC (A.J.C., D.W.B.); Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, Germany (C.W., J.E.); DZHK (German Research Center for Cardiovascular Research) partner site Hamburg-Lübeck-Kiel, Germany (C.W., J.E.); Deutsches Herzzentrum München, Technische Universität München, Germany (T.K., L.Z., H.S.); Klinikum rechts der Isar, München, Germany (T.K.); DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Germany (L.Z., H.S.); Department of Genetics, Washington University School of Medicine, St. Louis, MO (M.A.P., M.F.F.); Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston (A.G.); Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA (A.G.); Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Sweden (L.L.); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (N.L.P.); Department of Biostatistics Boston University School of Public Health Framingham Heart Study, MA (C.C.W.); Faculty of Medicine, University of Iceland, Reykjavik (A.V.S., V.G.); University of Helsinki, Institute for Molecular Medicine, Finland (FIMM) (A.J., M.P.); Department of Medicine, Mannheim Medical Faculty, Heidelberg University, Germany (M.E.K.); Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, United Kingdom (A.S.H.); Synlab Academy, Synlab Services GmbH, Mannheim, Germany and Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Austria (W.M.); National Heart, Lung, and Blood Institute and the Framingham Heart Study, National Institutes of Health, Bethesda, MD (C.O'D.); Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Sweden (E.I.); Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, CA (E.I.); Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (U.D.F.); Lebanese American University, School of Medicine, Beirut (P.Z.); Department of Health Sciences, University of Leicester, United Kingdom (J.R.T.); Imperial College Healthcare NHS Trust, London, United Kingdom (J.C.C., J.K.); Cardiovascular Science, National Heart and Lung Institute, Imperial College London, United Kingdom (J.K.); Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia (P.D.); deCODE Genetics, Sturlugata 8, IS-101 Reykjavik, Iceland (G.T., K.S.); University of Iceland, School of Medicine, Reykjavik, Iceland (G.T., K.S.); Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge (S.K.); Cardiovascular Research Center, Massachusetts General Hospital, Boston (S.K.); Center for Human Genetic Research, Massachusetts General Hospital, Boston (S.K.); Department of Medicine, Harvard Medical School, Boston, MA (S.K.); Department of Genetics, University of Pennsylvania, Philadelphia (D.J.R.); and Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (S.T.N., D.J.R.). saleheen@mail.med.upenn.edu mpr2144@cumc.columbia.edu. 2. From Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia (D.S., W.Z.); Center for Non-Communicable Diseases, Karachi, Pakistan (D.S., A.R., P.M.F., PROMIS); Department of Public Health and Primary Care, University of Cambridge, United Kingdom (R.Y., W.K.H., EPIC-CVD); Department of Cardiovascular Sciences, University of Leicester, United Kingdom (C.P.N., N.J.S.); Cardiology Division, Department of Medicine, Vanderbilt University, Nashville, TN (J.F.F., K.O.); Division of Cardiovascular Medicine, Radcliffe Department of Medicine & Wellcome Trust Centre for Human Genetics, University of Oxford, United Kingdom (A.G., M.F.); The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY (R.D.); Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY (R.D.); Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Canada (A.F.R.S., R.M.); Institute for Genetic Medicine and Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles (J.H., H.A.); Department of Epidemiology and Biostatistics, Imperial College London, United Kingdom (W.Z., J.C.C., J.K.); Department of Cardiology, Ealing Hospital NHS Trust, Middlesex, United Kingdom (W.Z., J.C.C.); Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden (R.J.S.); Helsinki University Central Hospital HUCH Heart and Lung Center, Helsinki, Uusimaa, Finland (J.S.); Cardiology Division, Department of Medicine and the Irving Institute for Clinical and Translational Research, Columbia University Medical Center, New York, NY (R.C.B., M.P.R.); William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (S.K., E.M., P.D.); Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands (S.S., A.D.); Department of Dietetics-Nutrition, Harokopio University, Athens, Greece (E.M., G.D.); National Institute for Health and Welfare, Helsinki, Finland (K.K., A.J., V.S., K.K., M.P.); MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, United Kingdom (J.H.Z., R.S.); INSERM, UMRS1138, Centre de Recherche des Cordeliers, Paris, France (D.G., N.W.); Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC (S.H.S.); Icelandic Heart Association, Kopavogur, Iceland (A.V.S., V.G.); Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, United Kingdom (N.v.Z., C.N.A.P.); Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC (A.J.C., D.W.B.); Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, Germany (C.W., J.E.); DZHK (German Research Center for Cardiovascular Research) partner site Hamburg-Lübeck-Kiel, Germany (C.W., J.E.); Deutsches Herzzentrum München, Technische Universität München, Germany (T.K., L.Z., H.S.); Klinikum rechts der Isar, München, Germany (T.K.); DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Germany (L.Z., H.S.); Department of Genetics, Washington University School of Medicine, St. Louis, MO (M.A.P., M.F.F.); Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston (A.G.); Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA (A.G.); Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Sweden (L.L.); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (N.L.P.); Department of Biostatistics Boston University School of Public Health Framingham Heart Study, MA (C.C.W.); Faculty of Medicine, University of Iceland, Reykjavik (A.V.S., V.G.); University of Helsinki, Institute for Molecular Medicine, Finland (FIMM) (A.J., M.P.); Department of Medicine, Mannheim Medical Faculty, Heidelberg University, Germany (M.E.K.); Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, United Kingdom (A.S.H.); Synlab Academy, Synlab Services GmbH, Mannheim, Germany and Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Austria (W.M.); National Heart, Lung, and Blood Institute and the Framingham Heart Study, National Institutes of Health, Bethesda, MD (C.O'D.); Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Sweden (E.I.); Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, CA (E.I.); Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (U.D.F.); Lebanese American University, School of Medicine, Beirut (P.Z.); Department of Health Sciences, University of Leicester, United Kingdom (J.R.T.); Imperial College Healthcare NHS Trust, London, United Kingdom (J.C.C., J.K.); Cardiovascular Science, National Heart and Lung Institute, Imperial College London, United Kingdom (J.K.); Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia (P.D.); deCODE Genetics, Sturlugata 8, IS-101 Reykjavik, Iceland (G.T., K.S.); University of Iceland, School of Medicine, Reykjavik, Iceland (G.T., K.S.); Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge (S.K.); Cardiovascular Research Center, Massachusetts General Hospital, Boston (S.K.); Center for Human Genetic Research, Massachusetts General Hospital, Boston (S.K.); Department of Medicine, Harvard Medical School, Boston, MA (S.K.); Department of Genetics, University of Pennsylvania, Philadelphia (D.J.R.); and Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (S.T.N., D.J.R.).
Abstract
BACKGROUND: Common diseases such as coronary heart disease (CHD) are complex in etiology. The interaction of genetic susceptibility with lifestyle factors may play a prominent role. However, gene-lifestyle interactions for CHD have been difficult to identify. Here, we investigate interaction of smoking behavior, a potent lifestyle factor, with genotypes that have been shown to associate with CHD risk. METHODS: We analyzed data on 60 919 CHD cases and 80 243 controls from 29 studies for gene-smoking interactions for genetic variants at 45 loci previously reported to be associated with CHD risk. We also studied 5 loci associated with smoking behavior. Study-specific gene-smoking interaction effects were calculated and pooled using fixed-effects meta-analyses. Interaction analyses were declared to be significant at a P value of <1.0×10-3 (Bonferroni correction for 50 tests). RESULTS: We identified novel gene-smoking interaction for a variant upstream of the ADAMTS7 gene. Every T allele of rs7178051 was associated with lower CHD risk by 12% in never-smokers (P=1.3×10-16) in comparison with 5% in ever-smokers (P=2.5×10-4), translating to a 60% loss of CHD protection conferred by this allelic variation in people who smoked tobacco (interaction P value=8.7×10-5). The protective T allele at rs7178051 was also associated with reduced ADAMTS7 expression in human aortic endothelial cells and lymphoblastoid cell lines. Exposure of human coronary artery smooth muscle cells to cigarette smoke extract led to induction of ADAMTS7. CONCLUSIONS: Allelic variation at rs7178051 that associates with reduced ADAMTS7 expression confers stronger CHD protection in never-smokers than in ever-smokers. Increased vascular ADAMTS7 expression may contribute to the loss of CHD protection in smokers.
BACKGROUND: Common diseases such as coronary heart disease (CHD) are complex in etiology. The interaction of genetic susceptibility with lifestyle factors may play a prominent role. However, gene-lifestyle interactions for CHD have been difficult to identify. Here, we investigate interaction of smoking behavior, a potent lifestyle factor, with genotypes that have been shown to associate with CHD risk. METHODS: We analyzed data on 60 919 CHD cases and 80 243 controls from 29 studies for gene-smoking interactions for genetic variants at 45 loci previously reported to be associated with CHD risk. We also studied 5 loci associated with smoking behavior. Study-specific gene-smoking interaction effects were calculated and pooled using fixed-effects meta-analyses. Interaction analyses were declared to be significant at a P value of <1.0×10-3 (Bonferroni correction for 50 tests). RESULTS: We identified novel gene-smoking interaction for a variant upstream of the ADAMTS7 gene. Every T allele of rs7178051 was associated with lower CHD risk by 12% in never-smokers (P=1.3×10-16) in comparison with 5% in ever-smokers (P=2.5×10-4), translating to a 60% loss of CHD protection conferred by this allelic variation in people who smoked tobacco (interaction P value=8.7×10-5). The protective T allele at rs7178051 was also associated with reduced ADAMTS7 expression in human aortic endothelial cells and lymphoblastoid cell lines. Exposure of human coronary artery smooth muscle cells to cigarette smoke extract led to induction of ADAMTS7. CONCLUSIONS: Allelic variation at rs7178051 that associates with reduced ADAMTS7 expression confers stronger CHD protection in never-smokers than in ever-smokers. Increased vascular ADAMTS7 expression may contribute to the loss of CHD protection in smokers.
Authors: Jason M Torres; Eric R Gamazon; Esteban J Parra; Jennifer E Below; Adan Valladares-Salgado; Niels Wacher; Miguel Cruz; Craig L Hanis; Nancy J Cox Journal: Am J Hum Genet Date: 2014-10-30 Impact factor: 11.025
Authors: Jaspal S Kooner; Danish Saleheen; Xueling Sim; Joban Sehmi; Weihua Zhang; Philippe Frossard; Latonya F Been; Kee-Seng Chia; Antigone S Dimas; Neelam Hassanali; Tazeen Jafar; Jeremy B M Jowett; Xinzhong Li; Venkatesan Radha; Simon D Rees; Fumihiko Takeuchi; Robin Young; Tin Aung; Abdul Basit; Manickam Chidambaram; Debashish Das; Elin Grundberg; Asa K Hedman; Zafar I Hydrie; Muhammed Islam; Chiea-Chuen Khor; Sudhir Kowlessur; Malene M Kristensen; Samuel Liju; Wei-Yen Lim; David R Matthews; Jianjun Liu; Andrew P Morris; Alexandra C Nica; Janani M Pinidiyapathirage; Inga Prokopenko; Asif Rasheed; Maria Samuel; Nabi Shah; A Samad Shera; Kerrin S Small; Chen Suo; Ananda R Wickremasinghe; Tien Yin Wong; Mingyu Yang; Fan Zhang; Goncalo R Abecasis; Anthony H Barnett; Mark Caulfield; Panos Deloukas; Timothy M Frayling; Philippe Froguel; Norihiro Kato; Prasad Katulanda; M Ann Kelly; Junbin Liang; Viswanathan Mohan; Dharambir K Sanghera; James Scott; Mark Seielstad; Paul Z Zimmet; Paul Elliott; Yik Ying Teo; Mark I McCarthy; John Danesh; E Shyong Tai; John C Chambers Journal: Nat Genet Date: 2011-08-28 Impact factor: 38.330
Authors: Stephanie Saade; Jean-Baptiste Cazier; Michella Ghassibe-Sabbagh; Sonia Youhanna; Danielle A Badro; Yoichiro Kamatani; Jörg Hager; Joumana S Yeretzian; Georges El-Khazen; Marc Haber; Angelique K Salloum; Bouchra Douaihy; Raed Othman; Nabil Shasha; Samer Kabbani; Hamid El Bayeh; Elie Chammas; Martin Farrall; Dominique Gauguier; Daniel E Platt; Pierre A Zalloua Journal: PLoS One Date: 2011-12-27 Impact factor: 3.240
Authors: Clint L Miller; D Ryan Anderson; Ramendra K Kundu; Azad Raiesdana; Sylvia T Nürnberg; Roxanne Diaz; Karen Cheng; Nicholas J Leeper; Chung-Hsing Chen; I-Shou Chang; Eric E Schadt; Chao Agnes Hsiung; Themistocles L Assimes; Thomas Quertermous Journal: PLoS Genet Date: 2013-07-18 Impact factor: 5.917
Authors: Elin Grundberg; Kerrin S Small; Åsa K Hedman; Alexandra C Nica; Alfonso Buil; Sarah Keildson; Jordana T Bell; Tsun-Po Yang; Eshwar Meduri; Amy Barrett; James Nisbett; Magdalena Sekowska; Alicja Wilk; So-Youn Shin; Daniel Glass; Mary Travers; Josine L Min; Sue Ring; Karen Ho; Gudmar Thorleifsson; Augustine Kong; Unnur Thorsteindottir; Chrysanthi Ainali; Antigone S Dimas; Neelam Hassanali; Catherine Ingle; David Knowles; Maria Krestyaninova; Christopher E Lowe; Paola Di Meglio; Stephen B Montgomery; Leopold Parts; Simon Potter; Gabriela Surdulescu; Loukia Tsaprouni; Sophia Tsoka; Veronique Bataille; Richard Durbin; Frank O Nestle; Stephen O'Rahilly; Nicole Soranzo; Cecilia M Lindgren; Krina T Zondervan; Kourosh R Ahmadi; Eric E Schadt; Kari Stefansson; George Davey Smith; Mark I McCarthy; Panos Deloukas; Emmanouil T Dermitzakis; Tim D Spector Journal: Nat Genet Date: 2012-09-02 Impact factor: 38.330
Authors: Michael V Holmes; Ruth Frikke-Schmidt; Daniela Melis; Robert Luben; Folkert W Asselbergs; Jolanda M A Boer; Jackie Cooper; Jutta Palmen; Pia Horvat; Jorgen Engmann; Ka-Wah Li; N Charlotte Onland-Moret; Marten H Hofker; Meena Kumari; Brendan J Keating; Jaroslav A Hubacek; Vera Adamkova; Ruzena Kubinova; Martin Bobak; Kay-Tee Khaw; Børge G Nordestgaard; Nick Wareham; Steve E Humphries; Claudia Langenberg; Anne Tybjaerg-Hansen; Philippa J Talmud Journal: Atherosclerosis Date: 2014-08-15 Impact factor: 5.162
Authors: Michael G Levin; Rachel L Kember; Renae Judy; David Birtwell; Heather Williams; Zolt Arany; Jay Giri; Marie Guerraty; Tom Cappola; Jinbo Chen; Daniel J Rader; Scott M Damrauer Journal: Circ Genom Precis Med Date: 2018-11
Authors: Yunfeng Huang; Qin Hui; Marta Gwinn; Yi-Juan Hu; Arshed A Quyyumi; Viola Vaccarino; Yan V Sun Journal: Genet Epidemiol Date: 2022-02-16 Impact factor: 2.135
Authors: Kenneth Chan; Xiangyuan Pu; Pratik Sandesara; Robin N Poston; Iain A Simpson; Arshed A Quyyumi; Shu Ye; Riyaz S Patel Journal: J Am Heart Assoc Date: 2017-10-31 Impact factor: 5.501