BACKGROUND: Recent genome-wide association studies (GWAS) have identified several novel loci that reproducibly associate with coronary artery disease (CAD) and/or myocardial infarction risk. However, known common CAD risk variants explain only 10% of the predicted genetic heritability of the disease, suggesting that important genetic signals remain to be discovered. METHODS AND RESULTS: We performed a discovery meta-analysis of 5 GWAS involving 13 949 subjects (7123 cases, 6826 control subjects) imputed at approximately 5 million single nucleotide polymorphisms, using pilot 1000 Genomes-based haplotypes. Promising loci were followed up in an additional 5 studies with 11 032 subjects (5211 cases, 5821 control subjects). A novel CAD locus on chromosome 6p21.3 in the major histocompatibility complex (MHC) between HCG27 and HLA-C was identified and achieved genome-wide significance in the combined analysis (rs3869109; p(discovery)=3.3×10(-7), p(replication)=5.3×10(-4)p(combined)=1.12×10(-9)). A subanalysis combining discovery GWAS showed an attenuation of significance when stringent corrections for European population structure were used (P=4.1×10(-10) versus 3.2×10(-7)), suggesting that the observed signal is partly confounded due to population stratification. This gene dense region plays an important role in inflammation, immunity, and self-cell recognition. To determine whether the underlying association was driven by MHC class I alleles, we statistically imputed common HLA alleles into the discovery subjects; however, no single common HLA type contributed significantly or fully explained the observed association. CONCLUSIONS: We have identified a novel locus in the MHC associated with CAD. MHC genes regulate inflammation and T-cell responses that contribute importantly to the initiation and propagation of atherosclerosis. Further laboratory studies will be required to understand the biological basis of this association and identify the causative allele(s).
BACKGROUND: Recent genome-wide association studies (GWAS) have identified several novel loci that reproducibly associate with coronary artery disease (CAD) and/or myocardial infarction risk. However, known common CAD risk variants explain only 10% of the predicted genetic heritability of the disease, suggesting that important genetic signals remain to be discovered. METHODS AND RESULTS: We performed a discovery meta-analysis of 5 GWAS involving 13 949 subjects (7123 cases, 6826 control subjects) imputed at approximately 5 million single nucleotide polymorphisms, using pilot 1000 Genomes-based haplotypes. Promising loci were followed up in an additional 5 studies with 11 032 subjects (5211 cases, 5821 control subjects). A novel CAD locus on chromosome 6p21.3 in the major histocompatibility complex (MHC) between HCG27 and HLA-C was identified and achieved genome-wide significance in the combined analysis (rs3869109; p(discovery)=3.3×10(-7), p(replication)=5.3×10(-4)p(combined)=1.12×10(-9)). A subanalysis combining discovery GWAS showed an attenuation of significance when stringent corrections for European population structure were used (P=4.1×10(-10) versus 3.2×10(-7)), suggesting that the observed signal is partly confounded due to population stratification. This gene dense region plays an important role in inflammation, immunity, and self-cell recognition. To determine whether the underlying association was driven by MHC class I alleles, we statistically imputed common HLA alleles into the discovery subjects; however, no single common HLA type contributed significantly or fully explained the observed association. CONCLUSIONS: We have identified a novel locus in the MHC associated with CAD. MHC genes regulate inflammation and T-cell responses that contribute importantly to the initiation and propagation of atherosclerosis. Further laboratory studies will be required to understand the biological basis of this association and identify the causative allele(s).
Authors: David-Alexandre Trégouët; Inke R König; Jeanette Erdmann; Alexandru Munteanu; Peter S Braund; Alistair S Hall; Anika Grosshennig; Patrick Linsel-Nitschke; Claire Perret; Maylis DeSuremain; Thomas Meitinger; Ben J Wright; Michael Preuss; Anthony J Balmforth; Stephen G Ball; Christa Meisinger; Cécile Germain; Alun Evans; Dominique Arveiler; Gérald Luc; Jean-Bernard Ruidavets; Caroline Morrison; Pim van der Harst; Stefan Schreiber; Katharina Neureuther; Arne Schäfer; Peter Bugert; Nour E El Mokhtari; Jürgen Schrezenmeir; Klaus Stark; Diana Rubin; H-Erich Wichmann; Christian Hengstenberg; Willem Ouwehand; Andreas Ziegler; Laurence Tiret; John R Thompson; Francois Cambien; Heribert Schunkert; Nilesh J Samani Journal: Nat Genet Date: 2009-02-08 Impact factor: 38.330
Authors: Philipp S Wild; Tanja Zeller; Arne Schillert; Silke Szymczak; Christoph R Sinning; Arne Deiseroth; Renate B Schnabel; Edith Lubos; Till Keller; Medea S Eleftheriadis; Christoph Bickel; Hans J Rupprecht; Sandra Wilde; Heidi Rossmann; Patrick Diemert; L Adrienne Cupples; Claire Perret; Jeanette Erdmann; Klaus Stark; Marcus E Kleber; Stephen E Epstein; Benjamin F Voight; Kari Kuulasmaa; Mingyao Li; Arne S Schäfer; Norman Klopp; Peter S Braund; Hendrik B Sager; Serkalem Demissie; Carole Proust; Inke R König; Heinz-Erich Wichmann; Wibke Reinhard; Michael M Hoffmann; Jarmo Virtamo; Mary Susan Burnett; David Siscovick; Per Gunnar Wiklund; Liming Qu; Nour Eddine El Mokthari; John R Thompson; Annette Peters; Albert V Smith; Emmanuelle Yon; Jens Baumert; Christian Hengstenberg; Winfried März; Philippe Amouyel; Joseph Devaney; Stephen M Schwartz; Olli Saarela; Nehal N Mehta; Diana Rubin; Kaisa Silander; Alistair S Hall; Jean Ferrieres; Tamara B Harris; Olle Melander; Frank Kee; Hakon Hakonarson; Juergen Schrezenmeir; Vilmundur Gudnason; Roberto Elosua; Dominique Arveiler; Alun Evans; Daniel J Rader; Thomas Illig; Stefan Schreiber; Joshua C Bis; David Altshuler; Maryam Kavousi; Jaqueline C M Witteman; Andre G Uitterlinden; Albert Hofman; Aaron R Folsom; Maja Barbalic; Eric Boerwinkle; Sekar Kathiresan; Muredach P Reilly; Christopher J O'Donnell; Nilesh J Samani; Heribert Schunkert; Francois Cambien; Karl J Lackner; Laurence Tiret; Veikko Salomaa; Thomas Munzel; Andreas Ziegler; Stefan Blankenberg Journal: Circ Cardiovasc Genet Date: 2011-05-23
Authors: Jeanette Erdmann; Christina Willenborg; Janja Nahrstaedt; Michael Preuss; Inke R König; Jens Baumert; Patrick Linsel-Nitschke; Christian Gieger; Stephanie Tennstedt; Petra Belcredi; Zouhair Aherrahrou; Norman Klopp; Christina Loley; Klaus Stark; Christian Hengstenberg; Petra Bruse; Jennifer Freyer; Arnika K Wagner; Anja Medack; Wolfgang Lieb; Anika Grosshennig; Hendrik B Sager; Adrian Reinhardt; Arne Schäfer; Stefan Schreiber; Nour Eddine El Mokhtari; Dorette Raaz-Schrauder; Thomas Illig; Christoph D Garlichs; Arif B Ekici; André Reis; Jürgen Schrezenmeir; Diana Rubin; Andreas Ziegler; H-E Wichmann; Angela Doering; Christa Meisinger; Thomas Meitinger; Annette Peters; Heribert Schunkert Journal: Eur Heart J Date: 2010-11-18 Impact factor: 29.983
Authors: Peter Duewell; Hajime Kono; Katey J Rayner; Cherilyn M Sirois; Gregory Vladimer; Franz G Bauernfeind; George S Abela; Luigi Franchi; Gabriel Nuñez; Max Schnurr; Terje Espevik; Egil Lien; Katherine A Fitzgerald; Kenneth L Rock; Kathryn J Moore; Samuel D Wright; Veit Hornung; Eicke Latz Journal: Nature Date: 2010-04-29 Impact factor: 49.962
Authors: Jeanette Erdmann; Anika Grosshennig; Peter S Braund; Inke R König; Christian Hengstenberg; Alistair S Hall; Patrick Linsel-Nitschke; Sekar Kathiresan; Ben Wright; David-Alexandre Trégouët; Francois Cambien; Petra Bruse; Zouhair Aherrahrou; Arnika K Wagner; Klaus Stark; Stephen M Schwartz; Veikko Salomaa; Roberto Elosua; Olle Melander; Benjamin F Voight; Christopher J O'Donnell; Leena Peltonen; David S Siscovick; David Altshuler; Piera Angelica Merlini; Flora Peyvandi; Luisa Bernardinelli; Diego Ardissino; Arne Schillert; Stefan Blankenberg; Tanja Zeller; Philipp Wild; Daniel F Schwarz; Laurence Tiret; Claire Perret; Stefan Schreiber; Nour Eddine El Mokhtari; Arne Schäfer; Winfried März; Wilfried Renner; Peter Bugert; Harald Klüter; Jürgen Schrezenmeir; Diana Rubin; Stephen G Ball; Anthony J Balmforth; H-Erich Wichmann; Thomas Meitinger; Marcus Fischer; Christa Meisinger; Jens Baumert; Annette Peters; Willem H Ouwehand; Panos Deloukas; John R Thompson; Andreas Ziegler; Nilesh J Samani; Heribert Schunkert Journal: Nat Genet Date: 2009-02-08 Impact factor: 38.330
Authors: Muredach P Reilly; Mingyao Li; Jing He; Jane F Ferguson; Ioannis M Stylianou; Nehal N Mehta; Mary Susan Burnett; Joseph M Devaney; Christopher W Knouff; John R Thompson; Benjamin D Horne; Alexandre F R Stewart; Themistocles L Assimes; Philipp S Wild; Hooman Allayee; Patrick Linsel Nitschke; Riyaz S Patel; Nicola Martinelli; Domenico Girelli; Arshed A Quyyumi; Jeffrey L Anderson; Jeanette Erdmann; Alistair S Hall; Heribert Schunkert; Thomas Quertermous; Stefan Blankenberg; Stanley L Hazen; Robert Roberts; Sekar Kathiresan; Nilesh J Samani; Stephen E Epstein; Daniel J Rader Journal: Lancet Date: 2011-01-14 Impact factor: 79.321
Authors: Sekar Kathiresan; Benjamin F Voight; Shaun Purcell; Kiran Musunuru; Diego Ardissino; Pier M Mannucci; Sonia Anand; James C Engert; Nilesh J Samani; Heribert Schunkert; Jeanette Erdmann; Muredach P Reilly; Daniel J Rader; Thomas Morgan; John A Spertus; Monika Stoll; Domenico Girelli; Pascal P McKeown; Chris C Patterson; David S Siscovick; Christopher J O'Donnell; Roberto Elosua; Leena Peltonen; Veikko Salomaa; Stephen M Schwartz; Olle Melander; David Altshuler; Diego Ardissino; Pier Angelica Merlini; Carlo Berzuini; Luisa Bernardinelli; Flora Peyvandi; Marco Tubaro; Patrizia Celli; Maurizio Ferrario; Raffaela Fetiveau; Nicola Marziliano; Giorgio Casari; Michele Galli; Flavio Ribichini; Marco Rossi; Francesco Bernardi; Pietro Zonzin; Alberto Piazza; Pier M Mannucci; Stephen M Schwartz; David S Siscovick; Jean Yee; Yechiel Friedlander; Roberto Elosua; Jaume Marrugat; Gavin Lucas; Isaac Subirana; Joan Sala; Rafael Ramos; Sekar Kathiresan; James B Meigs; Gordon Williams; David M Nathan; Calum A MacRae; Christopher J O'Donnell; Veikko Salomaa; Aki S Havulinna; Leena Peltonen; Olle Melander; Goran Berglund; Benjamin F Voight; Sekar Kathiresan; Joel N Hirschhorn; Rosanna Asselta; Stefano Duga; Marta Spreafico; Kiran Musunuru; Mark J Daly; Shaun Purcell; Benjamin F Voight; Shaun Purcell; James Nemesh; Joshua M Korn; Steven A McCarroll; Stephen M Schwartz; Jean Yee; Sekar Kathiresan; Gavin Lucas; Isaac Subirana; Roberto Elosua; Aarti Surti; Candace Guiducci; Lauren Gianniny; Daniel Mirel; Melissa Parkin; Noel Burtt; Stacey B Gabriel; Nilesh J Samani; John R Thompson; Peter S Braund; Benjamin J Wright; Anthony J Balmforth; Stephen G Ball; Alistair S Hall; Heribert Schunkert; Jeanette Erdmann; Patrick Linsel-Nitschke; Wolfgang Lieb; Andreas Ziegler; Inke König; Christian Hengstenberg; Marcus Fischer; Klaus Stark; Anika Grosshennig; Michael Preuss; H-Erich Wichmann; Stefan Schreiber; Heribert Schunkert; Nilesh J Samani; Jeanette Erdmann; Willem Ouwehand; Christian Hengstenberg; Panos Deloukas; Michael Scholz; Francois Cambien; Muredach P Reilly; Mingyao Li; Zhen Chen; Robert Wilensky; William Matthai; Atif Qasim; Hakon H Hakonarson; Joe Devaney; Mary-Susan Burnett; Augusto D Pichard; Kenneth M Kent; Lowell Satler; Joseph M Lindsay; Ron Waksman; Christopher W Knouff; Dawn M Waterworth; Max C Walker; Vincent Mooser; Stephen E Epstein; Daniel J Rader; Thomas Scheffold; Klaus Berger; Monika Stoll; Andreas Huge; Domenico Girelli; Nicola Martinelli; Oliviero Olivieri; Roberto Corrocher; Thomas Morgan; John A Spertus; Pascal McKeown; Chris C Patterson; Heribert Schunkert; Erdmann Erdmann; Patrick Linsel-Nitschke; Wolfgang Lieb; Andreas Ziegler; Inke R König; Christian Hengstenberg; Marcus Fischer; Klaus Stark; Anika Grosshennig; Michael Preuss; H-Erich Wichmann; Stefan Schreiber; Hilma Hólm; Gudmar Thorleifsson; Unnur Thorsteinsdottir; Kari Stefansson; James C Engert; Ron Do; Changchun Xie; Sonia Anand; Sekar Kathiresan; Diego Ardissino; Pier M Mannucci; David Siscovick; Christopher J O'Donnell; Nilesh J Samani; Olle Melander; Roberto Elosua; Leena Peltonen; Veikko Salomaa; Stephen M Schwartz; David Altshuler Journal: Nat Genet Date: 2009-02-08 Impact factor: 38.330
Authors: Jeffrey C Barrett; James C Lee; Charles W Lees; Natalie J Prescott; Carl A Anderson; Anne Phillips; Emma Wesley; Kirstie Parnell; Hu Zhang; Hazel Drummond; Elaine R Nimmo; Dunecan Massey; Kasia Blaszczyk; Timothy Elliott; Lynn Cotterill; Helen Dallal; Alan J Lobo; Craig Mowat; Jeremy D Sanderson; Derek P Jewell; William G Newman; Cathryn Edwards; Tariq Ahmad; John C Mansfield; Jack Satsangi; Miles Parkes; Christopher G Mathew; Peter Donnelly; Leena Peltonen; Jenefer M Blackwell; Elvira Bramon; Matthew A Brown; Juan P Casas; Aiden Corvin; Nicholas Craddock; Panos Deloukas; Audrey Duncanson; Janusz Jankowski; Hugh S Markus; Christopher G Mathew; Mark I McCarthy; Colin N A Palmer; Robert Plomin; Anna Rautanen; Stephen J Sawcer; Nilesh Samani; Richard C Trembath; Anath C Viswanathan; Nicholas Wood; Chris C A Spencer; Jeffrey C Barrett; Céline Bellenguez; Daniel Davison; Colin Freeman; Amy Strange; Peter Donnelly; Cordelia Langford; Sarah E Hunt; Sarah Edkins; Rhian Gwilliam; Hannah Blackburn; Suzannah J Bumpstead; Serge Dronov; Matthew Gillman; Emma Gray; Naomi Hammond; Alagurevathi Jayakumar; Owen T McCann; Jennifer Liddle; Marc L Perez; Simon C Potter; Radhi Ravindrarajah; Michelle Ricketts; Matthew Waller; Paul Weston; Sara Widaa; Pamela Whittaker; Panos Deloukas; Leena Peltonen; Christopher G Mathew; Jenefer M Blackwell; Matthew A Brown; Aiden Corvin; Mark I McCarthy; Chris C A Spencer; Antony P Attwood; Jonathan Stephens; Jennifer Sambrook; Willem H Ouwehand; Wendy L McArdle; Susan M Ring; David P Strachan Journal: Nat Genet Date: 2009-11-15 Impact factor: 38.330
Authors: William E Kraus; Christopher B Granger; Michael H Sketch; Mark P Donahue; Geoffrey S Ginsburg; Elizabeth R Hauser; Carol Haynes; L Kristin Newby; Melissa Hurdle; Z Elaine Dowdy; Svati H Shah Journal: J Cardiovasc Transl Res Date: 2015-08-14 Impact factor: 4.132
Authors: Nathan O Stitziel; Gina M Peloso; Marianne Abifadel; Angelo B Cefalu; Sigrid Fouchier; M Mahdi Motazacker; Hayato Tada; Daniel B Larach; Zuhier Awan; Jorge F Haller; Clive R Pullinger; Mathilde Varret; Jean-Pierre Rabès; Davide Noto; Patrizia Tarugi; Masa-Aki Kawashiri; Atsushi Nohara; Masakazu Yamagishi; Marjorie Risman; Rahul Deo; Isabelle Ruel; Jay Shendure; Deborah A Nickerson; James G Wilson; Stephen S Rich; Namrata Gupta; Deborah N Farlow; Benjamin M Neale; Mark J Daly; John P Kane; Mason W Freeman; Jacques Genest; Daniel J Rader; Hiroshi Mabuchi; John J P Kastelein; G Kees Hovingh; Maurizio R Averna; Stacey Gabriel; Catherine Boileau; Sekar Kathiresan Journal: Circ Cardiovasc Genet Date: 2015-01-27
Authors: David Della-Morte; Liyong Wang; Ashley Beecham; Susan H Blanton; Hongyu Zhao; Ralph L Sacco; Tatjana Rundek; Chuanhui Dong Journal: J Neurol Sci Date: 2014-06-14 Impact factor: 3.181
Authors: Iván Ferraz-Amaro; Robert Winchester; Peter K Gregersen; Richard J Reynolds; Mary Chester Wasko; Anette Oeser; Cecilia P Chung; C Michael Stein; Jon T Giles; Joan M Bathon Journal: Arthritis Rheumatol Date: 2017-03 Impact factor: 10.995
Authors: Josephine H Li; Sunil Suchindran; Svati H Shah; William E Kraus; Geoffrey S Ginsburg; Deepak Voora Journal: Pharmacogenomics Date: 2015 Impact factor: 2.533
Authors: Mitchell J Machiela; Constance Chen; Liming Liang; W Ryan Diver; Victoria L Stevens; Konstantinos K Tsilidis; Christopher A Haiman; Stephen J Chanock; David J Hunter; Peter Kraft Journal: Prostate Date: 2012-12-19 Impact factor: 4.104
Authors: Sergey Filippov; Stephen L Pinkosky; Richard J Lister; Catherine Pawloski; Jeffrey C Hanselman; Clay T Cramer; Rai Ajit K Srivastava; Timothy R Hurley; Cheryl D Bradshaw; Mark A Spahr; Roger S Newton Journal: J Lipid Res Date: 2013-05-24 Impact factor: 5.922