BACKGROUND: Coronary artery calcification (CAC) detected by computed tomography is a noninvasive measure of coronary atherosclerosis, which underlies most cases of myocardial infarction (MI). We sought to identify common genetic variants associated with CAC and further investigate their associations with MI. METHODS AND RESULTS: Computed tomography was used to assess quantity of CAC. A meta-analysis of genome-wide association studies for CAC was performed in 9961 men and women from 5 independent community-based cohorts, with replication in 3 additional independent cohorts (n=6032). We examined the top single-nucleotide polymorphisms (SNPs) associated with CAC quantity for association with MI in multiple large genome-wide association studies of MI. Genome-wide significant associations with CAC for SNPs on chromosome 9p21 near CDKN2A and CDKN2B (top SNP: rs1333049; P=7.58×10(-19)) and 6p24 (top SNP: rs9349379, within the PHACTR1 gene; P=2.65×10(-11)) replicated for CAC and for MI. Additionally, there is evidence for concordance of SNP associations with both CAC and MI at a number of other loci, including 3q22 (MRAS gene), 13q34 (COL4A1/COL4A2 genes), and 1p13 (SORT1 gene). CONCLUSIONS: SNPs in the 9p21 and PHACTR1 gene loci were strongly associated with CAC and MI, and there are suggestive associations with both CAC and MI of SNPs in additional loci. Multiple genetic loci are associated with development of both underlying coronary atherosclerosis and clinical events.
BACKGROUND:Coronary artery calcification (CAC) detected by computed tomography is a noninvasive measure of coronary atherosclerosis, which underlies most cases of myocardial infarction (MI). We sought to identify common genetic variants associated with CAC and further investigate their associations with MI. METHODS AND RESULTS: Computed tomography was used to assess quantity of CAC. A meta-analysis of genome-wide association studies for CAC was performed in 9961 men and women from 5 independent community-based cohorts, with replication in 3 additional independent cohorts (n=6032). We examined the top single-nucleotide polymorphisms (SNPs) associated with CAC quantity for association with MI in multiple large genome-wide association studies of MI. Genome-wide significant associations with CAC for SNPs on chromosome 9p21 near CDKN2A and CDKN2B (top SNP: rs1333049; P=7.58×10(-19)) and 6p24 (top SNP: rs9349379, within the PHACTR1 gene; P=2.65×10(-11)) replicated for CAC and for MI. Additionally, there is evidence for concordance of SNP associations with both CAC and MI at a number of other loci, including 3q22 (MRAS gene), 13q34 (COL4A1/COL4A2 genes), and 1p13 (SORT1 gene). CONCLUSIONS: SNPs in the 9p21 and PHACTR1 gene loci were strongly associated with CAC and MI, and there are suggestive associations with both CAC and MI of SNPs in additional loci. Multiple genetic loci are associated with development of both underlying coronary atherosclerosis and clinical events.
Authors: Anthony L Daniell; Nathan D Wong; John D Friedman; Nachum Ben-Yosef; Romalisa Miranda-Peats; Sean W Hayes; Xingping Kang; Maria G Sciammarella; Ling de Yang; Guido Germano; Daniel S Berman Journal: AJR Am J Roentgenol Date: 2005-12 Impact factor: 3.959
Authors: Anna Helgadottir; Gudmar Thorleifsson; Andrei Manolescu; Solveig Gretarsdottir; Thorarinn Blondal; Aslaug Jonasdottir; Adalbjorg Jonasdottir; Asgeir Sigurdsson; Adam Baker; Arnar Palsson; Gisli Masson; Daniel F Gudbjartsson; Kristinn P Magnusson; Karl Andersen; Allan I Levey; Valgerdur M Backman; Sigurborg Matthiasdottir; Thorbjorg Jonsdottir; Stefan Palsson; Helga Einarsdottir; Steinunn Gunnarsdottir; Arnaldur Gylfason; Viola Vaccarino; W Craig Hooper; Muredach P Reilly; Christopher B Granger; Harland Austin; Daniel J Rader; Svati H Shah; Arshed A Quyyumi; Jeffrey R Gulcher; Gudmundur Thorgeirsson; Unnur Thorsteinsdottir; Augustine Kong; Kari Stefansson Journal: Science Date: 2007-05-03 Impact factor: 47.728
Authors: Greta Lee Splansky; Diane Corey; Qiong Yang; Larry D Atwood; L Adrienne Cupples; Emelia J Benjamin; Ralph B D'Agostino; Caroline S Fox; Martin G Larson; Joanne M Murabito; Christopher J O'Donnell; Ramachandran S Vasan; Philip A Wolf; Daniel Levy Journal: Am J Epidemiol Date: 2007-03-19 Impact factor: 4.897
Authors: Douglas B Gould; F Campbell Phalan; Saskia E van Mil; John P Sundberg; Katayoun Vahedi; Pascale Massin; Marie Germaine Bousser; Peter Heutink; Jeffrey H Miner; Elisabeth Tournier-Lasserve; Simon W M John Journal: N Engl J Med Date: 2006-04-06 Impact factor: 91.245
Authors: Ruth McPherson; Alexander Pertsemlidis; Nihan Kavaslar; Alexandre Stewart; Robert Roberts; David R Cox; David A Hinds; Len A Pennacchio; Anne Tybjaerg-Hansen; Aaron R Folsom; Eric Boerwinkle; Helen H Hobbs; Jonathan C Cohen Journal: Science Date: 2007-05-03 Impact factor: 47.728
Authors: Nisha I Parikh; Shih-Jen Hwang; Martin G Larson; L Adrienne Cupples; Caroline S Fox; Emily S Manders; Joanne M Murabito; Joseph M Massaro; Udo Hoffmann; Christopher J O'Donnell Journal: Circulation Date: 2007-09-04 Impact factor: 29.690
Authors: Nilesh J Samani; Jeanette Erdmann; Alistair S Hall; Christian Hengstenberg; Massimo Mangino; Bjoern Mayer; Richard J Dixon; Thomas Meitinger; Peter Braund; H-Erich Wichmann; Jennifer H Barrett; Inke R König; Suzanne E Stevens; Silke Szymczak; David-Alexandre Tregouet; Mark M Iles; Friedrich Pahlke; Helen Pollard; Wolfgang Lieb; Francois Cambien; Marcus Fischer; Willem Ouwehand; Stefan Blankenberg; Anthony J Balmforth; Andrea Baessler; Stephen G Ball; Tim M Strom; Ingrid Braenne; Christian Gieger; Panos Deloukas; Martin D Tobin; Andreas Ziegler; John R Thompson; Heribert Schunkert Journal: N Engl J Med Date: 2007-07-18 Impact factor: 91.245
Authors: Albert Hofman; Guy G O Brusselle; Sarwa Darwish Murad; Cornelia M van Duijn; Oscar H Franco; André Goedegebure; M Arfan Ikram; Caroline C W Klaver; Tamar E C Nijsten; Robin P Peeters; Bruno H Ch Stricker; Henning W Tiemeier; André G Uitterlinden; Meike W Vernooij Journal: Eur J Epidemiol Date: 2015-09-19 Impact factor: 8.082
Authors: Mélissa Beaudoin; Rajat M Gupta; Hong-Hee Won; Ken Sin Lo; Ron Do; Christopher A Henderson; Claire Lavoie-St-Amour; Simon Langlois; Daniel Rivas; Stephanie Lehoux; Sekar Kathiresan; Jean-Claude Tardif; Kiran Musunuru; Guillaume Lettre Journal: Arterioscler Thromb Vasc Biol Date: 2015-04-02 Impact factor: 8.311
Authors: Albert Hofman; Sarwa Darwish Murad; Cornelia M van Duijn; Oscar H Franco; André Goedegebure; M Arfan Ikram; Caroline C W Klaver; Tamar E C Nijsten; Robin P Peeters; Bruno H Ch Stricker; Henning W Tiemeier; André G Uitterlinden; Meike W Vernooij Journal: Eur J Epidemiol Date: 2013-11-21 Impact factor: 8.082
Authors: Xiaoling Zhang; Andrew D Johnson; Audrey E Hendricks; Shih-Jen Hwang; Kahraman Tanriverdi; Santhi K Ganesh; Nicholas L Smith; Patricia A Peyser; Jane E Freedman; Christopher J O'Donnell Journal: Hum Mol Genet Date: 2013-09-20 Impact factor: 6.150
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