Genome-wide association study for coronary artery calcification with follow-up in myocardial infarction.
O'Donnell CJ., Kavousi M., Smith AV., Kardia SLR., Feitosa MF., Hwang S-J., Sun YV., Province MA., Aspelund T., Dehghan A., Hoffmann U., Bielak LF., Zhang Q., Eiriksdottir G., van Duijn CM., Fox CS., de Andrade M., Kraja AT., Sigurdsson S., Elias-Smale SE., Murabito JM., Launer LJ., van der Lugt A., Kathiresan S., CARDIoGRAM Consortium None., Krestin GP., Herrington DM., Howard TD., Liu Y., Post W., Mitchell BD., O'Connell JR., Shen H., Shuldiner AR., Altshuler D., Elosua R., Salomaa V., Schwartz SM., Siscovick DS., Voight BF., Bis JC., Glazer NL., Psaty BM., Boerwinkle E., Heiss G., Blankenberg S., Zeller T., Wild PS., Schnabel RB., Schillert A., Ziegler A., Münzel TF., White CC., Rotter JI., Nalls M., Oudkerk M., Johnson AD., Newman AB., Uitterlinden AG., Massaro JM., Cunningham J., Harris TB., Hofman A., Peyser PA., Borecki IB., Cupples LA., Gudnason V., Witteman JCM.
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.