Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms.
Howson JMM., Zhao W., Barnes DR., Ho W-K., Young R., Paul DS., Waite LL., Freitag DF., Fauman EB., Salfati EL., Sun BB., Eicher JD., Johnson AD., Sheu WHH., Nielsen SF., Lin W-Y., Surendran P., Malarstig A., Wilk JB., Tybjærg-Hansen A., Rasmussen KL., Kamstrup PR., Deloukas P., Erdmann J., Kathiresan S., Samani NJ., Schunkert H., Watkins H., CARDIoGRAMplusC4D None., Do R., Rader DJ., Johnson JA., Hazen SL., Quyyumi AA., Spertus JA., Pepine CJ., Franceschini N., Justice A., Reiner AP., Buyske S., Hindorff LA., Carty CL., North KE., Kooperberg C., Boerwinkle E., Young K., Graff M., Peters U., Absher D., Hsiung CA., Lee W-J., Taylor KD., Chen Y-H., Lee I-T., Guo X., Chung R-H., Hung Y-J., Rotter JI., Juang J-MJ., Quertermous T., Wang T-D., Rasheed A., Frossard P., Alam DS., Majumder AAS., Di Angelantonio E., Chowdhury R., EPIC-CVD None., Chen Y-DI., Nordestgaard BG., Assimes TL., Danesh J., Butterworth AS., Saleheen D.
Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10-8, in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms.