Genome-Wide Association Study for Coronary Artery Calcification With Follow-Up in Myocardial Infarction

Abstract

Background Coronary artery calcification (CAC) detected by computed tomography is a non-invasive measure of coronary atherosclerosis, that underlies most cases of myocardial infarction (MI). We aimed 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 carried out in 9,961 men and women from five independent community-based cohorts, with replication in three additional independent cohorts (n=6,032). 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 with 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.

Causal Effect of Plasminogen Activator Inhibitor Type 1 on Coronary Heart Disease

“…Thus, we considered the MR analyses viable and obtained summary statistics for circulating PAI‐1 levels, CHD and CHD risk factors from previous GWASs as listed in Table 1. These are based on the largest GWAS meta‐analysis for each phenotype at the time of analysis and primarily conducted on European ancestry samples 28, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42…”

MRAS gene marker rs9818870 is not associated with acute coronary syndrome in the Czech population and does not predict mortality in males after acute coronary syndrome

“…The minor allele frequency was almost identical to frequencies described in Western populations (~ 0.15 in Western Europeans, 0.16 in Czechs). 8,9 We did not confirm an association between the ACS and rs9818870 polymorphism (30.4% vs 29.4% of the minor T allele carriers [recessive model], p = 0.54; OR 1.05; 95% CI 0.89-1.24 for males and 32.1% vs 29.7% carriers of the T allele [recessive model], p = 0.28; OR 1.12; 95% CI 0.91-1.37 for females). No significant association was found when males and females were analyzed together ( Table 2).…”

“…8,9 In both studies, interestingly, polymorphisms at this locus were not associated with traditional risk factors. 8,9 Further, an association between the same locus and coronary arterial calcification was described, and Ellis et al identified rs9818870 as a CAD risk predictor in individuals without apparent heart disease from the pooled sample of the Coronary Disease Cohort Study (CDCS), Canterbury Healthy Volunteer study (HV) and PostMyocardial Infarction study (PMI). 9,10 Finally, a study of angiographed Saudi individuals suggests an association between the rs9818870 polymorphism and coronary artery disease, defined as narrowing of the coronary vessels by at least 50%.…”

“…8,9 Further, an association between the same locus and coronary arterial calcification was described, and Ellis et al identified rs9818870 as a CAD risk predictor in individuals without apparent heart disease from the pooled sample of the Coronary Disease Cohort Study (CDCS), Canterbury Healthy Volunteer study (HV) and PostMyocardial Infarction study (PMI). 9,10 Finally, a study of angiographed Saudi individuals suggests an association between the rs9818870 polymorphism and coronary artery disease, defined as narrowing of the coronary vessels by at least 50%. 11 We attempted to determine whether the rs9818870 variant at the MRAS locus would be associated with risk of ACS in the Czech Slavonic population, since, based on previous reports, the rs9818870 variant at the MRAS locus seems to be responsible for enhanced risk of coronary disease.…”

Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine

“…Several of the genes have previous associations to vascular disease (PHACTR1, 29,30 TGFBR2, 31 [43][44][45] and coronary artery calcification 46 and rs11624776 at ITPK1 with thyroid hormone levels 47 ). Six of the loci harbor genes that are involved in nitric oxide signaling and oxidative stress (REST 48 , GJA1 49 , YAP1 50 , PRDM16 51 , LRP1 52 , and MRVI1 53 ).…”