Recent genome wide association studies (GWAS) have identified 49 single nucleotide polymorphisms (SNPs) associated with clinically significant complications of CAD including myocardial infarction (MI), CABG, PCI, and/or angina. The mechanism by which these loci influence the risk of clinical CAD remains largely unclear. We hypothesized that variants at these loci collectively facilitate the formation of coronary plaque in a monotonic fashion throughout the life course. We used genetic data from dbGAP (SEA, FHS, and MESA) as well as from the Stanford-Kaiser ADVANCE study imputed to the 1000 genomes project to examine the association between a genetic risk score (GRS) of high-risk alleles at these 49 SNPs and the presence of subclinical atherosclerosis. Subclinical atherosclerosis was identified by either pathologic examination of the coronary arteries or by radiographic assessment of coronary artery calcification (CAC). We stratified white/European subjects within each study into one of five age groups (≤30, 31-45, 46-60, 61-75, >75 years) and defined cases as subjects with either any raised lesions in their right coronary artery on autopsy (SEA, 26.7% subjects aged 18 to 30 years at time of unexpected death) or with an age and sex specific CAC score >75th percentile (all other studies, age > 30 years). Among 1561 cases and 5068 controls, we found a one SD increase in the GRS was associated with a 28% increased risk of having advanced subclinical coronary atherosclerosis (p = 3.82 x 10
-16
). This increase in risk was significant in every age stratum (.01 > p > 9.4 x 10
-7
)
and was remarkably similar across all age strata (p test of heterogeneity = 0.99). We obtained near identical results and levels of significance when we restricted the GRS to 33 SNPs not associated with traditional risk factors. Our findings strongly support the notion that susceptibility alleles for clinical CAD uncovered through large-scale meta-analysis of GWAS uniformly promote the development of coronary atherosclerosis from birth. This predisposition is sustained at a constant level throughout one’s lifetime. Given it is observed at the earliest stage of plaque formation, it is unlikely to involve a concurrent predisposition to plaque rupture and/or thrombosis.
Race/Ethnic and Nativity Disparities in Later Life Physical Performance: The Role of Health and Socioeconomic Status Over the Life Course
