Genetic Profiling Using Genome-Wide Significant Coronary Artery Disease Risk Variants Does Not Improve the Prediction of Subclinical Atherosclerosis: The Cardiovascular Risk in Young Finns Study, the Bogalusa Heart Study and the Health 2000 Survey – A Meta-Analysis of Three Independent Studies

Abstract

BackgroundGenome-wide association studies (GWASs) have identified a large number of variants (SNPs) associating with an increased risk of coronary artery disease (CAD). Recently, the CARDIoGRAM consortium published a GWAS based on the largest study population so far. They successfully replicated twelve already known associations and discovered thirteen new SNPs associating with CAD. We examined whether the genetic profiling of these variants improves prediction of subclinical atherosclerosis – i.e., carotid intima-media thickness (CIMT) and carotid artery elasticity (CAE) – beyond classical risk factors.Subjects and MethodsWe genotyped 24 variants found in a population of European ancestry and measured CIMT and CAE in 2001 and 2007 from 2,081, and 2,015 subjects (aged 30–45 years in 2007) respectively, participating in the Cardiovascular Risk in Young Finns Study (YFS). The Bogalusa Heart Study (BHS; n = 1179) was used as a replication cohort (mean age of 37.5). For additional replication, a sub-sample of 5 SNPs was genotyped for 1,291 individuals aged 46–76 years participating in the Health 2000 population survey. We tested the impact of genetic risk score (GRS24SNP/CAD) calculated as a weighted (by allelic odds ratios for CAD) sum of CAD risk alleles from the studied 24 variants on CIMT, CAE, the incidence of carotid atherosclerosis and the progression of CIMT and CAE during a 6-year follow-up.ResultsCIMT or CAE did not significantly associate with GRS24SNP/CAD before or after adjusting for classical CAD risk factors (p>0.05 for all) in YFS or in the BHS. CIMT and CAE associated with only one SNP each in the YFS. The findings were not replicated in the replication cohorts. In the meta-analysis CIMT or CAE did not associate with any of the SNPs.ConclusionGenetic profiling, by using known CAD risk variants, should not improve risk stratification for subclinical atherosclerosis beyond conventional risk factors among healthy young adults.

Heart Disease and Stroke Statistics—2013 Update

“…10 Genetic markers have also not been shown to improve prediction of subclinical atherosclerosis beyond traditional risk factors. 11 …”

Association Between Coronary Artery Disease Genetic Variants and Subclinical Atherosclerosis: An Association Study and Meta-analysis

“…They also analyzed the association of the individual SNPs with the subclinical atherosclerosis measurements; although 2 SNPs tended to associate with carotid IMT (rs4977574) or carotid elasticity (rs4773144), these findings could not be replicated. 36 Finally, Zhang et al 28 selected 10 SNPs associated with CAD (only rs1333049 in common with our study) and analyzed their association with 4 subclinical atherosclerosis measurements (IMTcca and MTica, presence of carotid plaque, and pathologic ABI) in 5 community-based surveys. They found that the rs780094 (GCKR) was associated with carotid plaque in the American Indian population but not in European American, African American, or Mexican American populations.…”

“…Conde et al 35 used data from 3 European communitybased studies to assess the association between 12 genetic variants (7 of them included in our study, which added the LPA SNP and the ALOX5AP HapB) and mean common carotid artery IMT; none of the individual variants was associated with the outcome of interest. Hernesniemi et al 36 analyzed the association between a genetic risk score, based on 24 SNPs identified in GWAS as associated with CAD (7 of them included in our study), and carotid IMT and carotid elasticity in 2 Finnish populations and an American population. They found no association with carotid IMT measured at 2 different times (2001 and 2007) or with the progression of the thickness in this 6-year period.…”

“…We finally included 9 manuscripts, [28][29][30][31][32][33][34][35][36] and the number of Table 4 Age-and Sex-adjusted Analysis Across Genotype Groups participants included in the meta-analysis ranged from 6676 (rs17465637 and rs10455872) to 32056 (rs1333049). The results reported in the studies included in the meta-analysis are shown in Table 3 of the supplementary material.…”

Genetics of Coronary Artery Disease

“…There have been many attempts to assess various configurations from the single genetic risk variant 9p21 112 to combinations of ≤13 variants. [113][114][115][116][117] All of these studies show a good correlation between the genetic risk variants and the risk of CAD with some improvement in the prediction of CAD. However, the conventional criteria for significant improvement is judged on whether it changes the net reclassification index or improves discrimination by the conventional ethics, referred to as C-index.…”