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

Jussi A Hernesniemi, Ilkka Seppälä, Leo-Pekka Lyytikäinen, Nina Mononen, Niku Oksala, Nina Hutri-Kähönen, Markus Juonala, Leena Taittonen, Erin N Smith, Nicholas J Schork, Wei Chen, Sathanur R Srinivasan, Gerald S Berenson, Sarah S Murray, Tomi Laitinen, Antti Jula, Johannes Kettunen, Samuli Ripatti, Reijo Laaksonen, Jorma Viikari, Mika Kähönen, Olli T Raitakari, Terho Lehtimäki, Jussi A Hernesniemi, Ilkka Seppälä, Leo-Pekka Lyytikäinen, Nina Mononen, Niku Oksala, Nina Hutri-Kähönen, Markus Juonala, Leena Taittonen, Erin N Smith, Nicholas J Schork, Wei Chen, Sathanur R Srinivasan, Gerald S Berenson, Sarah S Murray, Tomi Laitinen, Antti Jula, Johannes Kettunen, Samuli Ripatti, Reijo Laaksonen, Jorma Viikari, Mika Kähönen, Olli T Raitakari, Terho Lehtimäki

Abstract

Background: Genome-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 methods: We 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 (GRS(24SNP/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.

Results: CIMT or CAE did not significantly associate with GRS(24SNP/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.

Conclusion: Genetic profiling, by using known CAD risk variants, should not improve risk stratification for subclinical atherosclerosis beyond conventional risk factors among healthy young adults.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Subclinical atherosclerosis and the genetic…
Figure 1. Subclinical atherosclerosis and the genetic predisposition to coronary artery disease (CAD).
Carotid artery Intima Media Thickness (CIMT) and Carotid Artery Elasticity (CAE) among healthy adults with different genetic risk for coronary artery disease (CAD). The study population (The Cardiovascular risk in Young Finns Study) is stratified into four groups according to CAD risk allele dosage (calculated weighted risk score).

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