TY - JOUR

T1 - Validated context-dependent associations of coronary heart disease risk with genotype variation in the chromosome 9p21 region

T2 - the Atherosclerosis Risk in Communities study

AU - Lusk, Christine M

AU - Dyson, Greg

AU - Clark, Andrew G

AU - Ballantyne, Christie M

AU - Frikke-Schmidt, Ruth

AU - Tybjærg-Hansen, Anne

AU - Boerwinkle, Eric

AU - Sing, Charles F

PY - 2014/9

Y1 - 2014/9

N2 - Markers of the chromosome 9p21 region are regarded as the strongest and most reliably significant genome-wide association study (GWAS) signals for Coronary heart disease (CHD) risk; this was recently confirmed by the CARDIoGRAMplusC4D Consortium meta-analysis. However, while these associations are significant at the population level, they may not be clinically relevant predictors of risk for all individuals. We describe here the results of a study designed to address the question: What is the contribution of context defined by traditional risk factors in determining the utility of DNA sequence variations marking the 9p21 region for explaining variation in CHD risk? We analyzed a sample of 7,589 (3,869 females and 3,720 males) European American participants of the Atherosclerosis Risk in Communities study. We confirmed CHD-SNP genotype associations for two 9p21 region marker SNPs previously identified by the CARDIoGRAMplusC4D Consortium study, of which ARIC was a part. We then tested each marker SNP genotype effect on prediction of CHD within sub-groups of the ARIC sample defined by traditional CHD risk factors by applying a novel multi-model strategy, PRIM. We observed that the effects of SNP genotypes in the 9p21 region were strongest in a sub-group of hypertensives. We subsequently validated the effect of the region in an independent sample from the Copenhagen City Heart Study. Our study suggests that marker SNPs identified as predictors of CHD risk in large population based GWAS may have their greatest utility in explaining risk of disease in particular sub-groups characterized by biological and environmental effects measured by the traditional CHD risk factors.

AB - Markers of the chromosome 9p21 region are regarded as the strongest and most reliably significant genome-wide association study (GWAS) signals for Coronary heart disease (CHD) risk; this was recently confirmed by the CARDIoGRAMplusC4D Consortium meta-analysis. However, while these associations are significant at the population level, they may not be clinically relevant predictors of risk for all individuals. We describe here the results of a study designed to address the question: What is the contribution of context defined by traditional risk factors in determining the utility of DNA sequence variations marking the 9p21 region for explaining variation in CHD risk? We analyzed a sample of 7,589 (3,869 females and 3,720 males) European American participants of the Atherosclerosis Risk in Communities study. We confirmed CHD-SNP genotype associations for two 9p21 region marker SNPs previously identified by the CARDIoGRAMplusC4D Consortium study, of which ARIC was a part. We then tested each marker SNP genotype effect on prediction of CHD within sub-groups of the ARIC sample defined by traditional CHD risk factors by applying a novel multi-model strategy, PRIM. We observed that the effects of SNP genotypes in the 9p21 region were strongest in a sub-group of hypertensives. We subsequently validated the effect of the region in an independent sample from the Copenhagen City Heart Study. Our study suggests that marker SNPs identified as predictors of CHD risk in large population based GWAS may have their greatest utility in explaining risk of disease in particular sub-groups characterized by biological and environmental effects measured by the traditional CHD risk factors.

KW - Atherosclerosis

KW - Chromosomes, Human, Pair 9

KW - Cohort Studies

KW - Coronary Artery Disease

KW - European Continental Ancestry Group

KW - Female

KW - Gene-Environment Interaction

KW - Genetic Markers

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Genotype

KW - Humans

KW - Male

KW - Maryland

KW - Middle Aged

KW - Minnesota

KW - Mississippi

KW - North Carolina

KW - Phenotype

KW - Polymorphism, Single Nucleotide

KW - Prospective Studies

KW - Risk Factors

U2 - 10.1007/s00439-014-1451-3

DO - 10.1007/s00439-014-1451-3

M3 - Journal article

C2 - 24889828

VL - 133

SP - 1105

EP - 1116

JO - Human Genetics

JF - Human Genetics

SN - 0340-6717

IS - 9

ER -