The contribution of individual and pairwise combinations of SNPs in the APOA1 and APOC3 genes to interindividual HDL-C variability

Apolipoproteins (apo) A-I and C-III are components of high-density lipoprotein-cholesterol (HDL-C), a quantitative trait negatively correlated with risk of cardiovascular disease (CVD). We analyzed the contribution of individual and pairwise combinations of single nucleotide polymorphisms (SNPs) in the APOA1/APOC3 genes to HDL-C variability to evaluate (1) consistency of published single-SNP studies with our single-SNP analyses; (2) consistency of single-SNP and two-SNP phenotype–genotype relationships across race-, gender-, and geographical location-dependent contexts; and (3) the contribution of single SNPs and pairs of SNPs to variability beyond that explained by plasma apo A-I concentration. We analyzed 45 SNPs in 3,831 young African–American (N=1,858) and European–American (N=1,973) females and males ascertained by the Coronary Artery Risk Development in Young Adults (CARDIA) study. We found three SNPs that significantly impact HDL-C variability in both the literature and the CARDIA sample. Single-SNP analyses identified only one of five significant HDL-C SNP genotype relationships in the CARDIA study that was consistent across all race-, gender-, and geographical location-dependent contexts. The other four were consistent across geographical locations for a particular race–gender context. The portion of total phenotypic variance explained by single-SNP genotypes and genotypes defined by pairs of SNPs was less than 3%, an amount that is miniscule compared to the contribution explained by variability in plasma apo A-I concentration. Our findings illustrate the impact of context-dependence on SNP selection for prediction of CVD risk factor variability.Electronic Supplementary Material Supplementary material is available in the online version of this article at CHRISTINE M. BROWN received her B.S. in Zoological Anthropology from the University of Michigan, Ann Arbor, MI, and is currently working towards her Masters degree in Epidemiology in the School of Public Health. She is presently a Research Associate in the Dept. of Human Genetics at the University of Michigan, Ann Arbor, MI.CHARLES F. SING received his Ph.D. in Statistics and Genetics from North Carolina State University in Raleigh, NC. He is currently a Professor in the Dept. of Human Genetics at the University of Michigan, Ann Arbor, MI.