title: The contribution of individual and pairwise combinations of SNPs in the APOA1 and APOC3 genes to interindividual HDL-C variability.
abstract: 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.
authors.affiliation: Department of Human Genetics, University of Michigan, Ann Arbor, 48109, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Brown
authors.forename: T J
authors.initials: TJ
authors.lastname: Rea
authors.forename: S C
authors.initials: SC
authors.lastname: Hamon
authors.forename: J E
authors.initials: JE
authors.lastname: Hixson
authors.forename: E
authors.initials: E
authors.lastname: Boerwinkle
authors.forename: A G
authors.initials: AG
authors.lastname: Clark
authors.forename: C F
authors.initials: CF
authors.lastname: Sing
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D016632:Apolipoprotein A-I / Q000097:blood / Q000235:genetics*; D053305:Apolipoprotein C-III / Q000235:genetics*; D015992:Body Mass Index; D008076:Cholesterol, HDL / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012727:Sex Characteristics
chemical_list: D016632:Apolipoprotein A-I; D053305:Apolipoprotein C-III; D008076:Cholesterol, HDL