Evaluate the consistency of the contribution of interactions between single nucleotide polymorphism (SNP) genotype effects to variation in measures of lipid metabolism across ethnic strata within gend Show more
Evaluate the consistency of the contribution of interactions between single nucleotide polymorphism (SNP) genotype effects to variation in measures of lipid metabolism across ethnic strata within gender. We considered 80 SNPs within the apolipoprotein (APO) A1/C3/A4/A5 gene cluster using an over-parameterized general linear model to identify SNPs whose genotype effects combine non-additively to influence plasma levels of high density lipoprotein cholesterol (HDL-C), total cholesterol (TC) and triglycerides (TG) in a consistent manner across ethnic strata. We analyzed population-based samples of unrelated 18 to 30 year old African-Americans (n = 1,858) and European-Americans (n = 1,973) ascertained without regard to health at four field centers (Birmingham, Ala.; Chicago, Ill.; Minneapolis, Minn. and Oakland, Calif., USA) by the Coronary Artery Risk Development in Young Adults (CARDIA) study. To identify which SNP genotype effects combine non-additively we used a two-tier analysis strategy. We first required that pairs of SNPs show statistically significant non-additivity in both ethnic strata within a gender, where experiment-wise significance was evaluated using a permutation test to determine the probability of observing the number of tests significant in both ethnic strata by chance alone. Second, we required no significant evidence of heterogeneity of the relationship between the phenotype and the two SNP genotypes across ethnic strata and across field centers within each ethnic group. From this strategy we identified ten pairs of SNPs, involving thirteen SNPs, that displayed statistically significant non-additivity of SNP genotype effects on TC. Only one of these thirteen SNPs had statistically significant genotype effects that were consistent across samples. Our analyses suggest that ignoring the contribution of interactions between SNP genotype effects when modeling multi-SNP genotype-phenotype relationships may result in an underestimate of the contribution of genetic variation to variation in quantitative cardiovascular disease (CVD) risk factor traits. Show less
Genetic variation in the apolipoprotein A-V gene (APOA5) has been associated with variation in plasma triglyceride (TG) levels in African American and white females and males older than 40 years and/o Show more
Genetic variation in the apolipoprotein A-V gene (APOA5) has been associated with variation in plasma triglyceride (TG) levels in African American and white females and males older than 40 years and/or at increased risk of coronary artery disease. We have examined whether plasma TG levels are associated with 16 APOA5 polymorphisms in young (18-30 years) African American (1,075 females and 783 males) and white (1,041 females and 932 males) individuals of the Coronary Artery Risk Development in Young Adults (CARDIA) Study selected without regard to health. Plasma TG was significantly (P < 0.01) associated with markers 27376 and 28837 (-3A/G) in both white females and males, with 27709 (-1131T/C) and 29085 in white males, with 29009 (S19W) in African American females and white males, and with 30966 in African American females. No statistically significant associations were observed in African American males. These six single-nucleotide polymorphisms individually accounted for 0-0.78% of lnTG variation among white females, 0-2.46% among white males, and 0-0.69% among African American females. The results of our study suggest a small but replicable context-dependent influence of the APOA5 gene region on plasma TG levels in young, healthy individuals. Show less