Vitamin D dependent effects of APOA5 polymorphisms on HDL cholesterol

ObjectivesVitamin D and serum lipid levels are risk factors for cardiovascular disease. We sought to determine if vitamin D (25OHD) interacts at established lipid loci potentially explaining additional variance in lipids.Methods1060 individuals from Utah families were used to screen 14 loci for SNPs potentially interacting with dietary 25OHD on lipid levels. Identified putative interactions were evaluated for (1) greater effect size in subsamples with winter measures, (2) replication in an independent sample, and (3) lack of gene-environment interaction for other correlated dietary factors. Maximum likelihood models were used to evaluate interactions. The replicate sample consisted of 2890 individuals from the Family Heart Study. Putative 25OHD receptor binding site modifying SNPs were identified and allele-specific, 25OHD-dependent APOA5 promoter activity examined using luciferase expression assays. An additional sample with serum 25OHD measures was analyzed.ResultsAn rs3135506-25OHD interaction influencing HDL-C was identified. The rs3135506 minor allele was more strongly associated with low HDL-C in individuals with low winter dietary 25OHD in initial and replicate samples (p = 0.0003 Utah, p = 0.002 Family Heart); correlated dietary factors did not explain the interaction. SNP rs10750097 was identified as a putative causative polymorphism, was associated with 25OHD-dependent changes in APOA5 promoter activity in HEP3B and HEK293 cells (p < 0.01), and showed similar interactions to rs3135506 in family cohorts. Linear interactions were not significant in samples with serum 25OHD measures; however, genotype-specific differences were seen at deficient 25OHD levels.ConclusionsA 25OHD receptor binding site modifying APOA5 promoter polymorphism is associated with lower HDL-C in 25OHD deficient individuals.

► A 25OHD receptor binding site modifying APOA5 promoter polymorphism was associated with lower HDL-C in 25OHD deficient individuals. ► Stronger interactions in subsamples evaluated in winter months suggest effects may be meaningful only at deficient levels of vitamin D. ► Gene-environment interactions with modifiable environmental components suggest potential strategies to improve cardiovascular risk.