Vitamin D dependent effects of APOA5 polymorphisms on HDL cholesterol
Shirts BH et al. – A 25OHD receptor binding site modifying APOA5 promoter polymorphism is associated with lower HDL–C in 25OHD deficient individuals.Methods
- 1060 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
- Greater effect size in subsamples with winter measures,
- Replication in an independent sample,
- And 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.
- An 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.