Vitamin D dependent effects of APOA5 polymorphisms on HDL cholesterol

Brian H. Shirts, Michael T. Howard, Sandra J. Hasstedt, M. Nazeem Nanjee, Stacey Knight, John F. Carlquist, Jeffrey L. Anderson, Paul N. Hopkins, Steven Hunt

Research output: Contribution to journalArticle

13 Citations (Scopus)


Objectives: Vitamin 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. 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 (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. Results: 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. Conclusions: A 25OHD receptor binding site modifying APOA5 promoter polymorphism is associated with lower HDL-C in 25OHD deficient individuals.

Original languageEnglish
Pages (from-to)167-174
Number of pages8
Issue number1
Publication statusPublished - May 2012
Externally publishedYes



  • Apolipoprotein A5
  • Cardiovascular disease risk
  • Causative variant
  • Gene-environment interaction
  • HDL cholesterol
  • Triglyceride
  • Vitamin D

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Shirts, B. H., Howard, M. T., Hasstedt, S. J., Nanjee, M. N., Knight, S., Carlquist, J. F., Anderson, J. L., Hopkins, P. N., & Hunt, S. (2012). Vitamin D dependent effects of APOA5 polymorphisms on HDL cholesterol. Atherosclerosis, 222(1), 167-174.