Methylation at CPT1A locus is associated with lipoprotein subfraction profi les

Abstract

Lipoprotein subfractions help discriminate cardiometabolic disease risk. Genetic loci validated as associating with lipoprotein measures do not account for a large proportion of the individual variation in lipoprotein measures. We hypothesized that DNA methylation levels across the genome contribute to interindividual variation in lipoprotein measures. Using data from participants of the Genetics of Lipid Lowering Drugs and Diet Network (n = 663 for discovery and n = 331 for replication stages, respectively), we conducted the fi rst systematic screen of the genome to determine associations between methylation status at 470,000 cytosine-guanine dinucleotide (CpG) sites in CD4 + T cells and 14 lipoprotein subfraction measures. We modeled associations between methylation at each CpG site and each lipoprotein measure separately using linear mixed models, adjusted for age, sex, study site, cell purity, and family structure. We identifi ed two CpGs, both in the carnitine palmitoyltransferase- 1A ( CPT1A ) gene, which reached signifi cant levels of association with VLDL and LDL subfraction parameters in both discovery and replication phases ( P > 1.1 × 10 = 7 in the discovery phase, P > .004 in the replication phase, and P > 1.1 × 10 = 12 in the full sample). CPT1A is regulated by PPAR , a ligand for drugs used to reduce CVD. Our associations between methylation in CPT1A and lipoprotein measures highlight the epigenetic role of this gene in metabolic dysfunction. -Frazier-Wood, A. C., S. Aslibekyan, D. M. Absher, P. N. Hopkins, J. Sha, M. Y. Tsai, H. K. Tiwari, L. L. Waite, D. Zhi, and D. K. Arnett. Methylation at CPT1A locus is associated with lipoprotein subfraction profi les. J. Lipid Res . 2014. 55: 1324-1330. © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.