Higher chylomicron remnants and LDL particle numbers associate with CD36 SNPs and DNA methylation sites that reduce CD36

Authors: LOVE-GREGORY, LATISHA - Washington University; KRAJA, ALDI - Washington University; ALLUM, FIONA - McGill University - Canada; ASLIBEKYAN, STELLA - University Of Alabama; HEDMAN, ASA - Uppsala University; DUAN, YANAN - Washington University; BORECKI, INGRID - Washington University; ARNETT, DONNA - University Of Alabama; MCCARTHY, MARK - Oxford University; DELOUKAS, PANOS - Queen Mary University Of London; ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; HOPKINS, PAUL - University Of Utah; GRUNDBERG, ELIN - McGill University - Canada; ABUMRAD, NADA - Washington University

Submitted to: Journal of Lipid Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/28/2016
Publication Date: 10/11/2016
Citation: Love-Gregory, L., Kraja, A.T., Allum, F., Aslibekyan, S., Hedman, A.K., Duan, Y., Borecki, I.B., Arnett, D.K., Mccarthy, M.I., Deloukas, P., Ordovas, J.M., Hopkins, P.N., Grundberg, E., Abumrad, N.A. 2016. Higher chylomicron remnants and LDL particle numbers associate with CD36 SNPs and DNA methylation sites that reduce CD36. Journal of Lipid Research. doi: 10.1194/jlr.P065250.

Interpretive Summary: Previous studies have shown significant associations between variants at the gene known as CD36 and fasting lipids and risk of metabolic syndrome. However, we don't know how these variants affect the levels of postprandial lipids, an independent risk factor for cardiovascular disease. We determined the effects of genetic variants in the CD36 region of chylomicron (CM) remnants and LDL particles at fasting and at 3.5 and 6 h following a high-fat meal (Genetics of Lipid Lowering Drugs and Diet Network study, 1,117 participants.) Several variants were associated with CMs, TG clearance, and LDL particle number. To assess mechanisms underlying the associations, we queried other datasets containing gene expression and methylation data. Several variants that associated with higher serum lipids correlated with lower adipose and heart CD36 mRNA and aligned to motifs for PPAR-gamma, a major CD36 regulator. The single nucleotide polymorphisms (SNPs) also associated with DNA methylation sites that related to reduced CD36 mRNA and higher serum lipids. The findings support contributions of CD36 variants that reduce adipose and heart CD36 RNA expression to inter-individual variability of postprandial lipid metabolism and document changes in CD36 DNA methylation that influence both CD36 expression and lipids. In summary, our findings link common CD36 SNPs that reduce adipose and heart CD36 levels to higher CM remnants and LDL in humans. These SNPs contribute to individual differences in the handling of dietary lipids and in susceptibility to diet-induced metabolic abnormalities. Factors that alter methylation of the CD36 gene impact lipid levels and potentially disease risk.

Technical Abstract: Cluster of differentiation 36 (CD36) variants influence fasting lipids and risk of metabolic syndrome, but their impact on postprandial lipids, an independent risk factor for cardiovascular disease, is unclear. We determined the effects of SNPs within a ~410 kb region encompassing CD36 and its proximal and distal promoters on chylomicron (CM) remnants and LDL particles at fasting and at 3.5 and 6 h following a high-fat meal (Genetics of Lipid Lowering Drugs and Diet Network study, n = 1,117). Five promoter variants associated with CMs, four with delayed TG clearance and five with LDL particle number. To assess mechanisms underlying the associations, we queried expression quantitative trait loci, DNA methylation, and ChIP-seq datasets for adipose and heart tissues that function in postprandial lipid clearance. Several SNPs that associated with higher serum lipids correlated with lower adipose and heart CD36 mRNA and aligned to active motifs for PPAR-gamma, a major CD36 regulator. The SNPs also associated with DNA methylation sites that related to reduced CD36 mRNA and higher serum lipids, but mixed-model analyses indicated that the SNPs and methylation independently influence CD36 mRNA. The findings support contributions of CD36 SNPs that reduce adipose and heart CD36 RNA expression to inter-individual variability of postprandial lipid metabolism and document changes in CD36 DNA methylation that influence both CD36 expression and lipids.