TY - JOUR
T1 - Higher chylomicron remnants and LDL particle numbers associate with CD36 SNPs and DNA methylation sites that reduce CD36
AU - Love-Gregory, Latisha
AU - Kraja, Aldi T.
AU - Allum, Fiona
AU - Aslibekyan, Stella
AU - Hedman, Åsa K.
AU - Duan, Yanan
AU - Borecki, Ingrid B.
AU - Arnett, Donna K.
AU - McCarthy, Mark I.
AU - Deloukas, Panos
AU - Ordovas, Jose M.
AU - Hopkins, Paul N.
AU - Grundberg, Elin
AU - Abumrad, Nada A.
N1 - Publisher Copyright:
Copyright © 2016 by the American Society for Biochemistry and Molecular Biology, Inc.
PY - 2016
Y1 - 2016
N2 - 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 PPARγ, 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.
AB - 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 PPARγ, 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.
KW - Cholesterol/metabolism
KW - Cluster of differentiation 36
KW - Deoxyribonucleic acid
KW - Dietary lipids
KW - Dyslipidemia
KW - Genetics
KW - Lipoproteins
KW - Low density lipoprotein
KW - Single nucleotide polymorphism
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U2 - 10.1194/jlr.P065250
DO - 10.1194/jlr.P065250
M3 - Article
C2 - 27729386
AN - SCOPUS:85002777688
SN - 0022-2275
VL - 57
SP - 2176
EP - 2184
JO - Journal of Lipid Research
JF - Journal of Lipid Research
IS - 12
ER -