title: Higher chylomicron remnants and LDL particle numbers associate with CD36 SNPs and DNA methylation sites that reduce CD36.
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 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.
authors.affiliation: Department of Medicine, Center for Human Nutrition Washington University School of Medicine, St. Louis, MO 63110. Electronic address: lgregory@dom.wustl.edu.
authors.forename: Latisha
authors.initials: L
authors.lastname: Love-Gregory
authors.affiliation: Department of Genetics, Division of Statistical Genomics, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Aldi T
authors.initials: AT
authors.lastname: Kraja
authors.affiliation: Department of Human Genetics, McGill University and Genome Quebec Innovation Centre, Montreal, Québec, Canada H3A 0G1.
authors.forename: Fiona
authors.initials: F
authors.lastname: Allum
authors.affiliation: Department of Epidemiology, University of Alabama, Birmingham, AL 35294.
authors.forename: Stella
authors.initials: S
authors.lastname: Aslibekyan
authors.affiliation: Departments of Medical Sciences and Molecular Epidemiology, and Science for Life Laboratory, Uppsala University, Uppsala 75185, Sweden.
authors.forename: Åsa K
authors.initials: ÅK
authors.lastname: Hedman
authors.affiliation: Department of Genetics, Division of Statistical Genomics, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Duan
authors.affiliation: Department of Genetics, Division of Statistical Genomics, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Ingrid B
authors.initials: IB
authors.lastname: Borecki
authors.affiliation: Department of Epidemiology, University of Alabama, Birmingham, AL 35294.
authors.forename: Donna K
authors.initials: DK
authors.lastname: Arnett
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK, and Oxford Centre for Diabetes, Endocrinology, and Metabolism and Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Oxford OX3 7JU, UK.
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.affiliation: Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Oxford OX3 7JU, UK; William Harvey Research Institute, Queen Mary University of London, EC1M 6BQ London, UK.
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.affiliation: JM-USDA-Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Ordovas
authors.affiliation: Cardiovascular Genetics Research, University of Utah, Salt Lake City, UT 84132.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Hopkins
authors.affiliation: Department of Human Genetics, McGill University and Genome Quebec Innovation Centre, Montreal, Québec, Canada H3A 0G1.
authors.forename: Elin
authors.initials: E
authors.lastname: Grundberg
authors.affiliation: Department of Medicine, Center for Human Nutrition Washington University School of Medicine, St. Louis, MO 63110. Electronic address: Nabumrad@wustl.edu.
authors.forename: Nada A
authors.initials: NA
authors.lastname: Abumrad
mesh_terms: D000328:Adult; D018955:CD36 Antigens / Q000235:genetics*; D053298:Chylomicron Remnants / Q000097:blood*; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D015870:Gene Expression; D005787:Gene Frequency; D056726:Genetic Association Studies; D006801:Humans; D008077:Lipoproteins, LDL / Q000097:blood*; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism; D009928:Organ Specificity; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D014280:Triglycerides / Q000097:blood
chemical_list: D018955:CD36 Antigens; D053298:Chylomicron Remnants; D008077:Lipoproteins, LDL; D014280:Triglycerides
keywords: cholesterol/metabolism; cluster of differentiation 36; deoxyribonucleic acid; dietary lipids; dyslipidemia; genetics; lipoproteins; low density lipoprotein; single nucleotide polymorphism