Variants in the CD36 gene associate with the metabolic syndrome and high-density lipoprotein cholesterol

Abstract

A region along chromosome 7q was recently linked to components of the metabolic syndrome (MetS) in several genome-wide linkage studies. Within this region, the CD36 gene, which encodes a membrane receptor for long-chain fatty acids and lipoproteins, is a potentially important candidate. CD36 has been documented to play an important role in fatty acid metabolism in vivo and subsequently may be involved in the etiology of the MetS. The protein also impacts survival to malaria and the influence of natural selection has resulted in high CD36 genetic variability in populations of African descent. We evaluated 36 tag SNPs across CD36 in the HyperGen population sample of 2020 African-Americans for impact on the MetS and its quantitative traits. Five SNPs associated with increased odds for the MetS [P = 0.0027-0.03, odds ratio (OR) = 1.3-1.4]. Coding SNP, rs3211938, previously shown to influence malaria susceptibility, is documented to result in CD36 deficiency in a homozygous subject. This SNP conferred protection against the MetS (P = 0.0012, OR = 0.61, 95%CI: 0.46-0.82), increased high-density lipoprotein cholesterol, HDL-C (P = 0.00018) and decreased triglycerides (P = 0.0059). Fifteen additional SNPs associated with HDL-C (P = 0.0028-0.044). We conclude that CD36 variants may impact MetS pathophysiology and HDL metabolism, both predictors of the risk of heart disease and type 2 diabetes.

Figure 1.

Plot of association analysis between 36 CD36 tag SNPs, the metabolic syndrome and its components. The horizontal dotted line indicates a P-value of 0.05 with significant associations above the line. SNPs (X-axis) are displayed according to the order on chromosome 7q (corresponding dbSNP ID shown in Table 1). (A) Regression analysis identified the following associations: 6 SNPs and the metabolic syndrome (filled circle, red) 16 SNPs and HDL-C (filled circle), 1 SNP and waist circumference (open circle), 2 SNPs and fasting glucose (triangle), 3 SNPs and hypertension (square), 1 SNP and triglycerides (diamond). (B) In the CD36 gene schematic, yellow boxes indicate coding exons, gray boxes indicate untranslated exonic regions. Pairwise measures of linkage disequilibrium (LD) between CD36 tag SNPs associated with the MetS. LD measures presented as D′ standard color scheme (bright red indicates D' = 1 with a LOD score ≥2) and values represent r², correlation coefficients generated using default settings in Haploview.

Figure 2.

Impact of SNPs 22, 1 and 6 on HDL-C levels (mg/dl ± SE) from pairwise genotype comparisons. Mean HDL-C for non-carriers (black bars), for heterozygous (gray bars) and subjects homozygous for the minor allele (white bars). Sample sizes (n) for non-carriers, heterozygous and homozygous subjects (in this order) for SNPs 22 (rs13583337) n = 574, 819, 430, for SNPs 1 (rs10499859) n = 564, 500, 142 and for SNP 6 (rs1049654) n = 630, 959, 318. Resulting P-values for SNP 22: *0.04, ***0.0007; SNP 1: *0.02, **0.032, ***0.0004; SNP 6: *0.035, **0.002.

Figure 3.

Impact of coding SNP 32 on HDL-C and TG levels (mg/dl ± SE) from pairwise genotype comparisons. (A) Mean HDL-C levels: non-carriers for SNP 32 (rs3111938) (T/T) = 52.94 ± 0.39; heterozygous (T/G) = 56.10 ± 0.82; homozygous (G/G) 47.78 ± 3.29. (B) Mean TG levels: T/T = 111.75 ± 3.10; T/G 99.29 ± 3.9; G/G 127.33 ± 22.9. Sample sizes are: n = 1576 (T/T), 334 (T/G) and 9 (G/G). Resulting P-values the pairwise comparisons: ***<0.0001, **00.008, *0.0015. (C) Absence of CD36 expression on monocytes and platelets from a subject homozygous for coding SNP 32 (rs3211938). Shown are representative histograms of flow cytometric analysis from a non-carrier and heterozygote (carrier) for SNP 32. (D) Representative western blots and densitometry analysis of total CD36 protein in monocytes and platelets from a non-carrier (−/−), a homozygote (+/+) and a heterozygote (−/+) for SNP 32. The RAN (ras-related nuclear protein) was used as the loading control.