Common CD36 SNPs reduce protein expression and may contribute to a protective atherogenic profile

Abstract

Membrane CD36 functions in the uptake of fatty acids (FAs), oxidized lipoproteins and in signal transduction after binding these ligands. In rodents, CD36 is implicated in abnormal lipid metabolism, inflammation and atherosclerosis. In humans, CD36 variants have been identified to influence free FA and high-density lipoprotein (HDL) levels and to associate with the risk of the metabolic syndrome, coronary artery disease and stroke. In this study, 15 common lipid-associated CD36 single nucleotide polymorphisms (SNPs) were evaluated for the impact on monocyte CD36 expression (protein and transcript) in 104 African Americans. In a subset of subjects, the SNPs were tested for association with monocyte surface CD36 (n=65) and platelet total CD36 (n=57). The relationship between CD36 expression and serum HDL and very low-density lipoproteins (VLDLs) levels was also examined. After a permutation-based correction for multiple tests, four SNPs (rs1761667, rs3211909, rs3211913, rs3211938) influenced monocyte CD36 protein and two (rs3211909, rs3211938) platelet CD36. The effect of the HDL-associated SNPs on CD36 expression inversely related to the impact on serum HDL and potential causality was supported by Mendelian randomization analysis. Consistent with this, monocyte CD36 protein negatively correlated with total HDL and HDL subfractions. In contrast, positive correlations were documented between monocyte CD36 and VLDL lipid, particle number and apolipoprotein B. In conclusion, CD36 variants that reduce protein expression appear to promote a protective metabolic profile. The SNPs in this study may have predictive potential on CD36 expression and disease susceptibility in African Americans. Further studies are warranted to validate and determine whether these findings are population specific.

CD36-deficient congenic strains show improved glucose tolerance and distinct shifts in metabolic and transcriptomic profiles

“…Although many of the studies including ours demonstrated the association of lack of Cd36 with metabolic syndrome features like insulin resistance or dyslipidemia (Aitman et al, 1997(Aitman et al, , 1999Febbraio et al, 1999;Pravenec et al, 2001;Seda et al, 2002), there are also reports suggesting that, in certain circumstances, the expression level of Cd36 actually correlates positively with unfavorable metabolic profile. Recently, it has been shown by Love-Gregory et al (2011) that in African-Americans the Cd36 variants that reduce protein expression appear to promote a protective metabolic profile, particularly concerning high-density lipoprotein and VLDL lipid levels Cd36 deficiency improves insulin sensitivity L Š edová et al (Love-Gregory et al, 2011). Also, the Cd36 knockout mice fed chow diet displayed lower fasting concentrations of glucose and insulin compared with wild-type controls (Hajri et al, 2002), similarly to PD.SHR4 congenics in the current study.…”

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

“…The rs1761665 SNP, in particular, is in strong LD with promoter SNPs previously shown to influence monocyte and platelet CD36 (58,59). Several of the promoter SNPs we identified here lie in close proximity to validated binding sites for PPAR and to methylation sites that associate with CD36 mRNA levels (Fig.…”

CD36 Protein Influences Myocardial Ca2+ Homeostasis and Phospholipid Metabolism

“…Association with left ventricular mass (8), a predictor of cardiovascular events (9), has also been reported. Common single nucleotide polymorphisms in the CD36 gene influence blood lipoprotein levels (10) and risk of the metabolic syndrome (11)(12)(13). The metabolic syndrome, a cluster of factors that include dyslipidemia, increases risk of heart disease and death from a heart attack (14).…”