A common haplotype at the CD36 locus is associated with high free fatty acid levels and increased cardiovascular risk in Caucasians

Abstract

CD36 is a class B scavenger receptor recognizing a variety of ligands including long-chain fatty acids and modified LDL. We investigated whether genetic variability at this locus is a determinant of free fatty acid (FFA) plasma levels and risk of coronary artery disease (CAD) in Caucasians. Typing of 21 polymorphic markers, evenly spanning the CD36 gene, revealed two linkage disequilibrium (LD) blocks that could be tagged by five polymorphisms (-33137A>G, -31118G>A, 25444G>A, 27645del>ins and 30294G>C). In 585 non-diabetic individuals of Caucasian origin, the 30294G>C polymorphism was significantly associated with FFA levels (P = 0.02)--an effect that was especially visible among men (P = 0.009). A similar association was observed in this gender at -33137 (P = 0.008) and -31118 (P = 0.028). When the five tag polymorphisms were considered together, men carrying the AGGIG haplotype had 31% higher FFA (P = 0.0002) and 20% higher triglycerides (P = 0.025) than non-carriers. The same haplotype was associated with increased risk of CAD in 197 type 2 diabetic individuals from the US (OR = 2.3, 95% CI 1.2-4.2). A similar tendency was observed in a group of 321 type 2 diabetic individuals from Italy (OR = 1.4, 0.9-2.3), resulting in an overall relative risk of 1.6 (1.1-2.3, P = 0.015) in the two populations considered together. By targeted resequencing, we identified a common variant in the CD36 promoter that is in strong LD with the AGGIG haplotype and could be partly responsible for these findings. In conclusion, this comprehensive study of CD36 variability indicates that the common polymorphisms at this locus modulate lipid metabolism and cardiovascular risk in Caucasians.

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

“…linked to diabetes-associated coronary artery disease (48) and stroke (44), as well as MetS (22). Overall, our findings support an important role of CD36 in the handling of dietary lipids in humans and are consistent with data in CD36-null mice showing defective CM metabolism and persistently high levels of CM remnants (9,(23)(24)(25).…”

“…The most significant promoter SNPs identified to influence CM levels and TG clearance (rs1931694, rs13228738, rs3211842) are in strong LD with variants previously associated with MetS or coronary artery disease (22,48,49). Similarly, the 3′UTR variant, rs7755, identified to associate with LDL and to trend with higher CM remnants has been CD36 transcriptional regulator (Fig.…”

Heterozygous caveolin-3 mice show increased susceptibility to palmitate-induced insulin resistance

“…Mutations in CD36 in humans lead to an increased risk of diabetes‐associated cardiovascular disease and metabolic syndrome (Ma et al. 2004; Love‐Gregory et al. 2008).…”

Endophenotypes Successfully Lead to Gene Identification: Results from the Collaborative Study on the Genetics of Alcoholism

“…Other fields have a history of using quantitative risk factors to identify susceptibility genes for disease; for example, cholesterol levels, blood pressure, and body fat have been analyzed to identify genetic risk factors influencing cardiovascular disease (Falchi et al, 2004;Ma et al, 2004). The application of this strategy to the study of psychiatric disorders has been more recent.…”