Evidence for CD36 gene in dyslipidemia
Previous genetic studies showed various effects between CD36 locus and metabolic syndrome components. A genome-wide linkage scan among 418 individuals from 27 extended Mexican American families found that two loci in chromosome 7 were suggested as being linked to HDL cholesterol and triglycerides levels, besides the most linkage site in chromosome 15q . In addition, among non-diabetic Mexican American families, quantitative trait locus study showed a strong linkage of one metabolic syndrome related factor, HDL and triglycerides, to chromosome 7 (LOD score up to 3.2) ; however, other metabolic factors, including obesity and blood pressure, cannot be identified to linkage to chromosome 7, in which CD36 gene exists. Moreover, another large-scale genome-wide linkage scan among 8664 participants from multiple ethnicities showed that 7q36, a site for CD36, was associated with fasting glucose and insulin resistance . To sum up, a meta-analysis based on genome-wide linkage studies on quantitative lipid traits from the families ascertained from type 2 diabetes showed that CD36 gene locus (7p11-q21.11) was significantly linked to triglycerides and triglycerides/HDL cholesterol ratio, but not linked to LDL or total cholesterol . Our findings also demonstrated significant association between CD36 gene polymorphism and triglycerides and HDL cholesterol, the traits predisposing to type 2 diabetes. In another study based on 1,375 patients with coronary heart disease, one SNP in CD36, rs3211956, was significantly associated with acute myocardial infarction as compared with stable coronary disease (allele frequency 11% vs. 8%, p = 0.04) . However, the strength decreased modestly after adjusting covariates and multiple comparisons. Among a cohort composed of 675 obese adults (age >40 yrs and body mass index >25) in the Netherlands, rs1527479, a C/T SNP in the upstream promoter region in the CD36 gene, homozygous carrier was associated with prevalent type 2 diabetes, and more so in women and high BMI (>27) group . Furthermore, the homozygous carriers were more likely to have a high homeostasis model assessment index value . Another case–control study on 61 CD36-deficient patients and 25 controls showed that the patients were likely to have a higher type 2 diabetes prevalence, fasting glucose, glycated hemoglobin and HDL-cholesterol, and likely to have a lower triglyceride value . In addition, the study based on screening the coding sequence of the CD36 gene in 272 French individuals showed that one promoter variant allele (−178A/C) was associated with adiponectin levels (p = 0.036 after multiple testing correction) . Among another French family study, a rare nonsense mutation (1079 T > G) in CD36 locus showed linkage with familial type 2 diabetes risk . In addition, genotyping 21 SNPs in the CD36 gene in 585 non-diabetic Caucasians, Ma and colleagues showed that 5 tagged SNPs for haplotype construction . The 30294 G > C polymorphism was associated with free fatty acid level (p = 0.02) and the association was apparent among men. Compared with non-carriers, individuals carrying the haplotype AGGIG had a 31% higher free fatty acids (p = 0.0002) and 20% higher triglycerides (p = 0.025) . Furthermore, this haplotype was associated with a higher risk of coronary heart disease among type 2 diabetic patients. However, a survey based on 831 adults from the health screening showed that one CD36 gene variant (Pro90Ser) was associated with free fatty acids, but not related to HDL cholesterol nor triglycerides . Extensive tagged SNP study on CD36 gene among African-Americans showed this gene was associated with metabolic syndrome and HDL cholesterol . A genome wide association study base on more than ten thousand individuals showed that biological lipoprotein metabolism related genes, such as CYP7A1, NPC1L1 and SCARB1, were related to lipid profiles . Our study showed that the CD36 variants with differential effects on triglycerides and HDL cholesterol, consistent with previous findings.
Our study has several strengths. First, the study sample size was moderate, which provided us with sufficient statistical power. In addition, the selection strategy on common htSNPs from public domain (HapMap website) could reduce genotyping costs, and provides an important tool to explore the candidate gene effects. Second, this study population is relatively homogenous and thus may reduce the effect of population stratification. We recruited the participants from the health checkup center in a tertiary university hospital, and these participants had relatively high socioeconomic status and their health behavior and health promotion motivation were high. Third, due to the high prevalence of dyslipidemia and high blood pressure in the control subjects, we believe the heterogeneity in the metabolic syndrome reduced the association strength between gene and the metabolic syndrome. Further study on the pathogenesis of CD36 gene expression and metabolic components, especially triglycerides and HDL cholesterol levels, is warranted.
This study has some limitations. First, some subjects of the metabolic syndrome may be due to phenocopies and other environmental factors, rather than genetic effects, causing the traits to be the same. This was apparently due to the relatively middle and elderly participants in our study. These phenocopies and misclassification would reduce the power of the association and it may bias our results toward the null. Second, although our study had sufficient statistical power to detect large effects resulting from common alleles, the power to evaluate small effects due to rare alleles or the effect of interaction was limited. Further gene-environment interaction study needs greater study numbers. Studying complex diseases has been shown to require very large sample sizes as multiple small effects may be expected. The study population in this study does exceed many very small studies, but may still lack power to detect small associations. Third, we did not include other genetic information, such as APOE, APOA5, and LPL genes. Indeed, our previous studies have shown that the APOA5 and APOA1-C3-A4 genetic polymorphism was associated with dyslipidemia in Taiwanese population [15, 38–40]. Finally, due to different components of the metabolic syndrome, multiple comparison issues may be a concern for inflating type I error.
In conclusion, our genetic association study demonstrated that CD36 gene variants were significantly associated with triglycerides and HDL-cholesterol levels. Further study on the pathogenesis of CD36 gene expression and metabolic components, especially with regards to triglycerides and HDL cholesterol levels, is warranted.