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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.

SUBMITTER: Love-Gregory L

PROVIDER: S-EPMC2655228 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Risk assessment of metabolic syndrome in adolescents using the triglyceride/high-density lipoprotein cholesterol ratio and the total cholesterol/high-density lipoprotein cholesterol ratio.

Project description:PurposeThis study was conducted to investigate the distributions of the triglyceride (TG) to high-density lipoprotein-cholesterol (HDL-C) ratio and total cholesterol (TC) to HDL-C ratio, and to explore their usefulness as markers of metabolic syndrome (MetS) in Korean adolescents.MethodsWe obtained data for 2,721 adolescents (1,436 boys and 1,285 girls) aged 10-18 years who participated in the Korean National Health and Nutrition Examination Surveys from 2008 to 2010. International Diabetes Federation criteria were used to define MetS.ResultsThere were no significant gender-related differences in TG/HDL-C or TC/HDL-C ratios. These lipid ratios showed significant associations with homeostatic model assessment for insulin resistance (HOMA-IR) and waist circumference. Areas under the receiver operating characteristic curve to identify MetS were 0.947 for TG/HDL-C and 0.924 for TC/HDL-C, which were higher than that of HOMA-IR (0.822). Optimal cutoff values (sensitivity, specificity) of TG/HDL-C and TC/HDL-C ratios for MetS prediction were 3.3 (85.7%, 89.9%), and 3.8 (92.9%, 82.8%), respectively. Odds ratio (OR; 95% confidence intervals [CIs]) for MetS in adolescents with TC/HDL-C ratio above the cutoff value was 14.8 (2.8-77.4), while that for TG/HDL-C ratio about the cutoff value was 30.6 (6.0-157.6). In adolescents who had both lipid ratios above the cutoff values, the OR (95% CI) for MetS was 36.2 (7.2-186.2).ConclusionTG/HDL-C and TC/HDL-C ratios are useful markers of metabolic syndrome with high predictive value in Korean adolescents.

| S-EPMC6449623 | biostudies-literature

Common sequence variants in CD36 gene and the levels of triglyceride and high-density lipoprotein cholesterol among ethnic Chinese in Taiwan.

Project description:BACKGROUND: Evidence of the genetic association between CD36 candidate gene and the risk of metabolic syndrome and its components has been inconsistent. This case-control study assessed the haplotype-tagged SNPs from CD36 on the risk of metabolic syndrome and components. METHODS AND RESULTS: We recruited 1,000 cases and age, gender-matched controls were randomly selected from the participants with metabolic syndrome defined by International Diabetes Federation. Overall, the haplotype tagged SNPs of CD36 gene were not related to the risk of metabolic syndrome. For individuals with normal lipid levels, several SNPs were significantly associated with the triglycerides and HDL-cholesterol levels: Subjects with rs3211848 homozygote had a higher triglyceride level (99.16 ± 2.61 mg/dL), compared with non-carriers (89.27 ± 1.45 mg/dL, P = 0.001). In addition, compared with non-carriers, individuals with rs1054516 heterozygous and homozygous genotypes had a significantly lower HDL-cholesterol (46.6 ± 0.46 mg/dL for non-carrier, 44.6 ± 0.36 mg/dL for heterozygous, and 44.3 ± 0.56 mg/dL for homozygous, P = 0.0008). CONCLUSION: The CD36 gene variants were significantly associated with triglycerides and HDL-cholesterol concentrations among ethnic Chinese in Taiwan.

| S-EPMC3575328 | biostudies-literature

Longitudinal associations of high-density lipoprotein cholesterol or low-density lipoprotein cholesterol with metabolic syndrome in the Chinese population: a prospective cohort study.

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| S-EPMC5942466 | biostudies-literature

AMP-kinase alpha2 subunit gene PRKAA2 variants are associated with total cholesterol, low-density lipoprotein-cholesterol and high-density lipoprotein-cholesterol in normal women.

Project description:Background5'-AMP-activated protein kinase (AMPK) inactivates critial ensymes in fatty acid and cholesterol synthesis. We hypothesised that the serum lipid profile may be influenced by genetic variation in the AMPK catalytic alpha2 subunit.MethodWe examined association of 5 tagging SNPs (tSNPs) in the PRKAA2 gene with serum lipids in 2777 normal Caucasian females (mean age 47.4+/-12.5 years).ResultsAll tSNPs were associated with total- and LDL-cholesterol, (p<0.001 to 0.034), explaining variances of 0.13-0.59% and 0.11-0.55% respectively. One haplotype (frequency 34.7%) showed lower total- and LDL-cholesterol compared with the most common haplotype (frequency 45.7%) (p< or =0.001), explaining 0.78% of total- and 0.75% of LDL-cholesterol. Another haplotype (frequency 10.5%) was significantly associated with lower HDL-cholesterol (p = 0.005), explaining 0.59% of variance.ConclusionsPRKAA2 gene variants are significantly associated with serum lipoproteins in a large sample of normal female Caucasians.

| S-EPMC1780024 | biostudies-literature

Threshold Effects in the Relationship Between Serum Non-High-Density Lipoprotein Cholesterol and Metabolic Syndrome.

Project description:BackgroundPrevious studies have suggested that the non-high-density lipoprotein cholesterol (non-HDL-C) is strongly associated with metabolic syndrome (MetS); however, the explicit relationship between them has not yet been clarified. The aim of this study was to reveal the explicit association between the non-HDL-C with MetS.MethodsThe present study was based on a cross-sectional study, which was carried out in Spain. A total of 60,799 workers were recruited between 2012 and 2016. Anthropometric parameters and blood indices (lipid profile and fasting blood glucose) were collected. Participants were divided into the MetS group or the non-MetS group based on the criteria of the National Cholesterol Education Program Adult Treatment Panel III. The relationship between serum non-HDL-C and the risk of MetS was evaluated using multivariate regression analysis, piece-wise linear regression analysis, smooth curve fitting and threshold saturation effect analysis after adjustment of potential confounders.ResultsThe risk of developing MetS increased with increasing non-HDL-C level. However, this association was only presented in the range of the non-HDL-C concentrations from 118 mg/dl to 247 mg/dl after adjusting for potential confounders. When compared to lower non-HDL-C level (<118 mg/dl), higher levels of non-HDL-C (118-247 mg/dl and >247 mg/dl) were related to higher incidence of MetS, with adjusted odds ratio (95% confidence interval) of 3.08 (2.77, 3.42) and 17.18 (14.29, 20.65), respectively (P for trend <0.05).ConclusionHigher serum non-HDL-C level was associated with increased MetS incidence; however, significant threshold saturation effects were observed when the non-HDL-C level <118 mg/dl or >247 mg/dl.

| S-EPMC6890221 | biostudies-literature

Dense genotyping of candidate gene loci identifies variants associated with high-density lipoprotein cholesterol.

Project description:Plasma levels of high-density lipoprotein cholesterol (HDL-C) are known to be heritable, but only a fraction of the heritability is explained. We used a high-density genotyping array containing single-nucleotide polymorphisms (SNPs) from HDL-C candidate genes selected on known biology of HDL-C metabolism, mouse genetic studies, and human genetic association studies. SNP selection was based on tagging SNPs and included low-frequency nonsynonymous SNPs.Association analysis in a cohort containing extremes of HDL-C (case-control, n=1733) provided a discovery phase, with replication in 3 additional populations for a total meta-analysis in 7857 individuals. We replicated the majority of loci identified through genome-wide association studies and present on the array (including ABCA1, APOA1/C3/A4/A5, APOB, APOE/C1/C2, CETP, CTCF-PRMT8, FADS1/2/3, GALNT2, LCAT, LILRA3, LIPC, LIPG, LPL, LRP4, SCARB1, TRIB1, ZNF664) and provide evidence that suggests an association in several previously unreported candidate gene loci (including ABCG1, GPR109A/B/81, NFKB1, PON1/2/3/4). There was evidence for multiple, independent association signals in 5 loci, including association with low-frequency nonsynonymous variants.Genetic loci associated with HDL-C are likely to harbor multiple, independent causative variants, frequently with opposite effects on the HDL-C phenotype. Cohorts comprising subjects at the extremes of the HDL-C distribution may be efficiently used in a case-control discovery of quantitative traits.

| S-EPMC3319351 | biostudies-literature

Candidate Gene Analysis Reveals Strong Association of CETP Variants With High Density Lipoprotein Cholesterol and PCSK9 Variants With Low Density Lipoprotein Cholesterol in Ghanaian Adults: An AWI-Gen Sub-Study.

Project description:Variations in lipid levels are attributed partly to genetic factors. Genome-wide association studies (GWASs) mainly performed in European, African American and Asian cohorts have identified variants associated with LDL-C, HDL-C, total cholesterol (TC) and triglycerides (TG), but few studies have been performed in sub-Saharan Africans. This study evaluated the effect of single nucleotide variants (SNVs) in eight candidate loci (ABCA1, LCAT, LPL, PON1, CETP, PCSK9, MVK, and MMAB) on lipid levels among 1855 Ghanaian adults. All lipid levels were measured directly using an automated analyser. DNA was extracted and genotyped using the H3Africa SNV array. Linear regression models were used to test the association between SNVs and log-transformed lipid levels, adjusting for sex, age and waist circumference. In addition Bonferroni correction was performed to account for multiple testing. Several variants of CETP, LCAT, PCSK9, and PON1 (MAF > 0.05) were associated with HDL-C, LDL-C and TC levels at p < 0.05. The lead variants for association with HDL-C were rs17231520 in CETP (? = 0.139, p < 0.0001) and rs1109166 in LCAT (? = -0.044, p = 0.028). Lower LDL-C levels were associated with an intronic variant in PCSK9 (rs11806638 [? = -0.055, p = 0.027]) and increased TC was associated with a variant in PON1 (rs854558 [? = 0.040, p = 0.020]). In silico functional analyses indicated that these variants likely influence gene function through their effect on gene transcription. We replicated a strong association between CETP variants and HDL-C and between PCSK9 variant and LDL-C in West Africans, with two potentially functional variants and identified three novel variants in linkage disequilibrium in PON1 which were associated with increasing TC levels in Ghanaians.

| S-EPMC7661969 | biostudies-literature

Rare SCARB1 mutations associate with high-density lipoprotein cholesterol but not with coronary artery disease.

Project description:Aims:Scavenger receptor Class B Type 1 (SR-BI) is a major receptor for high-density lipoprotein (HDL) that promotes hepatic uptake of cholesterol from HDL. A rare mutation p.P376L, in the gene encoding SR-BI, SCARB1, was recently reported to associate with elevated HDL cholesterol (HDL-C) and increased risk of coronary artery disease (CAD), suggesting that increased HDL-C caused by SR-BI impairment might be an independent marker of cardiovascular risk. We tested the hypothesis that alleles in or close to SCARB1 that associate with elevated levels of HDL-C also associate with increased risk of CAD in the relatively homogeneous population of Iceland. Methods and results:Using a large resource of whole-genome sequenced Icelanders, we identified thirteen SCARB1 coding mutations that we examined for association with HDL-C (n = 136 672). Three rare SCARB1 mutations, encoding p.G319V, p.V111M, and p.V32M (combined allelic frequency = 0.2%) associate with elevated levels of HDL-C (p.G319V: β = 11.1 mg/dL, P = 8.0 × 10-7; p.V111M: β = 8.3 mg/dL, P = 1.1 × 10-6; p.V32M: β = 10.2 mg/dL, P = 8.1 × 10-4). These mutations do not associate with CAD (36 886 cases/306 268 controls) (odds ratio = 0.90, 95% confidence interval 0.67-1.22, P = 0.49), despite effects on HDL-C comparable to that reported for p.P376L, both in terms of direction and magnitude. Furthermore, HDL-C raising alleles of three common SCARB1 non-coding variants, including one previously unreported (rs61941676-C: β = 1.25 mg/dL, P = 1.7 × 10-18), and of one low frequency coding variant (p.V135I) that independently associate with higher HDL-C, do not confer increased risk of CAD. Conclusion:Elevated HDL-C due to genetically compromised SR-BI function is not a marker of CAD risk.

| S-EPMC6001888 | biostudies-literature

Association of CD36 gene variants and metabolic syndrome in Iranians.

Project description:The CD36 gene encodes for a membrane receptor that facilitates fatty-acid uptake and utilization. Genetic variants of the CD36 gene have been associated with metabolic syndrome (MetS). We aimed to evaluate the association between the rs10499859A>G and rs13246513C>T polymorphisms and MetS components.For this case-control study, 140 MetS and 187 normal subjects were randomly selected from the Tehran Lipid and Glucose Study participants. Biochemical and anthropometrical variables were measured. Genotyping for both single nucleotide polymorphisms (SNPs) was performed by polymerase chain reaction-restriction fragment length polymorphism.Case and control groups were not different in allele and genotype frequencies for these SNPs. However, the A and T alleles of these SNPs were significantly associated with elevated levels of high-density lipoprotein cholesterol (HDL-C) before age and sex adjustment (p=0.027 and 0.016, respectively). Association between the A allele and body mass index (BMI) was also significant after adjustment for MetS under the dominant model (p=0.009, ?(2)=0.68).Based on our results, these polymorphisms do affect HDL-C level and BMI (MetS components), although the effect may be slight and restricted specifically to an environment-genotype.

| S-EPMC3326263 | biostudies-literature

Utility of Non-High-Density Lipoprotein Cholesterol to High-Density Lipoprotein Cholesterol Ratio in Evaluating Incident Diabetes Risk.

Project description:PurposeDiabetes is one of the most prevalent chronic diseases in the world, and its prevalence is expected to rise further. To help understand the utility of the ratio of non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol (NHHR) in diabetes prevention, this large-scale longitudinal cohort study aims to explore the association of NHHR with diabetes risk and compare it as a risk predictor with conventional lipid parameters.Patients and methodsThis observational study extracted data from the NAGALA longitudinal cohort study conducted in Japan between 2004 and 2015. Multivariate Cox regression analysis was used to evaluate the association between NHHR and the risk of diabetes. The dose-response relationship was analyzed by restricted cubic spline (RCS) regression and the potential risk threshold was estimated. The receiver operator characteristic curve (ROC) was used to analyze and calculate the predictive value and optimal threshold of NHHR and other conventional lipids for new-onset diabetes.ResultsOf the 15,464 people aged 18-79, 373 (2.41%) were diagnosed with new-onset diabetes during the study period, with a median age of 46 years. The sensitivity analysis based on multivariate adjustment showed that the independent positive correlation between diabetes and NHHR was stable in different populations. RCS and ROC analysis indicated that the association between NHHR and diabetes was non-linear, and the NHHR was a better marker for predicting diabetes risk than other conventional lipid parameters; Additionally, it is worth noting that an NHHR of approximately 2.74 may be the optimal threshold for intervention in diabetes risk.ConclusionIn the general population, NHHR is a better marker for predicting diabetes risk than conventional lipid parameters, and an NHHR of about 2.74 may be the optimal threshold for assessing diabetes risk.

| S-EPMC9166911 | biostudies-literature

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