Genetic Variation at the Scavenger Receptor Class B Type I Gene Locus Determines Plasma Lipoprotein Concentrations and Particle Size and Interacts with Type 2 Diabetes: The Framingham Study

Boston University, Boston, Massachusetts, United States
Journal of Clinical Endocrinology & Metabolism (Impact Factor: 6.21). 07/2003; 88(6):2869-79. DOI: 10.1210/jc.2002-021664
Source: PubMed


The scavenger receptor class B type I (SR-BI) is a key component in the reverse cholesterol transport pathway. We have previously reported three common polymorphisms associated with plasma lipids and body mass index. We hypothesized that diabetic status may interact with these polymorphisms in determining plasma lipid concentrations and particle size. We evaluated this hypothesis in 2463 nondiabetic (49% men) and 187 diabetic (64% men) participants in the Framingham Study. SR-BI and APOE genotypes, anthropometric, clinical, biochemical, and lifestyle variables were determined. After multivariate adjustment, we found a consistent association between the exon 8 polymorphism and high-density lipoprotein cholesterol concentration and particle size. Interaction effects were not significant for exon 8 and intron 5 polymorphisms. However, we found statistically significant interactions between SR-BI exon 1 genotypes and type 2 diabetes, indicating that diabetic subjects with the less common allele (allele A) have lower lipid concentrations. For low-density lipoprotein cholesterol, the adjusted means (+/-SE) were 3.31 +/- 0.03 and 3.29 +/- 0.04 mmol/liter for G/G and G/A or A/A in nondiabetics, respectively, compared with 3.19 +/- 0.10 and 2.75 +/- 0.01 mmol/liter for G/G and G/A or A/A in diabetics (P = 0.03 for interaction). Similar results were obtained for HDL(2)-C. In conclusion, SR-BI gene variation modulates the lipid profile, particularly in type 2 diabetes, contributing to the metabolic abnormalities in these subjects.

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Available from: Jose M Ordovas, Feb 27, 2014
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    • "The association between SCARB1 rs5888 SNP and serum lipid levels has been described in other several previous studies, which were recently summarized by Stanislovaitiene et al. 28, and also discussed in our recent reports 29,30. Some studies showed that the SCARB1 rs5888 SNP T allele was associated with increased serum HDL-C levels 16,18,20,24,27,28 and decreased serum non-HDL-C concentrations 17,20, and therefore has an atheroprotective effect. But other studies found that this SNP T allele has a pro-atherosclerosis serum lipid profile. "
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    ABSTRACT: Background: Our previous studies have showed that the rs5888 single nucleotide polymorphism (SNP) in Scavenger receptor class B type 1 (SCARB1) gene is associated with serum lipid levels in the general Chinese populations. The present study was undertaken to detect the associations between rs5888 SNP and the risk of coronary artery disease (CAD) and ischemic stroke (IS). Methods: A total of 1,716 unrelated subjects (CAD, 601; IS, 533; and healthy controls, 582) were included in this study. Genotyping of the rs5888 SNP were determined by polymerase chain reaction and restriction fragment length polymorphism. Results: The genotypic frequencies of SCARB1 rs5888 SNP were different between CAD patients and controls, the subjects with TT genotype had high risk of CAD (OR = 1.76, P = 0.038 for TT vs. CC; and OR = 1.75, P = 0.036 for TT vs. CC/CT). There was no significant association between genotypes and the risk of IS. Further analysis showed that the subjects with TT genotype in the total population had lower levels of high-density lipoprotein cholesterol than the subjects with CC/CT genotypes (P < 0.05), the subjects with TT genotype in controls but not in CAD or IS patients had higher levels of serum LDL-C and ApoB than those with CC genotype (P < 0.05 for each). Conclusions: The present study suggests that the SCARB1 rs5888 SNP influences serum lipid levels, and is associated with the risk of CAD.
    Full-text · Article · Oct 2013 · International journal of medical sciences
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    • "Much less is known regarding the role of SCARB1 in humans, although several studies have reported that the SNP of SCARB1 (rs5888) is associated with the lipid profile and the development of CHD [9,12,13]. The frequencies of the SCARB1 alleles in our population were similar to frequencies that have been reported for French and North American populations [30]. "
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    ABSTRACT: Dyslipidemia is one of several known risk factors for coronary heart disease, a leading cause of death in Lithuania. Blood lipid levels are influenced by multiple genetic and environmental factors. Epidemiological studies demonstrated the impact of nutrition on lipid levels within the Lithuanian population although the role of genetic factors for dyslipidemias has not yet been studied. The objective of this study was to assess the distribution of the APOE, SCARB1, PPARalpha genotypes in the Lithuanian adult population and to determine the relationship of these genotypes with dyslipidemia. A cross-sectional health survey was carried out in a representative random sample of the Lithuanian population aged 25--64 (n=1030). A variety of single-nucleotide polymorphisms (SNPs) of the APOE (rs429358 and rs7412), SCARB1 (rs5888) and PPARalpha (rs1800206) genes were assessed using real-time polymerase chain reaction. Serum lipids were determined using enzymatic methods.Results/Principal findings: Men and women with the APOE2 genotype had the lowest level of total and low-density lipoprotein cholesterol (LDL-C). Men with the APOE2 genotype had significantly higher levels of triglycerides (TG) than those with the APOE3 genotype. In men, the carriers of the APOE4 genotype had higher odds ratios (OR) of reduced (<1.0 mmol/L) high density lipoprotein cholesterol (HDL-C) levels versus APOE3 carriers (OR=1.98; 95% CI=1.05-3.74). The odds of having elevated (>1.7 mmol/L) TG levels was significantly lower in SCARB1 genotype CT carriers compared to men with the SCARB1 genotype CC (OR=0.50; 95% CI=0.31-0.79). In men, carriers of the PPARalpha genotype CG had higher OR of elevated TG levels versus carriers of PPARalpha genotype CC (OR=2.67; 95% CI=1.15-6.16). The odds of having high LDL-C levels were lower in women with the APOE2 genotype as compared to APOE3 genotype carriers (OR=0.35; 95% CI=0.22-0.57).Conclusions/Significance: Our data suggest a gender difference in the associations between APOE, SCARB1, PPARalpha genotypes and lipid levels. In men, the APOE4 genotype and PPARalpha genotype CG were correlated with an atherogenic lipid profile while the SCARB1 genotype CT had an atheroprotective effect. In women, APOE2 carriers had the lowest odds of high LDL-C.
    Full-text · Article · Aug 2013 · Lipids in Health and Disease
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    • "↑HDL-Chol, ↓LDL-Chol. Osgood et al.; 2003 [18] Aged 26–79 yrs. "
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    ABSTRACT: Mutation in SCARB1 gene, exon 8 rs5888, has been associated with altered lipid levels and cardiovascular risk in humans though the results have been inconsistent. We analysed the impact of SCARB1 single nucleotide polymorphism (SNP) rs5888 with plasma lipid profile and association with coronary artery disease (CAD) in a Lithuanian population characterized by high morbidity and mortality from CAD and high prevalence of hypercholesterolemia. The study included 1976 subjects from a random sample (reference group) and an myocardial infarction (MI) group of 463 patients. Genotyping of SCARB1 (rs5888) was carried out using the real-time polymerase chain reaction method. RESULTS/PRINCIPAL FINDINGS: Analysis of rs5888 C/T gene polymorphism in the reference group revealed that male TT genotype carriers (25-74 years) had significantly higher total cholesterol and triglyceride concentrations (5.70 mmol/l vs. 5.49 mmol/l; p = 0.036, and 1.70 mmol/l vs. 1.40 mmol/l, p = 0.023, respectively) than CT carriers and the oldest males (65-74 years) TT carriers had significantly higher high density lipoprotein cholesterol concentrations in comparison to heterozygous (1.52 mmol/l vs. 1.36 mmol/l, p = 0.033). The youngest female (25-44 years) TT genotype carriers had significantly lower low density lipoprotein cholesterol concentrations in comparison to C homozygous (2.59 mmol/l vs. 2.92 mmol/l, p = 0.023). The frequency of the SCARB1 TT genotype in the oldest male MI group (65-74 years) was significantly lower than in the corresponding reference group subjects (9.4% vs. 22.3%, p = 0.006). SCARB1 TT genotype was associated with decreased odds of MI in males aged 65-75 years (OR = 0.24, 95% CI 0.10-0.56, p = 0.001). SCARB1 polymorphism is associated with lipid metabolism and CAD in an age- and gender- dependent manner. Analysis of SCARB1 SNP rs5888 C/T genotypes revealed an atheroprotective phenotype of lipid profile in older men and in young women TT genotype carriers in the reference group. SCARB1 TT genotype was associated with decreased odds of MI in aged men.
    Full-text · Article · Mar 2013 · Lipids in Health and Disease
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