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

ABSTRACT: 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.

SUBMITTER: Helgadottir A

PROVIDER: S-EPMC6001888 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundHigh-density lipoprotein cholesterol (HDL-C) is shown to be an independent protective factor against coronary artery diseases (CAD). Yet there are limited studies focusing on the association between HDL-C and coronary artery bypass graft (CABG) surgery outcomes.HypothesisLow levels of HDL-C are associated with higher incidence of adverse outcomes in patients undergoing CABG.MethodsThis registry-based study included 17,772 patients who underwent elective isolated CABG between 2007 and 2017. Patients were classified into low and desirable HDL-C groups based on their serum HDL-C levels at admission and were followed for one-year post-surgery. The study population included 13,321 patients with low HDL-C and 4,451 with desirable HDL-C. proportional hazard Cox models were performed to evaluate the association between HDL-C levels and incidence of mortality as well as major adverse cardiovascular and cerebrovascular events (MACCE), while adjusting for potential confounders. Moreover, participants were stratified based on sex and the association was also investigated in each subgroup separately.ResultsNo significant difference was found between the groups regarding incidence of both mortality and MACCE, after adjusting with Inverse Probability Weighting (IPW) [HR (95%CI): 0.84 (0.46-1.53), p-value:0.575 and HR (95% CI): 0.91 (0.56-1.50), p-value:0.733, respectively]. According to the sex-based subgroup analysis, no significant association was observed after adjustment with IPW analysis. However, as we examined the association between the interaction of HDL-C levels, sex and cardiovascular outcomes, we found a significant association (HR;1.19 (95%CI: 1.04-1.45); p = 0.030).ConclusionHDL-C level was not associated with either mortality or MACCE during one year after CABG procedure. Sex-based analysis showed that in males, HDL-C is significantly more protective against these outcomes, compared to females. Further studies are necessary to elucidate the exact mechanisms mediating such association.

Project description:Background: Coronary artery disease (CAD) is the leading cause of death worldwide, which has a long asymptomatic period of atherosclerosis. Thus, it is crucial to develop efficient strategies or biomarkers to assess the risk of CAD in asymptomatic individuals. Methods: A total of 356 consecutive CAD patients and 164 non-CAD controls diagnosed using coronary angiography were recruited. Blood lipids, other baseline characteristics, and clinical information were investigated in this study. In addition, low-density lipoprotein cholesterol (LDL-C) subfractions were classified and quantified using the Lipoprint system. Based on these data, we performed comprehensive analyses to investigate the risk factors for CAD development and to predict CAD risk. Results: Triglyceride, LDLC-3, LDLC-4, LDLC-5, LDLC-6, and total small and dense LDL-C were significantly higher in the CAD patients than those in the controls, whereas LDLC-1 and high-density lipoprotein cholesterol (HDL-C) had significantly lower levels in the CAD patients. Logistic regression analysis identified male [odds ratio (OR) = 2.875, P < 0.001], older age (OR = 1.018, P = 0.025), BMI (OR = 1.157, P < 0.001), smoking (OR = 4.554, P < 0.001), drinking (OR = 2.128, P < 0.016), hypertension (OR = 4.453, P < 0.001), and diabetes mellitus (OR = 8.776, P < 0.001) as clinical risk factors for CAD development. Among blood lipids, LDLC-3 (OR = 1.565, P < 0.001), LDLC-4 (OR = 3.566, P < 0.001), and LDLC-5 (OR = 6.866, P < 0.001) were identified as risk factors. To predict CAD risk, six machine learning models were constructed. The XGboost model showed the highest AUC score (0.945121), which could distinguish CAD patients from the controls with a high accuracy. LDLC-4 played the most important role in model construction. Conclusions: The established models showed good performance for CAD risk prediction, which can help screen high-risk CAD patients in asymptomatic population, so that further examination and prevention treatment might be taken before any sudden or serious event.

Project description:Objective- The cell-cholesterol efflux capacity of HDL (high-density lipoprotein) is inversely associated with coronary heart disease risk. ABCA1 (ATP-binding cassette transporter A1) plays a crucial role in cholesterol efflux from macrophages to preβ-1-HDL. We tested the hypothesis that coronary heart disease patients have functionally abnormal preβ-1-HDL. Approach and Results- HDL cell-cholesterol efflux capacity via the ABCA1 and the SR-BI (scavenger receptor class B type I) pathways, HDL antioxidative capacity, apo (apolipoprotein) A-I-containing HDL particles, and inflammatory- and oxidative-stress markers were measured in a case-control study of 100 coronary heart disease cases and 100 sex-matched controls. There were significant positive correlations between ABCA1-dependent cholesterol efflux and the levels of small lipid-poor preβ-1 particles ( R2=0.535) and between SR-BI-dependent cholesterol efflux and the levels of large lipid-rich (α-1+α-2) HDL particles ( R2=0.712). Cases had significantly higher (87%) preβ-1 concentrations than controls, but the functionality of their preβ-1 particles (preβ-1 concentration normalized ABCA1-dependent efflux capacity) was significantly lower (-31%). Cases had significantly lower (-12%) mean concentration of large HDL particles, but the functionality of their particles (α-1+α-2 concentration normalized SR-BI-dependent efflux capacity) was significantly higher (22%) compared with that of controls. HDL antioxidative capacity was significantly lower (-16%) in cases than in controls. There were no significant correlations between either preβ-1 functionality or large HDL particle functionality with HDL antioxidative capacity or the concentrations of inflammatory- and oxidative-stress markers. Conclusions- HDL cell-cholesterol efflux capacity is significantly influenced by both the concentration and the functionality of specific HDL particles participating in cell-cholesterol efflux. Coronary heart disease patients have higher than normal preβ-1 concentrations with decreased functionality and lower than normal large HDL particle concentrations with enhanced functionality.

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

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