Cardiology · Medical Literature
Association of SCARB1 Polymorphisms with Coronary Artery Disease Risk: A Systematic Review and Meta-Analysis.
Abstract
Coronary artery disease (CAD) remains a major cause of morbidity and mortality worldwide. Variants in the lipid metabolism gene SCARB1 may influence CAD susceptibility, but existing evidence is inconsistent. We systematically searched PubMed, Embase, Web of Science, the Cochrane Library, and Scopus up to 13 February 2026 for case-control studies on SCARB1 polymorphisms and CAD risk. Three polymorphisms, rs5888, rs4238001, and rs10846744, were included. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated under multiple genetic models. Subgroup analyses were conducted for rs5888 by sex, ethnicity, and clinical outcome. Heterogeneity was assessed using I2. 12 eligible case-control studies involving 3947 CAD cases and 5076 controls were included. Overall, rs5888 was not significantly associated with CAD in any genetic model, either in the pooled analysis or in subgroup analyses by ethnicity and clinical outcome. In sex-stratified analyses, males carrying the TT genotype had a significantly lower CAD risk under the recessive model (OR = 0.73, 95% CI: 0.57-0.93), whereas no significant association was observed in females. No significant association was found between rs4238001 and CAD under any model. In contrast, the rs10846744 G allele was significantly associated with reduced CAD risk under the allelic (OR = 0.78, 95% CI: 0.64-0.94), dominant (OR = 0.68, 95% CI: 0.50-0.93), homozygote (OR = 0.65, 95% CI: 0.44-0.94), and additive models (OR = 0.80, 95% CI: 0.67-0.96). SCARB1 rs5888 showed a male-specific association with CAD, while rs10846744 showed a suggestive inverse association that requires further validation.
Clinical relevance
Coronary artery disease remains a leading cause of global morbidity and mortality, and identifying genetic susceptibility variants in lipid metabolism pathways such as SCARB1 may refine cardiovascular risk stratification beyond traditional risk factors. This systematic review and meta-analysis addresses inconsistent prior evidence regarding SCARB1 polymorphisms and CAD risk across diverse populations. Clinicians and cardiogenomics specialists should be aware of these findings as precision medicine approaches increasingly incorporate polygenic risk assessment into preventive cardiology workflows.
Key findings
1. The meta-analysis included 12 eligible case-control studies comprising 3,947 CAD cases and 5,076 controls, providing a pooled dataset for analysis of three SCARB1 polymorphisms: rs5888, rs4238001, and rs10846744. 2. rs5888 was not significantly associated with CAD risk in the overall pooled analysis under any genetic model, nor in subgroup analyses stratified by ethnicity or clinical outcome. 3. In sex-stratified analysis of rs5888, males carrying the TT genotype demonstrated a significantly lower CAD risk under the recessive model (OR = 0.73, 95% CI: 0.57–0.93), while no significant association was observed in females, indicating a male-specific protective signal. 4. rs4238001 showed no significant association with CAD risk under any genetic model tested. 5. The rs10846744 G allele was significantly associated with reduced CAD risk across multiple genetic models: allelic model (OR = 0.78, 95% CI: 0.64–0.94), dominant model (OR = 0.68, 95% CI: 0.50–0.93), homozygote model (OR = 0.65, 95% CI: 0.44–0.94), and additive model (OR = 0.80, 95% CI: 0.67–0.96). 6. Heterogeneity across studies was assessed using I², though specific I² values and p-values for individual model heterogeneity were not reported in the abstract; the authors characterize the rs10846744 finding as a 'suggestive inverse association' requiring further validation.
Practice implications
Clinicians involved in cardiovascular risk stratification should note that SCARB1 rs10846744 G allele carriage shows a consistent inverse association with CAD across multiple genetic models, though its designation as 'suggestive' mandates cautious interpretation until larger, prospective, multi-ethnic cohorts validate these findings before clinical genotyping can be recommended. The male-specific protective effect of the rs5888 TT genotype under the recessive model underscores the importance of sex-disaggregated analyses in cardiovascular genetics and suggests that any future SCARB1 genotyping panels should incorporate sex as a biologically relevant covariate in risk algorithms. At present, these polymorphisms are not ready for routine clinical use but may inform the design of polygenic risk scores for CAD and highlight SCARB1-mediated HDL cholesterol metabolism as a candidate pathway for sex-differentiated therapeutic targeting.