Pleiotropic cardiometabolic effects of the LDLR rs6511720 T allele: an evaluation of genetic risk across metabolic states

Background and aims: The functional LDLR rs6511720 polymorphism has been implicated in lipid metabolism and cardiometabolic risk. We aimed to investigate its association with clinically relevant Low-Density Lipoprotein cholesterol (LDL-C) threshold (≥130 mg/dL), cardiometabolic burden, and type 2 diabetes mellitus (T2DM), with emphasis on sex-specific effects. Methods and results: A cross-sectional data analysis was conducted on community-based cohort of 1,442 adults (68.4% females; mean age 58.8 ± 14.0 years). Genotype, anthropometric, biochemical and lifestyle data were collected. Logistic regression analyses were performed under dominant, recessive, and additive genetic models, stratified by sex and adjustment for age, body mass index (BMI) and medications. Cohort genotype frequencies were 8.6% for TT, 18.3% for TG, and 73% for GG. Females T allele carriers were significantly associated with reduced odds of LDL-C ≥130 mg/dL under dominant (OR = 0.72; 95% CI: 0.52–0.98; p = 0.036), and additive (OR = 0.77; 95% CI: 0.62–0.96; p = 0.02) models. Conversely, the G allele was linked to elevated odds of LDL-C ≥130 mg/dL under recessive (OR = 1.40; 95% CI: 1.02–1.91; p = 0.03), and additive (OR = 1.30; 95% CI: 1.04–1.63; p = 0.02) models. The frequency of the GG genotype increased significantly with LDL-C severity, among females with ≥2 cardiometabolic risk factors (p = 0.02). Notably, female T allele carriers (TG + TT) had over twice the odds of T2DM compared to GG homozygotes (10.9% vs. 5.4%; OR = 2.18; 95% CI: 1.28–3.70; p = 0.004). Conclusion: LDLR rs6511720 exerts sex-specific pleiotropic effects, with the T allele protective against hypercholesterolemia while associated with increased T2DM susceptibility in females.