Genetic and polygenic contributions to familial hypercholesterolemia in Thailand: Implications for diagnosis and lipid management.

Background: Familial hypercholesterolemia (FH) is a major risk factor for cardiovascular diseases; however, the issue of underdiagnosis remains a global challenge. This study investigates the prevalence of FH-associated variants in Thailand and examines the clinical and lipid profile characteristics of variant carriers to improve diagnostic strategies.

Methods: We analyzed the genetic data of 4879 participants across 2 cohorts, identifying variants in LDLR, APOB, and PCSK9. A 12-single-nucleotide polymorphism (12-SNP) polygenic risk score (PRS) for low-density lipoprotein cholesterol (LDL-C) was calculated. Longitudinal lipid profiles, including LDL-C, total cholesterol (TC), triglyceride, and high-density lipoprotein cholesterol (HDL-C) were assessed to evaluate the sustained impact of FH-associated variants.

Results: FH-associated variants were identified in 0.59% of participants, with 68.96% carrying variants in LDLR and 31.04% in APOB. FH-associated variant carriers had significantly higher LDL-C (125.5 mg/dL vs 107.8 mg/dL, P =0.015) and TC levels (208.5 mg/dL vs 190.0 mg/dL, P = .004) than noncarriers, though overlap in lipid profiles was observed. PRS analysis revealed that FH-associated variants contributed more significantly to LDL-C levels than polygenic factors. Long-term follow-up showed persistent elevation of LDL-C and TC in FH-associated variant carriers.

Conclusion: This study provides the first prevalence analysis of FH in Thailand, highlighting the limitations of lipid-based diagnostic criteria. Incorporating genetic screening and developing tailored diagnostic criteria are critical for addressing FH underdiagnosis and improving lipid management in Thailand.