Lp(a) and a 43-variant genetic risk score predict sudden cardiac death in older men with high triglycerides, UK Biobank cohort of 323,666 (Mayo Clin Proc 2026)

Objective: To examine the association of serum Lipoprotein(a) [Lp(a)] levels and LPA genetic risk score (GRS) with the risk of sudden cardiac death (SCD) and determine whether these associations vary by age, sex, triglyceride (TG) levels and APOE genotypes.

Methods: This prospective cohort study included 323,666 participants from the UK Biobank. Serum Lp(a) concentrations and a 43-variant weighted LPA GRS were used to evaluate associations with SCD using Cox proportional hazards models. Analyses were stratified by age, sex, and TG levels to identify susceptible subgroups. Interaction analyses were conducted to examine the modifying role of APOE genotypes (2/3/4). The study was conducted from January 15, 2025, through June 10, 2025.

Results: Higher Lp(a) levels were associated with increased SCD risk in older males with elevated TG [hazard ratio (HR) per standard deviation (SD) increase 1.178, 95% confidence interval (CI) 1.039 to 1.335; P=.01] and in younger males with normal TG (HR per SD increase 1.079, 95% CI 1.026 to 1.133; P=.003). Genetically, each SD increase in LPA GRS conferred a 16.6% higher SCD risk in older males with elevated TG (HR per SD increase 1.166, 95% CI 1.028 to 1.323; P=.02). Individuals with APOE3 showed the highest risk when exposed to high Lp(a) or LPA GRS.

Conclusion: Elevated serum Lp(a) level and LPA GRS are associated with increased SCD risk in older males with elevated TG, with APOE genotypes modulating these effects. This study identifies Lp(a) as a genetically informed, clinically relevant biomarker for targeted SCD risk stratification and prevention.