Genetics
Relationship between Genetically Determined LDL-Cholesterol and Stroke: A Prospective Cohort Study Sun Ha Jee* Sun Ha Jee Sunmi lee
Background: Conventional epidemiologic studies have reported a significant association between low LDL cholesterol and the risk of hemorrhagic stroke. This association has even been incorporated into predictive models for hemorrhagic stroke. This study aims to analyze the relationship between genetically determined LDL-cholesterol and stroke through a prospective cohort.
Methods: Data from the Korean Cancer Prevention Study-II were used, with a total of 159,844 participants. These individuals underwent health check-ups at 18 screening centers in Korea from 2004 to 2013 and provided written consent for participation. The participants were linked to the National Health Insurance Service’s hospitalization records to confirm stroke occurrences until 2021. Among them, 139,877 participants (86,874 males) underwent GSA and K-chip testing, and the data from both chips were combined and analyzed after imputation using 1000 Genomes and impute 5. Genetically determined LDL-c was created by extracting SNPs with a GWAS analysis of LDL and calculating a weighted genetic score. Cholesterol levels were divided into quintiles, and their association was analyzed using Cox proportional hazard ratios.
Results: The mean age of the participants was 41.0 years (41.7 years for males), and over a mean follow-up period of 13 years, 3,883 cases of ischemic heart disease (IHD) and 2,662 cases of stroke occurred. Ischemic stroke accounted for 1,213 cases, and hemorrhagic stroke for 525 cases. Overall, the risk of IHD was significantly increased in the highest LDL-c quintile (Q5) compared to the lowest quintile (Q1) in both conventional epidemiologic study (HR=1.58, 95%CI=1.42-1.77) and genetic epidemiologic study (HR=1.26, 95%CI=1.14-1.40). However, the risk of hemorrhagic stroke showed a different pattern. According to conventional epidemiology, the highest LDL-c quintile (Q5) was significantly associated with a lower risk of hemorrhagic stroke compared to other ranges (HR=0.74, 95%CI=0.57-0.96). However, the relationship between genetically determined LDL-cholesterol and stroke was not significant.
Conclusion: Low genetically determined LDL-cholesterol did not increase the risk of stroke. The previously reported association between low cholesterol and hemorrhagic stroke in conventional epidemiologic studies is considered biased due to confounding variables or reverse causation.
*This study was supported by research funding from Basgen Bio for the years 2021-2026.