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Jungeun Kim 1 Article
Causal association between serum bilirubin and ischemic stroke: multivariable Mendelian randomization
Jong Won Shin, Keum Ji Jung, Mikyung Ryu, Jungeun Kim, Heejin Kimm, Sun Ha Jee
Epidemiol Health. 2024;46:e2024070.   Published online August 19, 2024
DOI: https://doi.org/10.4178/epih.e2024070
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Abstract
OBJECTIVES
Previous research has predominantly focused on total bilirubin levels without clearly distinguishing between direct and indirect bilirubin. In this study, the differences between these forms were examined, and their potential causal relationships with ischemic stroke were investigated.
METHODS
Two-sample multivariable Mendelian randomization (MVMR) analysis was employed, extracting summary data on bilirubin from the Korean Cancer Prevention Study-II (n=159,844) and the Korean Genome and Epidemiology Study (n=72,299). Data on ischemic stroke were obtained from BioBank Japan (n=201,800). Colocalization analysis was performed, focusing on the <i>UGT1A1, SLCO1B1</i>, and <i>SLCO1B3</i> genes, which are the primary loci associated with serum bilirubin levels.
RESULTS
Crude 2-sample Mendelian randomization analysis revealed a significant negative association between total bilirubin levels and ischemic stroke. However, in MVMR analyses, only indirect bilirubin demonstrated a significant negative association with ischemic stroke (odds ratio, 0.76; 95% confidence interval, 0.59 to 0.98). Colocalization analysis did not identify a shared causal variant between the 3 genetic loci related to indirect bilirubin and the risk of ischemic stroke.
CONCLUSIONS
Our study establishes a causal association between higher genetically determined levels of serum indirect bilirubin and reduced risk of ischemic stroke in an Asian population. Future research should include more in-depth analysis of shared genetic variants between indirect bilirubin and ischemic stroke.
Summary
Korean summary
이 연구는 혈청 빌리루빈의 세 가지 형태(총, 직접, 간접 빌리루빈)와 허혈성 뇌졸중 간의 인과적 연관성을 다루었습니다. 다변수 멘델리안 무작위 분석(MVMR)을 통해 간접 빌리루빈이 허혈성 뇌졸중 위험을 유의미하게 감소시키는 것으로 나타났습니다. 이 결과는 빌리루빈의 항산화 역할과 허혈성 뇌졸중 간의 상관관계를 심화 이해하는 데 기여합니다.
Key Message
This study investigated the causal associations between three forms of serum bilirubin (total, direct, and indirect) and ischemic stroke. Multivariable Mendelian randomization (MVMR) analysis revealed a significant inverse association between indirect bilirubin and the risk of ischemic stroke. These findings contribute to a deeper understanding of the relationship between bilirubin's antioxidant role and ischemic stroke.

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