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Original article Causal association between serum bilirubin and ischemic stroke: multivariable Mendelian randomization
Jong Won Shin1orcid , Keum Ji Jung1orcid , Mikyung Ryu2orcid , Jungeun Kim3orcid , Heejin Kimm1orcid , Sun Ha Jee1orcid
Epidemiol Health 2024;e2024070
DOI: https://doi.org/10.4178/epih.e2024070 [Accepted]
Published online: August 19, 2024
1Graduate School of Public Health, Yonsei University, Seoul, Korea
2Institute on Aging, Ajou University Medical Center, Suwon, Korea
3Basgenbio, Inc, Seoul, Korea
Corresponding author:  Sun Ha Jee,
Email: jsunha@yuhs.ac
Received: 28 March 2024   • Revised: 3 July 2024   • Accepted: 16 July 2024
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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 (KCPS-II; n=159,844) and the Korean Genome and Epidemiology Study (KoGES; n=72,299). Data on ischemic stroke were obtained from BioBank Japan (BBJ; n=201,800). Colocalization analysis was performed, focusing on the UGT1A1, SLCO1B1, and SLCO1B3 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.

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