以前的研究主要集中在总胆红素水平上，没有明确区分直接胆红素和间接胆红素。在本研究中，检查了这些形式之间的差异，并调查了它们与缺血性中风的潜在因果关系。采用双样本多变量孟德尔随机化（MVMR）分析，从韩国癌症预防研究 II 中提取胆红素的汇总数据（ KCPS-II；n=159,844）和韩国基因组和流行病学研究（KoGES；n=72,299）。缺血性中风的数据来自日本生物银行（BBJ；n=201,800）。进行了共定位分析，重点关注 UGT1A1、SLCO1B1 和 SLCO1B3 基因，这些基因是与血清胆红素水平相关的主要基因座。粗略的 2 样本孟德尔随机化分析显示总胆红素水平与缺血性中风之间存在显着负相关。然而，在 MVMR 分析中，只有间接胆红素与缺血性中风呈显着负相关（比值比，0.76；95% 置信区间，0.59 至 0.98）。共定位分析未发现与间接胆红素相关的 3 个基因位点与缺血性中风风险之间存在共同的因果变异。我们的研究建立了亚洲人群中较高的遗传决定的血清间接胆红素水平与降低的缺血性中风风险之间的因果关系。未来的研究应包括对间接胆红素和缺血性中风之间共有的遗传变异进行更深入的分析。

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.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.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.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.