OBJECTIVE A number of epidemiological studies have reported that decreased serum bilirubin, an endogenous antioxidant, is associated with cardiovascular disease. However, previous Mendelian randomization analyses conducted using a single sample have shown no evidence of association. Approach and Results: A 2-sample summary Mendelian randomization study was performed by obtaining exposure and outcome data from separate nonoverlapping samples. We utilized data from the KoGES (Korean Genome and Epidemiology Study; n=25 406) and KCPS-II (Korean Cancer Prevention Study-II; n=14 541) biobank for serum bilirubin and stroke, respectively. Using KoGES, a total of 1784 single nucleotide polymorphisms associated with serum bilirubin levels were discovered using a genome-wide significance threshold (P<5×10-8), of which 10 single nucleotide polymorphisms were identified as independent (R2<0.005) and adopted as genetic instruments. From KCPS-II, total and ischemic stroke cases were identified (n=1489 and n=686), with 12 366 acting as controls. Various 2-sample summary Mendelian randomization methods were employed, with Mendelian randomization estimates showing an inverse causal association between serum bilirubin levels and total stroke risk (odds ratio, 0.481 [95% CI, 0.234-0.988]; P=0.046). This association increased in magnitude when restricting the analysis to ischemic stroke cases (odds ratio, 0.302 [95% CI, 0.105-0.868]; P=0.026). CONCLUSIONS Our findings provide evidence of significant causal relationship between high levels of bilirubin and decreased stroke risk in Korean population in agreement with observational approaches. This highlights the potential for bilirubin to serve as a therapeutic target for oxidative stress-related diseases such as stroke and suggests that previous findings were not a consequence of unmeasured confounding.

中文翻译：

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血清胆红素水平与卒中风险降低之间的因果关系：孟德尔随机抽样的两样本研究。

目的许多流行病学研究表明，血清胆红素（一种内源性抗氧化剂）的减少与心血管疾病有关。但是，以前使用单个样本进行的孟德尔随机分析未显示关联的证据。方法和结果：通过从不同的非重叠样本中获取暴露和结果数据，进行了2样本孟德尔随机汇总研究。我们分别利用了KoGES（韩国基因组和流行病学研究； n = 25 406）和KCPS-II（韩国癌症预防研究-II； n = 14 541）生物库中的血清胆红素和中风数据。使用KoGES，使用全基因组范围的显着性阈值（P <5×10-8）发现了与血清胆红素水平相关的1784个单核苷酸多态性，其中10个单核苷酸多态性被鉴定为独立的（R2 <0.005）并被用作遗传工具。从KCPS-II中，确定了全部和缺血性中风病例（n = 1489和n = 686），其中12366例为对照。采用了各种2样本汇总孟德尔随机方法，孟德尔随机估计值显示血清胆红素水平与总卒中风险之间存在因果关系的反相关关系（优势比为0.481 [95％CI，0.234-0.988]； P = 0.046）。当将分析局限于缺血性卒中病例时，这种关联的程度会增加（比值比为0.302 [95％CI，0.105-0.868]； P = 0.026）。结论我们的发现提供了证据，表明高胆红素与韩国人群卒中风险降低之间存在显着的因果关系，这与观察方法一致。