Zhang Jun, Zhou Peng, Hu Shuqiong, Cai Shiya, He Tao
Department of Ophthalmology Renmin Hospital of Wuhan University Wuhan Hubei China.
College of Architecture Changsha University of Science and Technology Changsha Hunan China.
Health Sci Rep. 2024 Feb 1;7(2):e1847. doi: 10.1002/hsr2.1847. eCollection 2024 Feb.
Several observational studies have suggested an association between low serum bilirubin levels and Behçet's disease uveitis. However, the causal inference between bilirubin level and juvenile idiopathic arthritis-associated uveitis (JIAU) remains ambiguous. We investigated the potential causal relationship between serum bilirubin levels and JIAU using a bidirectional two-sample Mendelian randomization (MR) framework.
We systemically integrated summary-level data from published large-scale genome-wide association studies on bilirubin level and JIAU in a Caucasian British population. To determine the causal effect of bilirubin level on JIAU, we constructed strong instrumental variables using 47 and 80 single-nucleotide polymorphisms (SNPs) specific to direct bilirubin and total bilirubin levels, respectively. For reverse causal inference, seven SNPs associated with JIAU were included in our study. Multiple complementary methods were further performed to evaluate the robustness of MR estimates.
The inverse-variance weighted estimate did not show any significant causal associations of genetically predicted serum direct or total bilirubin level with the risk of JIAU (odds ratio [OR]: 1.010, 95% confidence interval [CI]: 0.750-1.359, = 0.947; OR: 0.867, 95% CI: 0.688-1.093; = 0.227, respectively). MR-Egger and weighted median methods also obtained similar associations. Additionally, the results of reverse MR analyses using JIAU as exposure showed no associations of genetically predicted risk of JIAU with serum bilirubin levels ( > 0.05). In sensitivity analysis, the causal estimate between serum bilirubin levels and JIAU did not differ when SNPs associated with possible confounders were omitted.
Genetic evidence from our bidirectional analysis did not support a causal association between serum bilirubin levels and JIAU risk in the Caucasian British population. Future large-scale studies should be conducted to validate these findings and explore any causal effects on the disease process.
多项观察性研究表明血清胆红素水平低与白塞病葡萄膜炎之间存在关联。然而，胆红素水平与青少年特发性关节炎相关性葡萄膜炎（JIAU）之间的因果推断仍不明确。我们使用双向双样本孟德尔随机化（MR）框架研究了血清胆红素水平与JIAU之间的潜在因果关系。
我们系统整合了来自已发表的关于英国白种人群胆红素水平和JIAU的大规模全基因组关联研究的汇总水平数据。为了确定胆红素水平对JIAU的因果效应，我们分别使用47个和80个特定于直接胆红素和总胆红素水平的单核苷酸多态性（SNP）构建了强工具变量。对于反向因果推断，我们的研究纳入了7个与JIAU相关的SNP。进一步采用多种互补方法评估MR估计值的稳健性。
逆方差加权估计未显示遗传预测的血清直接胆红素或总胆红素水平与JIAU风险之间存在任何显著的因果关联（优势比[OR]：1.010，95%置信区间[CI]：0.750 - 1.359，P = 0.947；OR：0.867，95% CI：0.688 - 1.093；P = 0.227）。MR-Egger和加权中位数方法也得到了类似的关联。此外，以JIAU为暴露因素的反向MR分析结果显示，遗传预测的JIAU风险与血清胆红素水平之间无关联（P > 0.05）。在敏感性分析中，当省略与可能的混杂因素相关的SNP时，血清胆红素水平与JIAU之间的因果估计无差异。
我们双向分析的遗传证据不支持英国白种人群中血清胆红素水平与JIAU风险之间存在因果关联。未来应开展大规模研究以验证这些发现，并探索对疾病进程的任何因果效应。
