血液代谢物与肺结核的相关性：双向孟德尔随机化研究

Association between Blood Metabolites and Pulmonary Tuberculosis: A Mendelian Randomization Analysis

摘要: 目的：利用双向双样本孟德尔随机化研究揭示了特定血液代谢物对肺结核的潜在因果效应。方法：工具变量来源于全基因组关联研究(GWAS)。应用五种不同的回归拟合方法进行双样本MR分析，主要分析方法为逆方差加权法(Inverse-variance weighted, IVW)，MR-Egger、Weighted median、Simple mode、Weighted mode作为补充方法；此外，还考虑了连锁不平衡和弱工具变量引起的潜在偏差。为保证结果的可靠性，还进行了敏感性分析：水平多效性分析(MR-Egger intercept检验)和异质性分析(Cochran’s Q检验和Funnel plot检验)均不符合标准的代谢物被认为对结果没有实质性的因果效应；同时应用Leave-one-out分析保证结果稳健性。结果：研究证实42种血液代谢与肺结核有关，其中包括13种风险因素(5-羟基吲哚硫酸盐的风险比最高，OR = 1.3035，95% CI：1.1074~1.5344，P = 0.0014)和29种防御因素(磷酸盐与甘油的比值最高，OR = 0.7512，95% CI：0.6296~0.8964，P = 0.0015)。为了评估肺结核对这些血液代谢物是否有反向因果关系，我们进行了反向MR分析。结果表明两者之间没有反向因果关系。结论：遗传学证据表明，5-羟基吲哚硫酸盐水平等13种血液代谢物是肺结核的风险因素，磷酸盐与甘油的比值等29种血液代谢物是肺结核的防御因素。

Abstract: Objective: To evaluate the causal relationship between blood metabolites and pulmonary tuberculosis (PTB) using a bidirectional two-sample Mendelian randomization (MR) approach. Methods: Instrumental variables were derived from Genome-Wide Association Studies (GWAS). Five distinct MR methods were applied for two-sample MR analysis: inverse-variance weighted (IVW) as the primary method, supplemented by MR-Egger, weighted median, simple mode, and weighted mode. Potential biases due to linkage disequilibrium and weak instrumental variables were also considered. To ensure the reliability of the results, sensitivity analyses were conducted. Metabolites that did not meet the standards in horizontal pleiotropy analysis (MR-Egger intercept test) and heterogeneity analysis (Cochran’s Q test and funnel plot test) were considered to have no substantial causal effect on the outcome; Leave-one-out analysis was used to ensure robustness of results. Results: Elevated levels of 42 blood metabolites were associated with PTB risk, comprising 13 risk factors (e.g.,5-hydroxyindole sulfate, highest OR = 1.3035, 95%CI: 1.1074~1.5344, P = 0.0014) and 29 protective factors (e.g., ratio of phosphate to glycerol, Lowest OR = 0.7512, 95%CI: 0.6296~0.8964, P = 0.0015). To assess whether there was a reverse causal relationship between pulmonary tuberculosis and these blood metabolites, we performed a reverse MR analysis. The results showed no reverse causal relationship. Conclusion: Genetic evidence suggests that 13 blood metabolites, including 5-hydroxyindole sulfate, are risk factors for pulmonary tuberculosis, while 29 blood metabolites, including the phosphate-to-glycerol ratio, are defensive factors against pulmonary tuberculosis.