谷丙转氨酶与胆石症之间的因果关系：一项双样本孟德尔随机研究

Association between Alanine Transaminase and Cholelithiasis: A Two-Sample Mendelian Randomization Study

摘要: 背景：转氨酶，即丙氨酸氨基转移酶(ALT)和天门冬氨酸氨基转移酶(AST)，主要存在于肝脏细胞中。转氨酶水平升高通常是肝细胞损害的指标。胆系结石的形成主要与胆汁中的胆盐、胆固醇等成分的平衡失调有关，一些肝脏疾病或损害，例如肝炎、脂肪肝、肝硬化等，可能间接地增加胆结石的风险。丙氨酸氨基转移酶(ALT)水平升高是否会导致胆系结石的发病率升高的因果关系尚不清楚。本研究使用两个样本孟德尔随机化(MR)来阐明丙氨酸氨基转移酶(ALT)水平升高是否会提高胆系结石发病率的潜在因果关系。方法：使用逆方差加权(IVW)、加权中值和MR-Egger回归方法进行双样本孟德尔随机化(MR)分析。我们使用公开的全基因组关联研究(GWAS)荟萃分析汇总统计数据集，对欧洲血统个体(n = 437,267)的谷丙转氨酶(Alanine Transaminase)进行暴露，并使用GWAS进行非癌症疾病代码自我报告：胆石症(Cholelithiasis)中包含的个体(总数 = 487,553)作为结果。结果：我们从谷丙转氨酶(Alanine Transaminase)的GWAS中选择了240个具有全基因组意义的单核苷酸多态性作为工具变量。IVW方法显示证据支持谷丙转氨酶(Alanine Transaminase)和胆石症(Cholelithiasis)之间存在因果关系(β = 1.959, SE = 0.542, P = 0.0003)。MR-Egger回归显示，定向多效性不太可能使结果产生偏差(截距 = 0.0027, P = 0.549)，但显示谷丙转氨酶和胆石症之间没有因果关系(β= 1.44, SE = 1.021, P = 0.1596)。然而，加权中位数方法得出了Liver enzyme levels (Alanine Transaminase)和胆石症(Cholelithiasis)之间存在因果关系的证据(β= 1.959, SE = 0.5422, P = 0.0003)。Cochran的Q检验和漏斗图表明没有异质性和不对称性的证据，表明没有方向性多效性。结论：孟德尔随机化分析结果支持丙氨酸氨基转移酶(ALT)水平升高会提高胆石症发病率。

Abstract: Background: Transaminases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), are found primarily in liver cells. Elevated aminotransferase levels are usually an indicator of liver cell damage. The formation of stones in the biliary system is mainly related to an imbalance in the balance of bile salts, cholesterol, and other components of bile. Some liver diseases or damage, such as hepatitis, fatty liver, and cirrhosis, may indirectly increase the risk of gallstones. Whether elevated alanine aminotransferase (ALT) levels causally contribute to the increased incidence of biliary system stones is not known. This study used two-sample Mendelian randomization (MR) to elucidate the potential causality of whether elevated alanine aminotransferase (ALT) levels increase the incidence of gallstones. Methods: Two-sample Mendelian randomization (MR) analyses were performed using inverse variance weighting (IVW), weighted median, and MR-Egger regression methods. We used publicly available genome-wide association study (GWAS) meta-analysis summary statistics sets for exposure to alanine transaminase in individuals of European ancestry (n = 437,267) and self-reporting of non-cancer disease codes using the GWAS: individuals included in Cholelithiasis (Total = 487,553) as outcomes. Results: We selected 240 single nucleotide polymorphisms of genome-wide significance as instrumental variables from the GWAS of alanine transaminase. IVW methods showed evidence supporting a causal relationship between alanine transaminase and cholelithiasis (β = 1.959, SE = 0.542, P = 0.0003). MR-Egger regression showed that directed pleiotropy was unlikely to bias the results (intercept = 0.0027, P = 0.549), but showed no causal relationship between ghrelin and cholelithiasis (β= 1.44, SE = 1.021, P = 0.1596). However, the weighted median approach yielded evidence of a causal relationship between liver enzyme levels (Alanine Transaminase) and cholelithiasis (β= 1.959, SE = 0.5422, P = 0.0003). Cochran’s Q-test and funnel plots showed no evidence of heterogeneity or asymmetry, indicating no directional pleiotropy. Conclusion: The results of Mendelian randomization analysis support that elevated alanine aminotransferase (ALT) levels increase the incidence of cholelithiasis.