基于孟德尔随机化探索2型糖尿病与衰弱的因果关系

Causality between Type 2 Diabetes and Frailty Based on Mendelian Randomization

摘要: 背景：随着我国经济水平的持续发展和人口老龄化的不断加重，T2DM和衰弱的发病率持续增加。目的：探究2型糖尿病与衰弱之间的因果关系，为糖尿病与衰弱发病风险关联提供遗传学证据支持。方法：研究采用MR-Egger回归法(MR-Egger regression)、加权中位数法(Weighted median, WME)、逆方差加权法(Inverse variance weighted, IVW)、简单估计法(Simple mode)、加权模型法及逆方差加权随机效应法(Inverse variance weighted random effects) 6种回归模型对2型糖尿病与衰弱的因果关系进行孟德尔随机化分析。结果：IVW模型显示糖尿病为衰弱的危险因素，IVW随机效应模型则显示2型糖尿病有统计学意义的影响因素；MR-Egger回归截距项P值均>0.05，即筛选出的SNP不存在基因多效性，因此孟德尔随机化在本研究中为因果推断的有效方法；异质性检验结果P值均<0.001，故应重点关注随机效应IVW模型。结论：利用两样本孟德尔随机化方法排除混杂因素和反向因果关联后，得到无偏估计的结果，据此可以确定2型糖尿病与衰弱之间存在因果关系。

Abstract: Background: With the continuous development of China’s economic level and the aging of the population, the incidence of T2DM and frailty continues to increase. Objective: To explore the causal relationship between type 2 diabetes and frailty and provide genetic evidence for the risk association between diabetes and frailty. Methods: This study employed six regression models, namely MR-Egger regression, weighted median (WME), inverse variance weighted (IVW), simple mode, weighted model, and inverse variance weighted random effects, to conduct Mendelian randomization analysis on the causal relationship between type 2 diabetes and frailty. Results: The IVW model showed that diabetes is a risk factor for frailty, while the IVW random effects model demonstrated a statistically significant impact of type 2 diabetes. The P-values for the intercept terms in the MR-Egger regression were all more than 0.05, indicating no genetic pleiotropy for the selected SNPs, thus confirming that Mendelian randomization is an effective method for causal inference in this study. The P-values for heterogeneity tests were all <0.001, highlighting the importance of the random effects IVW model. Conclusion: By employing the two-sample Mendelian randomization method to account for confounding factors and reverse causality, unbiased estimates were obtained, supporting the existence of a causal relationship between type 2 diabetes and frailty.