目的 采用两样本孟德尔随机化(Mendelian randomization, MR)方法探究男性和女性睾酮与非酒精性脂肪肝(nonalcoholic fatty liver disease, NAFLD)的因果关联。 方法 利用全基因组关联研究(genome-wide association study, GWAS)汇总数据，使用女性、男性睾酮(总睾酮、生物有效性睾酮)以及性激素结合球蛋白(sex hormone-binding globulin, SHBG)的遗传变异作为工具变量，采用逆方差加权法(inverse variance weighted, IVW)为主分析方法，同时结合基于其他模型假设下的6种单变量MR方法评估女性、男性睾酮(总睾酮、生物有效性睾酮)以及SHBG与NAFLD的因果关系。此外，应用芬兰生物银行(FinnGen)的NAFLD数据对探索性分析的结果进行验证。进一步采用Cochran′s Q检验，MR-Egger回归和留一法等方法进行敏感性分析，评估工具变量的异质性水平、基因多效性和稳定性。 结果 探索性分析IVW模型结果表明，女性生物有效性睾酮和SHBG与NAFLD具有因果关联，女性生物有效性睾酮水平每增加一个单位，NAFLD发病风险增高24%(OR＝1.24, 95%CI 1.07～1.43, P＝0.004)；女性SHBG每降低一个单位，NAFLD发病风险增高31%(OR＝0.69, 95%CI 0.57～0.83, P<0.001)。然而，男性睾酮(总睾酮，生物有效性睾酮)以及SHBG和女性总睾酮与NAFLD并未显示出因果关系。其他6种MR方法的结果与IVW法基本一致。外部验证数据的结果进一步证明了女性生物有效性睾酮和SHBG与NAFLD的因果关系。 结论 较高的女性生物有效性睾酮水平与较低的SHBG水平可能会增加NAFLD的发病风险。 Objective To investigate the causal association between testosterone and nonalcoholic fatty liver disease(NAFLD) in men and women using a two-sample Mendelian randomization(MR) approach. Methods Genetic variation in testosterone(total testosterone, bioavailable testosterone) and sex hormone-binding globulin(SHBG) in females and males was used as an instrumental variable using the genome-wide association study(GWAS) pooled data, and the inverse variance weighting method was applied. Inverse variance weighted(IVW) was used as the main analytical method, along with six univariate MR methods based on other modeling assumptions to assess the causal relationship between testosterone(total testosterone, bioavailable testosterone) as well as SHBG and NAFLD in women and men. In addition, NAFLD data from Finnish Biobank(FinnGen) were applied to validate the results of the exploratory analysis. Further, sensitivity analyses were performed to assess the level of heterogeneity, genetic pleiotropy, and stability of the instrumental variables using Cochran′s Q test, MR-Egger regression, and leave-one-out methods. Results The results of exploratory analysis of IVW model showed that bioavailable testosterone and SHBG were causally associated with NAFLD in women, for each unit increase in bioavailable testosterone levels, the risk of developing non-alcoholic fatty liver disease(NAFLD) rose by 24%(OR=1.24, 95%CI 1.07-1.43, P=0.004) and with each unit decrease in women′s SHBG, the NAFLD risk increased by 31%(OR=0.69, 95%CI 0.57-0.83, P<0.001). However, testosterone(total testosterone, bioavailable testosterone) as well as SHBG in men and female total testosterone did not show a causal relationship with NAFLD. The results of the other six MR methods were generally consistent with the IVW method. The results of the external validation data provided further evidence of a causal relationship between female bioavailable testosterone and SHBG and NAFLD. Conclusion Elevated levels of bioavailable testosterone along lower levels of SHBG may increase the risk of developing NAFLD in women.
Testosterone and non-alcoholic fatty liver disease in men and women: A Mendelian randomization study
Objective To investigate the causal association between testosterone and nonalcoholic fatty liver disease(NAFLD) in men and women using a two-sample Mendelian randomization(MR) approach. Methods Genetic variation in testosterone(total testosterone, bioavailable testosterone) and sex hormone-binding globulin(SHBG) in females and males was used as an instrumental variable using the genome-wide association study(GWAS) pooled data, and the inverse variance weighting method was applied. Inverse variance weighted(IVW) was used as the main analytical method, along with six univariate MR methods based on other modeling assumptions to assess the causal relationship between testosterone(total testosterone, bioavailable testosterone) as well as SHBG and NAFLD in women and men. In addition, NAFLD data from Finnish Biobank(FinnGen) were applied to validate the results of the exploratory analysis. Further, sensitivity analyses were performed to assess the level of heterogeneity, genetic pleiotropy, and stability of the instrumental variables using Cochran′s Q test, MR-Egger regression, and leave-one-out methods. Results The results of exploratory analysis of IVW model showed that bioavailable testosterone and SHBG were causally associated with NAFLD in women, for each unit increase in bioavailable testosterone levels, the risk of developing non-alcoholic fatty liver disease(NAFLD) rose by 24%(OR=1.24, 95%CI 1.07-1.43, P=0.004) and with each unit decrease in women′s SHBG, the NAFLD risk increased by 31%(OR=0.69, 95%CI 0.57-0.83, P<0.001). However, testosterone(total testosterone, bioavailable testosterone) as well as SHBG in men and female total testosterone did not show a causal relationship with NAFLD. The results of the other six MR methods were generally consistent with the IVW method. The results of the external validation data provided further evidence of a causal relationship between female bioavailable testosterone and SHBG and NAFLD. Conclusion Elevated levels of bioavailable testosterone along lower levels of SHBG may increase the risk of developing NAFLD in women.
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