抗体介导的免疫反应与非酒精性脂肪性肝病：一项双向孟德尔随机化研究

Antibody-Mediated Immune Response and Non-Alcoholic Fatty Liver Disease: A Bidirectional Mendelian Randomization Study

摘要: 背景：先前的研究已将抗体介导的免疫反应与非酒精性脂肪性肝病(NAFLD)联系起来，但其因果关系仍不明确。目的：进一步明确抗体免疫反应与NAFLD之间的因果关系。方法：抗体介导的免疫反应和NAFLD的汇总统计数据来自欧洲人群的全基因组关联研究(GWAS)。研究采用双向孟德尔随机化分析，主要通过逆方差加权法(IVW)评估46种抗体介导的免疫反应与NAFLD之间的因果关系。潜在的多效性使用MR-Egger和MR-PRESSO法进行评估，异质性通过Cochran’s Q检验进行检测，敏感性分析则采用leave-one-out法进行评估。结果：基于IVW的孟德尔随机化分析结果表明，两种抗体介导的免疫反应可能会增加NAFLD的风险：(沙眼衣原体tarp-D F1抗体水平：OR 1.068, 95% CI: 1.006~1.133, P-value = 0.032和幽门螺杆菌UREA抗体水平：OR 1.084, 95% CI: 1.001~1.174, P-value = 0.047)。反向孟德尔随机化显示，随着NAFLD风险的增加，幽门螺杆菌UREA抗体水平和抗单纯疱疹病毒1型IgG血清阳性也增加。相反，抗沙眼衣原体IgG血清阳性和抗多瘤病毒2 IgG血清阳性则呈下降趋势。结论：这项研究证实了抗体介导的免疫反应与NAFLD之间的因果关系，为免疫反应在NAFLD发展中的作用提供了新的证据，对NAFLD的预防和治疗具有重要意义。

Abstract: Background: Previous studies have linked antibody-mediated immune responses to non-alcoholic fatty liver disease (NAFLD), but the causal relationship remains unclear. Aims: To further understand the causal relationship between immune responses and NAFLD. Methods: Summary statistics for antibody-mediated immune response and NAFLD were derived from GWAS data based on European participants. Bidirectional Mendelian randomization mainly applying Inverse variance weighted (IVW) method was employed to assess the causal relationships between 46 antibody-mediated immune responses and NAFLD. Potential pleiotropy was evaluated using MR-Egger and MR-PRESSO methods, heterogeneity was examined with Cochran’s Q test, and sensitivity was assessed through leave-one-out analysis. Results: Based on IVW method, our Mendelian randomization showed that two antibody-mediated immune responses potentially causally increase NAFLD risk (Chlamydia trachomatis tarp-D F1 antibody levels: OR 1.068, 95% CI: 1.006~1.133, P-value = 0.032 and Helicobacter pylori UREA antibody levels: OR 1.084, 95% CI: 1.001~1.174, P-value = 0.047). Reverse Mendelian randomization revealed increased NAFLD risk causally associated with higher Helicobacter pylori UREA antibody levels and Anti-herpes simplex virus 1 IgG seropositivity. Conversely, Anti-Chlamydia trachomatis IgG and Anti-polyomavirus 2 IgG seropositivity showed a decreasing trend. There was no evidence of heterogeneity or horizontal pleiotropy detected. Conclusions: This study confirms causal relationships between antibody-mediated immune response and NAFLD, offering new evidence for the role of immune responses in NAFLD development and presenting significant implications for its prevention and treatment.