Liu Yi, Xiao Zhihan, Ye Kun, Xu Linlin, Zhang Yanping
Department of Digestive System, Anqing Municipal Hospital, Anqing, China.
Department of Digestive System, Wannan Medical College, Wuhu, China.
Front Genet. 2023 Jan 6;13:992080. doi: 10.3389/fgene.2022.992080. eCollection 2022.
Observational evidence has shown that smoking, alcohol consumption, type 2 diabetes, and body mass index (BMI) are risk factors for peptic ulcer disease (PUD), including gastric ulcer (GU) and duodenal ulcer (DU). However, the observed associations may be confounding factors. Herein, we use Mendelian randomization (MR) to examine causal associations such as smoking, alcohol, type 2 diabetes, BMI, and risks of PUD. We used 8,17,41,325,82, 231, and 616 identified genetic variants as proxies for age of smoking initiation (AgeSmk), smoking cessation (SmkCes, current/former), number of cigarettes smoked per day (CigDay), smoking status (SmkIni, ever/never), alcohol consumption, type 2 diabetes, and BMI to obtain unconfounded effect estimates on the GU and DU levels among 452,264 participants from the Gene ATLAS. The causal relationship was estimated by using inverse-variance weighted (IVW) as the main method. Sensitivity analysis includes Cochran's Q test, the MR-Egger test, MR pleiotropy residual sum and outlier (MR-PRESSO), and MR-robust adjusted profile score (MR-RAPS). In addition, secondary MR analysis was conducted within summary data using genetic risk scores (GRSs) as instrumental variables (IVs). In our two-sample MR analyses, genetic predisposition to smoking (SmkInit) and BMI were associated with an increased risk of GU. The beta values were 0.0035 (95% CI, 0.0021, 0.0049, = 1.56E-06) for smoking (SmkInit) and 0.0021 (95% CI, 0.0009, 0.0033, = 0.0008) for BMI. Genetic predisposition to smoking (SmkInit) and higher genetically predicted BMI were associated with an increased risk of DU. The beta values of DU were 0.0029 (95% CI, 0.0017, 0.0041, = 2.43E-06) for smoking (SmkInit) and 0.0018 (95% CI, 0.0007, 0.0029, = 0.001) for BMI. No other causal association between smoking (AgeSmk, CigDay, and SmkCes), alcohol consumption, type 2 diabetes, and GU or DU was observed. Consistent results were obtained in sensitivity analyses. Furthermore, the GRS approach showed similar results in the several MR methods. These findings do not support a causal role of AgeSmk, CigDay, SmkCes, alcohol consumption, and type 2 diabetes in the development of GU and DU. However, it is confirmed that SmkInit and BMI have a causal part in the development of GU and DU.
观察性证据表明，吸烟、饮酒、2型糖尿病和体重指数（BMI）是消化性溃疡疾病（PUD）的危险因素，包括胃溃疡（GU）和十二指肠溃疡（DU）。然而，观察到的关联可能是混杂因素。在此，我们使用孟德尔随机化（MR）来研究吸烟、饮酒、2型糖尿病、BMI与PUD风险之间的因果关联。我们使用8个、17个、41个、325个、82个、231个和616个已识别的基因变异作为开始吸烟年龄（AgeSmk）、戒烟（SmkCes，当前/曾经）、每天吸烟数量（CigDay）、吸烟状态（SmkIni，曾经/从不）、饮酒、2型糖尿病和BMI的代理变量，以获得来自基因图谱的452,264名参与者中GU和DU水平的无混杂效应估计值。因果关系采用逆方差加权（IVW）作为主要方法进行估计。敏感性分析包括 Cochr an's Q检验、MR-Egger检验、MR多效性残差和异常值（MR-PRESSO）以及MR稳健调整轮廓得分（MR-RAPS）。此外，在汇总数据中使用基因风险评分（GRSs）作为工具变量（IVs）进行了二次MR分析。在我们的两样本MR分析中，吸烟（SmkInit）和BMI的遗传易感性与GU风险增加相关。吸烟（SmkInit）的β值为0.0035（95%CI，0.0021，0.0049，P = 1.56E-06），BMI的β值为0.0021（95%CI，0.0009，0.0033，P = 0.0008）。吸烟（SmkInit）的遗传易感性和较高的遗传预测BMI与DU风险增加相关。DU的β值对于吸烟（SmkInit）为0.0029（95%CI，0.0017，0.0041，P = 2.43E-06），对于BMI为0.0018（95%CI，0.0007，0.0029，P = 0.001）。未观察到吸烟（AgeSmk、CigDay和SmkCes）、饮酒、2型糖尿病与GU或DU之间的其他因果关联。敏感性分析得到了一致的结果。此外，GRS方法在几种MR方法中显示出相似的结果。这些发现不支持AgeSmk、CigDay、SmkCes、饮酒和2型糖尿病在GU和DU发生中的因果作用。然而，证实SmkInit和BMI在GU和DU的发生中具有因果作用。
