Smoking,Alcohol Consumption,Type 2 Diabetes,Body Mass Index,and Peptic Ulcer Risk:A Two-Sample Mendelian Randomization Study

Objective: This study used Mendelian Randomization(MR)to investigate the causative relationships among type 2 diabetes,alcohol consumption,smoking,Body Mass Index(BMI),and Peptic Ulcer Disease(PUD)risk.PUD specifically refers to Gastric Ulcer(GU)and Duodenal Ulcer(DU)in this study.Methods: 1.Collecting data.First,numerous international public databases were used to gather the pertinent data for the genome wide association study(GWAS).2.organize data.Data were selected and organized according to the three requirements(relevance,independence,and exclusivity)that must be met by the instrumental variable(IV)in MR studies;Smoking initiation phenotypes included age of initiation of regular smoking(Age Smk;8 associated variants),and whether an individual had ever smoked regularly(Smk Init;325 associated variants).Heaviness of smoking was measured with cigarettes per day(Cig Day;41 associated variants;for current and former smokers,quantitative measurements were packed into five boxes or collected in predefined boxes as follows: 1=1-5,2=6-15,3=16-25,4=26-35 and 5=36+ cigarettes).Smoking cessation(Smk Ces;17 associated variants)was contrasting current versus former smokers.Available measures of alcohol use were simpler,with drinks per week(Drnk Wk;82associated variants)widely available and similarly measured across studies.231 variants were associated with type 2 diabetes and 616 variants were associated with BMI.3.The main method of analysis in this study was inverse variance weighting(IVW),and the main effect measure was beta,including the 95% confidence interval(CI).4.Quality assurance.Sensitivity analyses,such as Cochran’s Q test,MR-egger test,MR multiple residual and outlier(MR-presso),and MR Robust adjusted profile score(RAPS),were utilized to ensure the robustness of the results of this study.It is statistically significant if P<0.05.Additionally,the pooled data were subjected to a secondary MR analysis using the Genetic risk score(GRS).Results: In our two-sample MR Analysis,the IVW analysis results showed that:Correlation analysis between smoking and the risk of GU and DU:1.Age Smk and GU: beta = 0.0029(95% CI:-0.0066-0.0123,P = 0.55);Age Smk and DU: beta =-0.0037(95% CI:-0.0117-0.0044,P = 0.37);2.Cig Day and GU: beta = 0.0012(95% CI:-0.0016-0.0041,P = 0.4);Cig Day and DU: beta = 0.0020(95% CI:-0.0004-0.0045,P = 0.10);3.Smk Ces and GU: beta = 0.0005(95% CI:-0.0028-0.0038,P = 0.76);Smk Ces and DU: beta = 0.0009(95% CI:-0.0020-0.0037,P = 0.55);4.Smk Init and GU: beta = 0.0035(95% CI: 0.0021-1.0049,P = 3.67E-07);Smk Init and DU: beta = 0.0029(95% CI: 0.0018-0.0041,P = 7.57E-07).The above results show that there is a significant association between Smk Init and GU and DU at the genetic level,and no causal association between Age Smk,Cig Day,Smk Ces and GU and DU risk has been found.The correlation analysis between drinking and GU and DU:1.Drnk Wk and GU: beta =-0.0030(95% CI:-0.0078-0.0018,P = 0.23);2.Drnk Wk and DU: beta = 0.0027(95% CI:-0.0014-0.0069,P = 0.20);The above results suggest that there is no clear causal relationship between alcohol consumption and GU and DU.The correlation analysis between type 2 diabetes mellitus and GU and DU:1.Type 2 diabetes mellitus and GU: beta = 0.0002(95% CI:-0.0003-0.0007,P = 0.43);2.Type 2 diabetes mellitus and DU: beta = 0.0002(95% CI: 0.0006-0.24,P = 0.88);The above results suggest that there is no clear causal relationship between type 2 diabetes mellitus and GU and DU.BMI and GU correlation analysis:1.BMI and GU: BMI increases by one standard deviation with the beta of GU and the corresponding 95% CI is 0.0021(95% CI,0.0009-0.0033,P = 0.001);2.BMI and DU: BMI increases by one standard deviation with the beta of DU and the corresponding 95% CI is 0.0018(95% CI,0.000-0.0028,P = 0.006);The above results show that BMI is significantly associated with GU and DU at the genetic level.The sensitivity analysis results were consistent with the above analysis results,indicating that the above causal inference was not affected by confounding factors.In addition,the GRSs method also showed similar results.Conclusion: 1.In this study,the Mendelian randomization analysis of two samples was used to provide genetic evidence for the causal association between Smk Init and BMI in the development of GU and DU when influencing factors such as reverse causal association and confounding factors were excluded.2.The results of the study proved that Age Smk,Cig Day,Smk Ces,alcohol consumption and type 2 diabetes mellitus have no direct causal association in the development of GU and DU.