基于孟德尔随机化探究炎症性肠病和非黑色素瘤皮肤癌的关系及筛选关键基因

Exploring the relationship between inflammatory bowel disease and non-melanoma skin cancer and screening for key genes using Mendelian randomization

目的采用孟德尔随机化方法研究炎症性肠病(inflammatory bowel disease,IBD)和非黑色素瘤皮肤癌发病风险的关系,并筛选关键基因。方法从GWAS数据库获取IBD及其亚型克罗恩病(Crohn’s disease,CD)和溃疡性结肠炎(ulcerative colitis,UC)和非黑色素瘤皮肤癌(non-melanoma skin cancer,NMSC)的数据。本文的主要分析方法为逆方差加权法,利用Cochran’s Q检验异质性,MR-Egger-intercept检验是否存在水平多效性。依据指南筛选相关药物,从DrugBank与DGIdb数据库查找出4个药物靶点,进行eQTL的MR分析与共定位分析。结果MR分析的结果表明,IBD(P=0.009,95%CI:1.001~1.005,OR=1.003)及UC(P=0.003,95%CI:1.001~1.005,OR=1.003)是NMSC的危险因素,CD(P=0.064,95%CI:1.000~1.003,OR=1.002)与NMSC没有因果关系。筛选出3个靶基因PTCH1、RXRB、SUFU与NMSC有因果关系,其中PTCH1、SUFU与IBD具有因果关系。结论IBD、UC与NMSC发病风险有因果关联。PTCH1和SUFU在两个疾病中有一定的因果关系,为IBD防治提供一定的参考价值。

Objective To investigate the relationship between inflammatory bowel disease(IBD)and the risk of developing non-melanoma skin cancer(NMSC)using Mendelian randomization(MR)and to identify key genes.Methods Data on IBD,its subtypes Crohn’s disease(CD)and ulcerative colitis(UC),and NMSC were obtained from GWAS databases.The primary analytical method employed was inverse-variance weighted(IVW)analysis.Heterogeneity was assessed using Cochran’s Q test,and the presence of horizontal pleiotropy was examined using the MR-Egger intercept test.Relevant drugs were screened according to guidelines,and four drug targets were identified from the DrugBank and DGIdb databases for eQTL-based MR analysis and colocalization analysis.Results The MR analysis revealed that IBD(P=0.009,95%CI:1.001~1.005,OR=1.003)and UC(P=0.003,95%CI:1.001~1.005,OR=1.003)were risk factors for NMSC,while CD(P=0.064,95%CI:1.000~1.003,OR=1.002)was not causally related to NMSC.Three target genes,PTCH1,RXRB,and SUFU,were identified as causally related to NMSC,with PTCH1 and SUFU also causally related to IBD.Conclusion IBD and UC have a causal association with the risk of developing NMSC.PTCH1 and SUFU exhibit a certain causal relationship in both diseases,providing valuable insights for the prevention and treatment of IBD.