两样本孟德尔随机化分析原发性硬化性胆管炎与结直肠癌发生风险的关系

Association between primary sclerosing cholangitis and the risk of colorectal cancer:A two-sample Mendelian randomization study

目的运用两样本孟德尔随机化(TSMR)评估原发性硬化性胆管炎(PSC)与结直肠癌(CRC)之间的关联。方法PSC与CRC相关的单核苷酸多态性(SNP)数据分别来自芬兰生物银行及英国生物银行,对基于全基因组关联研究(GWAS)的所有汇总数据进行二次数据分析,选择与PSC密切关联的遗传位点作为工具变量,分别以孟德尔随机化Egger回归法、中位数加权法、IVW随机效应模型、最大似然比法、线性中位数加权法、IVW radial法、IVW固定效应模型七种方法做TSMR,以OR值评价PSC和CRC风险之间的因果关系。结果基因预测的PSC对CRC存在正向因果关系,以IVW固定效应模型为例,遗传决定的患PSC患者发生CRC风险增加(OR=1.002243,95%CI:1.001319~1.003167)。TSMR结果不存在异质性(P=0.87),无水平多效性(P=0.95)。本次所选PSC的3个工具变量为强工具变量(F=11.86)。结论TSMR发现PSC具有与CRC风险相关的遗传证据。无论是否合并炎症性肠病,在PSC患者中积极进行肠镜筛查或可有利于CRC的早期发现与及时干预。

Objective To investigate the association between primary sclerosing cholangitis(PSC)and colorectal cancer(CRC)by using two-sample Mendelian randomization(TSMR).Methods The single nucleotide polymorphism(SNP)data associated with PSC and CRC were obtained from Finland Biobank and UK Biobank,respectively.A secondary data analysis was performed for all pooled data based on genome-wide association studies to select the genetic loci closely associated with PSC as instrumental variables,and TSMR was conducted by seven methods,i.e.,Egger regression in Mendelian randomization,weighted median,inverse variance weighted(IVW)random effects model,maximum likelihood,linear weighted median,IVW radial method,and IVW fixed effects model.Odds ratio(OR)value was used to evaluate the causal relationship between PSC and the risk of CRC.Results There was a positive causal relationship between gene predicted PSC and CRC,and with the IVW fixed effects model as an example,genetically determined patients with PSC could increase the risk of CRC(OR=1.002243,95%confidence interval:1.001319-1.003167).TSMR results showed no heterogeneity(P=0.87)or horizontal pleiotropy(P=0.95).The three instrumental variables selected for PSC were strong instrumental variables(F=11.86).Conclusion TSMR shows the genetic evidence for the association between PSC and the risk of CRC.Regardless of the presence or absence of inflammatory bowel disease,active enteroscopy screening among patients with PSC may help with the early identification and timely intervention of CRC.