背景:多项研究发现原发性硬化性胆管炎(PSC)和炎症性肠病(IBD)密切相关。然而,它们相互作用的方向和因果关系尚不清楚.因此,本研究采用孟德尔随机化法,探讨基因预测的PSC与IBD之间是否存在因果关系.
方法:使用与PSC的全基因组关联研究(GWAS)相关的遗传变异作为工具变量。IBD的统计数据,包括溃疡性结肠炎(UC),克罗恩病(CD)来源于GWAS。然后,五种方法用于评估遗传预测的PSC对IBD的影响,包括艾格先生,加权中位数(WM),反向方差加权(IVW),简单模式,和加权模式。最后,我们还评估了多效性效应,异质性,以及驱动因果关联的留一敏感性分析,以确认分析的有效性。
结果:遗传预测的PSC与UC风险增加显著相关,根据研究(比值比[OR]IVW=1.0014,P<0.05)。然而,MR方法均未发现CD中遗传预测的PSC的显著因果证据(所有P>0.05)。敏感性分析结果表明,遗传预测PSC对IBD的因果效应估计是稳健的,并且没有水平多效性或统计异质性。
结论:我们的研究证实了遗传预测的PSC和UC之间的因果关系,但遗传预测的PSC和CD之间没有因果关系。然后,我们识别PSC和UC的共享SNP,包括rs3184504、rs9858213、rs725613、rs10909839、rs4147359。需要更多的动物实验和临床观察研究来进一步阐明PSC和IBD的潜在机制。
BACKGROUND: Several studies have found that primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) are closely associated. However, the direction and causality of their interactions remain unclear. Thus, this
study employs Mendelian Randomization to explore whether there are causal associations of genetically predicted PSC with IBD.
METHODS: Genetic variants associated with the genome-wide association
study (GWAS) of PSC were used as instrumental variables. The statistics for IBD, including ulcerative colitis (UC), and Crohn\'s disease (CD) were derived from GWAS. Then, five methods were used to estimate the effects of genetically predicted PSC on IBD, including MR Egger, Weighted median (WM), Inverse variance weighted (IVW), Simple mode, and Weighted mode. Last, we also evaluated the pleiotropic effects, heterogeneity, and a leave-one-out sensitivity analysis that drives causal associations to confirm the validity of the analysis.
RESULTS: Genetically predicted PSC was significantly associated with an increased risk of UC, according to the
study (odds ratio [OR] IVW= 1.0014, P<0.05). However, none of the MR methods found significant causal evidence of genetically predicted PSC in CD (All P>0.05). The sensitivity analysis results showed that the causal effect estimations of genetically predicted PSC on IBD were robust, and there was no horizontal pleiotropy or statistical heterogeneity.
CONCLUSIONS: Our
study corroborated a causal association between genetically predicted PSC and UC but did not between genetically predicted PSC and CD. Then, we identification of shared SNPs for PSC and UC, including rs3184504, rs9858213, rs725613, rs10909839, and rs4147359. More animal experiments and clinical observational studies are required to further clarify the underlying mechanisms of PSC and IBD.