The causal effects of inflammatory bowel disease on primary biliary cholangitis: A bidirectional two‐sample Mendelian randomization study

Abstract

Background Observational studies have indicated that the incidence of primary biliary cholangitis (PBC) is higher in inflammatory bowel disease (IBD) patients than that in healthy people. However, whether the correlation is causal remains unclear. Methods The genetic associations with IBD were obtained from publicly available genome‐wide association studies (GWAS) of European ancestry with 31 665 cases and 33 977 controls, consisting of 17 897 Crohn's disease (CD) and 13 768 ulcerative colitis (UC) cases. The genetic associations with PBC were obtained from a European GWAS with 2764 cases and 10 475 controls. A bidirectional two‐sample Mendelian randomization (MR) design was implemented to determine the causal relationship between IBD and PBC. In the forward MR, the IBD was treated as the exposure while the PBC was the exposure in the reverse MR. The inverse‐variance‐weighted (IVW) method was utilized as the main statistic method, and a series of sensitivity analyses were performed to detect heterogeneity and horizontal pleiotropy. Results A total of 99 valid instrumental variables (IVs) were selected for IBD and the number of IVs for PBC was 18. The forward MR analysis indicated that genetically predicted IBD (UC and CD) was significantly associated with an increased risk of PBC (IVW OR = 1.343; 95% CI: 1.220–1.466). Similar casual associations were observed in UC (IVW OR = 1.244; 95% CI: 1.057–1.430) and CD (IVW OR = 1.269; 95% CI: 1.159–1.379). Such results were still consistent in multiple MR methods. The reverse MR analysis implicated that genetic susceptibility to PBC might not alter the risk of IBD (IVW OR = 1.070; 95% CI: 0.984–1.164). Conclusion Our study found that genetically predicted IBD can increase the risk of PBC while not vice versa in the European population, which may enlighten the aetiology of PBC, together with the IBD patient management.

Dissecting causal relationships between primary biliary cholangitis and extrahepatic autoimmune diseases based on Mendelian randomization

“…Meanwhile, PBC contributes genetically to IBD and UC. These results were similar to the previous MR results 9 as well as conventional observations 38 – 40 . Compared to Zhang 9 , we conducted a study with larger sample sizes and achieved inconsistent estimates across the four statistical methods used.…”

“…These results were similar to the previous MR results 9 as well as conventional observations 38 – 40 . Compared to Zhang 9 , we conducted a study with larger sample sizes and achieved inconsistent estimates across the four statistical methods used. In contrast to the findings of Zhao et al 41 , we emphasized the positive promoting effect of PBC on UC onset.…”

“…However, the study did not account for the possible influence of MHC regions on the outcome, which could have led to a bias. In the MR study of IBD on PBC 9 , the authors did not utilize the latest GWAS data for PBC, and the impact of UC on PBC was inconsistent. As a result, the findings may not be entirely accurate and require validation with a larger sample size.…”

Investigating shared genetic architecture between inflammatory bowel diseases and primary biliary cholangitis

“… 6 There has been an increasing body of evidence supporting the reciprocal comorbidity between PBC and IBD in recent years. 7 Several cases of co-occurrence of PBC-associated IBD have also been reported. [8] , [9] , [10] …”

Primary sclerosing cholangitis causally affects kidney function decline: A Mendelian randomization study

“…In regard to PSC, previous MR studies revealed the causal linkage between PSC and IBD, emphasizing the importance of surveillance strategies for patients with IBD. 10,11 In this study, we conducted a two-sample summary-level MR analysis to demonstrate the causal association between PSC and kidney function. We hypothesized that the genetically predicted PSC is associated with impaired kidney function.…”