Review for 10.1186/s12876-024-03162-6 (2024)

Title: Investigating the shared genetic architecture between multiple Primary sclerosing
cholangitis and inflammatory bowel diseases: A Mendelian randomization study
Version: 0 Date: 11 Jan 2024
Reviewer's report:
In this study, the authors used Mendelian randomisation to investigate the causal associations
between genetically predicted PSC and IBD. 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.
Overall, 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. The authors also evaluated the pleiotropic effects, heterogeneity, and a
leave-one-out sensitivity analysis that drives causal associations to confirm the validity of the
analysis.
They found that 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).
Importantly, the sensitivity analysis strongly showed the causal effect estimations of genetically
predicted PSC on IBD, a nd there was no horizontal pleiotropy or statistical heterogeneity.
The authors concluded that their results corroborated a causal association between genetically
predicted PSC and UC but did not between genetically predicted PSC and CD.
The study is of interest and explore the link between two, frequently associated, diseases with
potential therapeutic impact for novel treatment approaches. However, some issues deserve
further data and should be addressed.
-the authors reported that the sample sizes of datasets for PSC, UC, and CD, were 14,890 cases,
463,010 cases, and 212,356 cases, respectively. However, no clinical data of enrolled patients
are provided. The authors should at least describe the diagnostic criteria used ofr PSC, UC
and CD diagnoses. It would be also clinically relevant to describe, if available, the associated
autoimmune disorders in enrolled patients since PSC, UC and CD are frequently associated with
other autoimmune and immune-mediated disease such as celiac disease, autoimmune hepatitis,
rheumatological disorders.
-Discussing the link between primary sclerosing cholangitis and inflammatory bowel diseases,
the authors should discuss the importance of gut-liver axis in the pathogenitic mechanisms
underlying the disease pathogenesis. Importantly, an alterated intestinal permeability has been
described in IBD and PSC and, an immuno-serological link between PSC and UC has been
supported by the positivity of serum anti-neutrophil cytoplasm antibodies in both PSC and UC,
as recently discussed (Anti-neutrophil cytoplasm antibodies (ANCA) in autoimmune diseases:
A matter of laboratory technique and clinical setting. Autoimmun Rev. 2021 Apr;20(4):102787.
doi: 10.1016/j.autrev.2021.102787).
More importantly, a further immunoserological proof of the crucial role of an increased intestinal
permeability, linking  IBD, and other autoimmune diseases such as celiac disease and primary
biliary cholangitis,  is the frequent positivity rate of Anti-saccharomyces cerevisiae antibodies
(ASCA) in all above mentioned disease, as previously demonstrated (Aliment Pharmacol Ther.
2005 Apr 1;21(7):881-7. doi: 10.1111/j.1365-2036.2005.02417.x.;
Anti-saccharomyces cerevisiae antibodies (ASCA) in coeliac disease. Gut. 2006
Feb;55(2):296. ; Anti-Saccharomyces cerevisiae antibodies (ASCA) and autoimmune liver
diseases. Clin Exp Immunol. 2003 Jun;132(3):473-6. doi: 10.1046/j.1365-2249.2003.02166.x.).