Title: Investigating the shared genetic architecture between multiple Primary sclerosing
cholangitis and inflammatory bowel diseases: A Mendelian randomization study
Version: 0 Date: 26 Dec 2023
Reviewer's report:
In this study, the authors investigated the causal associations of genetically predicted primary
sclerosing cholangitis (PSC)  with Inflammatory bowel disease (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.
Five methods were used to evaluate the effects of genetically predicted PSC on IBD, including
MR Egger, Weighted median (WM), Inverse variance weighted (IVW), Simple mode, and
Weighted mode. They found that genetically predicted PSC was significantly associated with
an increased risk of UC. However, none of the MR methods found significant causal evidence
of genetically predicted PSC in CD. They concluded that the study corroborated a causal
association between genetically predicted PSC and UC but did not between genetically predicted
PSC and CD.
The study is of interest, however, some issue should be addressed.
1) Methods: the authors reported that the summary statistics of PSC, UC, and CD was
derived from the IEU Open GWAS project. However, no clinical informations are provided.
In particular, both IBD and PSC, are frequently associated to other autoimmune diseases and
this might be significantly affected by a different genetic background. Therefore, since this my
introduce an unintetional selection bias, the comparison should consider homogeneous patient
groups.
2) Discussing the genetic factors associated with PSC, the authors inluded two references (ref 43:
J Immunol Res 2014, 2014:921285,  and 51: Clin Rev Allergy Immunol 2015, 48(2-3):316-321.)
that, however, refer to two studies of primary biliary cirrhosis patients (and not PSC patients).
3) discussing the impact of genetic factors in immune system, the authors should also
recall the role of genetic background in the serum antibody development. In this regard, the
authors should also discuss the likely role of genetic factors in the development of serum
antibodies found in diverse immune-mediated diseases. In particular, it is well known that
patients with UC develop serum Anti-Saccharomyces cerevisiae  antibodies (ASCA), which,
however, are also found in patients with celiac disease (Aliment Pharmacol Ther. 2005
Apr 1;21(7):881-7. doi: 10.1111/j.1365-2036.2005.02417.x.; Gut. 2005 Sep;54(9):1232-6. doi:
10.1136/gut.2004.060228.) and autoimmune liver diseases as previously demonstrated (Clin
Exp Immunol. 2003 Jun;132(3):473-6. doi: 10.1046/j.1365-2249.2003.02166.x.).
Title: Investigating the shared genetic architecture between multiple Primary sclerosing
cholangitis and inflammatory bowel diseases: A Mendelian randomization study
Version: 0 Date: 26 Dec 2023
Reviewer's report:
In this study, the authors investigated the causal associations of genetically predicted primary
sclerosing cholangitis (PSC)  with Inflammatory bowel disease (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.
Five methods were used to evaluate the effects of genetically predicted PSC on IBD, including
MR Egger, Weighted median (WM), Inverse variance weighted (IVW), Simple mode, and
Weighted mode. They found that genetically predicted PSC was significantly associated with
an increased risk of UC. However, none of the MR methods found significant causal evidence
of genetically predicted PSC in CD. They concluded that the study corroborated a causal
association between genetically predicted PSC and UC but did not between genetically predicted
PSC and CD.
The study is of interest, however, some issue should be addressed.
1) Methods: the authors reported that the summary statistics of PSC, UC, and CD was
derived from the IEU Open GWAS project. However, no clinical informations are provided.
In particular, both IBD and PSC, are frequently associated to other autoimmune diseases and
this might be significantly affected by a different genetic background. Therefore, since this my
introduce an unintetional selection bias, the comparison should consider homogeneous patient
groups.
2) Discussing the genetic factors associated with PSC, the authors inluded two references (ref 43:
J Immunol Res 2014, 2014:921285,  and 51: Clin Rev Allergy Immunol 2015, 48(2-3):316-321.)
that, however, refer to two studies of primary biliary cirrhosis patients (and not PSC patients).
3) discussing the impact of genetic factors in immune system, the authors should also
recall the role of genetic background in the serum antibody development. In this regard, the
authors should also discuss the likely role of genetic factors in the development of serum
antibodies found in diverse immune-mediated diseases. In particular, it is well known that
patients with UC develop serum Anti-Saccharomyces cerevisiae  antibodies (ASCA), which,
however, are also found in patients with celiac disease (Aliment Pharmacol Ther. 2005
Apr 1;21(7):881-7. doi: 10.1111/j.1365-2036.2005.02417.x.; Gut. 2005 Sep;54(9):1232-6. doi:
10.1136/gut.2004.060228.) and autoimmune liver diseases as previously demonstrated (Clin
Exp Immunol. 2003 Jun;132(3):473-6. doi: 10.1046/j.1365-2249.2003.02166.x.).
Please review this paper.
user
Title: Investigating the shared genetic architecture between multiple Primary sclerosing
cholangitis and inflammatory bowel diseases: A Mendelian randomization study
Version: 0 Date: 26 Dec 2023
Reviewer's report:
In this study, the authors investigated the causal associations of genetically predicted primary
sclerosing cholangitis (PSC)  with Inflammatory bowel disease (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.
Five methods were used to evaluate the effects of genetically predicted PSC on IBD, including
MR Egger, Weighted median (WM), Inverse variance weighted (IVW), Simple mode, and
Weighted mode. They found that genetically predicted PSC was significantly associated with
an increased risk of UC. However, none of the MR methods found significant causal evidence
of genetically predicted PSC in CD. They concluded that the study corroborated a causal
association between genetically predicted PSC and UC but did not between genetically predicted
PSC and CD.
The study is of interest, however, some issue should be addressed.
1) Methods: the authors reported that the summary statistics of PSC, UC, and CD was
derived from the IEU Open GWAS project. However, no clinical informations are provided.
In particular, both IBD and PSC, are frequently associated to other autoimmune diseases and
this might be significantly affected by a different genetic background. Therefore, since this my
introduce an unintetional selection bias, the comparison should consider homogeneous patient
groups.
2) Discussing the genetic factors associated with PSC, the authors inluded two references (ref 43:
J Immunol Res 2014, 2014:921285,  and 51: Clin Rev Allergy Immunol 2015, 48(2-3):316-321.)
that, however, refer to two studies of primary biliary cirrhosis patients (and not PSC patients).
3) discussing the impact of genetic factors in immune system, the authors should also
recall the role of genetic background in the serum antibody development. In this regard, the
authors should also discuss the likely role of genetic factors in the development of serum
antibodies found in diverse immune-mediated diseases. In particular, it is well known that
patients with UC develop serum Anti-Saccharomyces cerevisiae  antibodies (ASCA), which,
however, are also found in patients with celiac disease (Aliment Pharmacol Ther. 2005
Apr 1;21(7):881-7. doi: 10.1111/j.1365-2036.2005.02417.x.; Gut. 2005 Sep;54(9):1232-6. doi:
10.1136/gut.2004.060228.) and autoimmune liver diseases as previously demonstrated (Clin
Exp Immunol. 2003 Jun;132(3):473-6. doi: 10.1046/j.1365-2249.2003.02166.x.).
assistant