Title: Primary biliary cholangitis has causal effects on systemic rheumatic diseases: A
Mendelian randomization study
Version: 2 Date: 18 Jun 2024
Reviewer:  Cristiana Sieiro Santos
Reviewer's report:
The manuscript evaluates the causal effects of PBC on SRDs through Mendelian randomization
(MR).
The introduction provides a clear overview of PBC, highlighting its autoimmune nature,
prevalence, and the need for better therapeutic strategies. It effectively sets up the rationale for
investigating the link between PBC and SRDs.
- Please change: "Characterized by destoryed interlobular bile ducts" should be corrected
to "characterized by destroyed interlobular bile ducts."; "an increased requirement for liver
transplantation" could be rephrased for clarity to "an increased need for liver transplantation."
and "PBC is female-predominant, and the prevalence of PBC is on the rise" is redundant. It could
be simplified to "PBC is predominantly found in females, and its prevalence is increasing."
- The introduction should emphasize the significance of using MR to establish causality in
epidemiological research: "Using genetic variation as instrumental variables in MR analysis
helps evaluate the causal effects of exposures on outcomes, potentially reducing the impact of
confounding factors."
The methods:
The section could benefit from a brief description of how genetic variants are chosen as
instrumental variables (IVs) for readers unfamiliar with MR analysis.
Discussion:
- Typographical Errors: Correct minor typos, such as "destoryed" to "destroyed" and "unsolved"
to "unresolved."
- Ensure consistent use of abbreviations, e.g., "SRDs" for systemic rheumatic diseases.
- Improve sentence clarity. For example, "Our research aimed to evaluate the causal effect of
PBC on SRDs, a matter that was unresolved in previous observational epidemiological studies."
- Highlight more prominently how the study’s findings align or contrast with previous
observational studies. For example, "Previous studies have reported associations between PBC
and SRDs, but our MR analysis provides stronger evidence for a causal relationship."
- Expand on the potential mechanisms linking PBC and SRDs. For instance, "The liver, as
a major lymphoid organ, plays a crucial role in immune responses, which may explain the
observed associations."
-  Provide a deeper discussion of immune mechanisms, such as the role of Th1/Th17 cells and
specific cytokines in PBC and SRDs.
- Discuss the shared genetic pathways, such as IL12-mediated signaling involving STAT4 and
IRF5, in more detail.
- Address the limitations related to the study population. "Our MR analysis was conducted in
a European population, and the findings may not generalize to other ethnic groups. Gender-
specific effects were also not explored due to data limitations."
- Mention the limitation of analyzing only six SRDs. "While our study focused on six SRDs,
other autoimmune conditions might also be associated with PBC."
Title: Primary biliary cholangitis has causal effects on systemic rheumatic diseases: A
Mendelian randomization study
Version: 2 Date: 18 Jun 2024
Reviewer:  Cristiana Sieiro Santos
Reviewer's report:
The manuscript evaluates the causal effects of PBC on SRDs through Mendelian randomization
(MR).
The introduction provides a clear overview of PBC, highlighting its autoimmune nature,
prevalence, and the need for better therapeutic strategies. It effectively sets up the rationale for
investigating the link between PBC and SRDs.
- Please change: "Characterized by destoryed interlobular bile ducts" should be corrected
to "characterized by destroyed interlobular bile ducts."; "an increased requirement for liver
transplantation" could be rephrased for clarity to "an increased need for liver transplantation."
and "PBC is female-predominant, and the prevalence of PBC is on the rise" is redundant. It could
be simplified to "PBC is predominantly found in females, and its prevalence is increasing."
- The introduction should emphasize the significance of using MR to establish causality in
epidemiological research: "Using genetic variation as instrumental variables in MR analysis
helps evaluate the causal effects of exposures on outcomes, potentially reducing the impact of
confounding factors."
The methods:
The section could benefit from a brief description of how genetic variants are chosen as
instrumental variables (IVs) for readers unfamiliar with MR analysis.
Discussion:
- Typographical Errors: Correct minor typos, such as "destoryed" to "destroyed" and "unsolved"
to "unresolved."
- Ensure consistent use of abbreviations, e.g., "SRDs" for systemic rheumatic diseases.
- Improve sentence clarity. For example, "Our research aimed to evaluate the causal effect of
PBC on SRDs, a matter that was unresolved in previous observational epidemiological studies."
- Highlight more prominently how the study’s findings align or contrast with previous
observational studies. For example, "Previous studies have reported associations between PBC
and SRDs, but our MR analysis provides stronger evidence for a causal relationship."
- Expand on the potential mechanisms linking PBC and SRDs. For instance, "The liver, as
a major lymphoid organ, plays a crucial role in immune responses, which may explain the
observed associations."
-  Provide a deeper discussion of immune mechanisms, such as the role of Th1/Th17 cells and
specific cytokines in PBC and SRDs.
- Discuss the shared genetic pathways, such as IL12-mediated signaling involving STAT4 and
IRF5, in more detail.
- Address the limitations related to the study population. "Our MR analysis was conducted in
a European population, and the findings may not generalize to other ethnic groups. Gender-
specific effects were also not explored due to data limitations."
- Mention the limitation of analyzing only six SRDs. "While our study focused on six SRDs,
other autoimmune conditions might also be associated with PBC."
Please review this paper.
user
Title: Primary biliary cholangitis has causal effects on systemic rheumatic diseases: A
Mendelian randomization study
Version: 2 Date: 18 Jun 2024
Reviewer:  Cristiana Sieiro Santos
Reviewer's report:
The manuscript evaluates the causal effects of PBC on SRDs through Mendelian randomization
(MR).
The introduction provides a clear overview of PBC, highlighting its autoimmune nature,
prevalence, and the need for better therapeutic strategies. It effectively sets up the rationale for
investigating the link between PBC and SRDs.
- Please change: "Characterized by destoryed interlobular bile ducts" should be corrected
to "characterized by destroyed interlobular bile ducts."; "an increased requirement for liver
transplantation" could be rephrased for clarity to "an increased need for liver transplantation."
and "PBC is female-predominant, and the prevalence of PBC is on the rise" is redundant. It could
be simplified to "PBC is predominantly found in females, and its prevalence is increasing."
- The introduction should emphasize the significance of using MR to establish causality in
epidemiological research: "Using genetic variation as instrumental variables in MR analysis
helps evaluate the causal effects of exposures on outcomes, potentially reducing the impact of
confounding factors."
The methods:
The section could benefit from a brief description of how genetic variants are chosen as
instrumental variables (IVs) for readers unfamiliar with MR analysis.
Discussion:
- Typographical Errors: Correct minor typos, such as "destoryed" to "destroyed" and "unsolved"
to "unresolved."
- Ensure consistent use of abbreviations, e.g., "SRDs" for systemic rheumatic diseases.
- Improve sentence clarity. For example, "Our research aimed to evaluate the causal effect of
PBC on SRDs, a matter that was unresolved in previous observational epidemiological studies."
- Highlight more prominently how the study’s findings align or contrast with previous
observational studies. For example, "Previous studies have reported associations between PBC
and SRDs, but our MR analysis provides stronger evidence for a causal relationship."
- Expand on the potential mechanisms linking PBC and SRDs. For instance, "The liver, as
a major lymphoid organ, plays a crucial role in immune responses, which may explain the
observed associations."
-  Provide a deeper discussion of immune mechanisms, such as the role of Th1/Th17 cells and
specific cytokines in PBC and SRDs.
- Discuss the shared genetic pathways, such as IL12-mediated signaling involving STAT4 and
IRF5, in more detail.
- Address the limitations related to the study population. "Our MR analysis was conducted in
a European population, and the findings may not generalize to other ethnic groups. Gender-
specific effects were also not explored due to data limitations."
- Mention the limitation of analyzing only six SRDs. "While our study focused on six SRDs,
other autoimmune conditions might also be associated with PBC."
assistant