Reviewer’s report
Title: 
Genotype-Phenotype Associations of Polymorphisms within the Gene
Locus of NOD-like Receptor Pyrin Domain Containing 3 in Swiss inflammatory
bowel disease patients
Version: 
0 
Date: 
01 May 2021
Reviewer's report:
In their paper, Yoganathan et al describe the effects of three NLRP3-associated
SNPs on the clinical parameters of Swiss IBD patients. 
The authors describe that
the polymorphisms have opposite effects in Crohn's disease (less severe) vs
ulcerative colitis (more severe). 
The topic is of interest to the IBD field and the
manuscript is well written. 
However, some issues must be addressed before this
work is accepted for publication.
Major comments
1. Do authors have access to patient material? 
Would it be feasible to measure
NLRP3 function, or IL1b and/or IL18 protein levels from serum? 
Authors
comment quite extensively on how NLRP3-inflammasome activity influences
levels of these cytokines in the discussion and include one reference on how IL-
1b levels are decreased in one of the SNPs, but what about the other
polymorphisms? 
Is anything known about NLRP3 function and/or cytokine
levels in patients with multiple SNPs?
Without knowing NLRP3 function and IL-1b levels in this current IBD cohort
Authors should not draw conclusions on how SNPs in CD vs UC might alter
NLRP3 function and cytokine levels and how in turn these polymorphisms might
affect treatment decisions (Discussion, p13 line39 - p13 line 12). 
This work is
still very important without this patient data and thus I would rather emphasize,
as main conclusion, the need of proper analyses on how these SNPs influence
inflammasome function and downstream cytokine production.
2. Authors mention "major allele" several times throughout the paper, but it is
not clear to the reviewer whether they mean the major allele within the healthy
population, or within the examined cohort of patients. 
Please clarify.
3. Figure1: text states that "presence of the major (G) allele … was associated
with a significantly lower maximal CDAI value (p = 0.011)." 
However, this
significance is not indicated in the figure, please correct.
As authors find 2 other significant associations with CD (longer disease duration
and fewer operations due to stenosis), this should also be shown in a figure,
maybe added to Figure 1 as Figure 1C and D.
4. Similarly, the significant association with higher age at disease onset in UC
should be added to Figure2 (eg as Fig2C).
5. Although sometimes mentioned in the text very broadly (eg p10, line 53) there
is no information on the therapy patients received. 
If possible, please comment
on this, for example whether patients needed treatment intensification, need for
biological therapies etc.
Minor comments
1. Although the English is high quality throughout the manuscript, some typos
and comma mistakes do occur (eg "swiss" instead of "Swiss" in the title). 
The
manuscript should be carefully checked and these should be corrected.
2. Background, last paragraph: I would include at least one sentence on what the
findings are before starting the "Our findings…" sentence.
3. What is "last patient visit" on p7, line14 (time from diagnosis until last patient
visit)? 
Please clarify.
4. Authors report less operations as treatment of stenosis in CD (p7). 
Was the
frequency of stenosis also lower, or was the percentage of stenosis requiring
surgery lower?
5. Who do authors define as an "ordinary IBD patient" (p11, line 56)?
6. Table 2, rs4353135 vs rs55646866, TT (p20, line 59): total should be 317, not
217.
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find the details of processing in Publons’ privacy policy
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No
Declaration of competing interests
Please complete a declaration of competing
interests, considering the following questions:
1
. 
Have you in the past five years received reimbursements, fees, funding, or
salary from an organisation that may in any way gain or lose financially
from the publication of this manuscript, either now or in the future?
2
. 
Do you hold any stocks or shares in an organisation that may in any way
gain or lose financially from the publication of this manuscript, either now
or in the future?
3
. 
Do you hold or are you currently applying for any patents relating to the
content of the manuscript?
4
. 
Have you received reimbursements, fees, funding, or salary from an
organization that holds or has applied for patents relating to the content of
the manuscript?
5
. 
Do you have any other financial competing interests?
6
. 
Do you have any non-financial competing interests in relation to this
paper?
If you can answer no to all of the above, write 'I declare that I have no competing
interests' below. If your reply is yes to any, please give details below.
I declare that I have no competing interests.
Reviewer Publication Consent.
 I agree for my report to be made available
under an Open Access Creative Commons CC-BY License (
http://creativecommons.org/licenses/by/4.0
) if this manuscript is accepted for
publication. Any comments that I do not wish to be included in the published
report have been included as confidential comments to the editor, which will not
be published.
If you are not happy for us to publish this report, please contact the
editorial office before completing the review.
If you wish, you can include your
name in your published report. Please note you must decide whether to include
your name at the start of the process and confirm this decision whenever
prompted. If you change your decision later, we will not be able to publish your
name.
I agree to the terms of the CC-BY 4.0 license; please 
do not
 publish my name
with my report. (default)
Is the study design appropriate to answer the research question (including the use
of appropriate controls), and are the conclusions supported by the evidence
presented?
No
Are the methods sufficiently described to allow the study to be repeated?
Yes
Is the use of statistics and treatment of uncertainties appropriate?
Yes
Is the presentation of the work clear?
Yes
Are the images in this manuscript (including electrophoretic gels and blots) free
from apparent manipulation?
Yes
Reviewer’s report
Title: 
Genotype-Phenotype Associations of Polymorphisms within the Gene
Locus of NOD-like Receptor Pyrin Domain Containing 3 in Swiss inflammatory
bowel disease patients
Version: 
0 
Date: 
01 May 2021
Reviewer's report:
In their paper, Yoganathan et al describe the effects of three NLRP3-associated
SNPs on the clinical parameters of Swiss IBD patients. 
The authors describe that
the polymorphisms have opposite effects in Crohn's disease (less severe) vs
ulcerative colitis (more severe). 
The topic is of interest to the IBD field and the
manuscript is well written. 
However, some issues must be addressed before this
work is accepted for publication.
Major comments
1. Do authors have access to patient material? 
Would it be feasible to measure
NLRP3 function, or IL1b and/or IL18 protein levels from serum? 
Authors
comment quite extensively on how NLRP3-inflammasome activity influences
levels of these cytokines in the discussion and include one reference on how IL-
1b levels are decreased in one of the SNPs, but what about the other
polymorphisms? 
Is anything known about NLRP3 function and/or cytokine
levels in patients with multiple SNPs?
Without knowing NLRP3 function and IL-1b levels in this current IBD cohort
Authors should not draw conclusions on how SNPs in CD vs UC might alter
NLRP3 function and cytokine levels and how in turn these polymorphisms might
affect treatment decisions (Discussion, p13 line39 - p13 line 12). 
This work is
still very important without this patient data and thus I would rather emphasize,
as main conclusion, the need of proper analyses on how these SNPs influence
inflammasome function and downstream cytokine production.
2. Authors mention "major allele" several times throughout the paper, but it is
not clear to the reviewer whether they mean the major allele within the healthy
population, or within the examined cohort of patients. 
Please clarify.
3. Figure1: text states that "presence of the major (G) allele … was associated
with a significantly lower maximal CDAI value (p = 0.011)." 
However, this
significance is not indicated in the figure, please correct.
As authors find 2 other significant associations with CD (longer disease duration
and fewer operations due to stenosis), this should also be shown in a figure,
maybe added to Figure 1 as Figure 1C and D.
4. Similarly, the significant association with higher age at disease onset in UC
should be added to Figure2 (eg as Fig2C).
5. Although sometimes mentioned in the text very broadly (eg p10, line 53) there
is no information on the therapy patients received. 
If possible, please comment
on this, for example whether patients needed treatment intensification, need for
biological therapies etc.
Minor comments
1. Although the English is high quality throughout the manuscript, some typos
and comma mistakes do occur (eg "swiss" instead of "Swiss" in the title). 
The
manuscript should be carefully checked and these should be corrected.
2. Background, last paragraph: I would include at least one sentence on what the
findings are before starting the "Our findings…" sentence.
3. What is "last patient visit" on p7, line14 (time from diagnosis until last patient
visit)? 
Please clarify.
4. Authors report less operations as treatment of stenosis in CD (p7). 
Was the
frequency of stenosis also lower, or was the percentage of stenosis requiring
surgery lower?
5. Who do authors define as an "ordinary IBD patient" (p11, line 56)?
6. Table 2, rs4353135 vs rs55646866, TT (p20, line 59): total should be 317, not
217.
Publons Reviewer Recognition
. Springer Nature can send verification of this
review directly to Publons (a subsidiary of Clarivate Analytics). If you would
like to take advantage of this service, please click on the “Yes” option below.
Your name, email address, title of the reviewed manuscript, name of the journal,
and date of your review submission (the “Review Data”) will then be transmitted
to Publons after the final decision on the manuscript has been made. If you have
already registered at Publons, they will notify you of the receipt of this review
and update your profile 
as per your settings and their policy. If you are not
registered with Publons, you will receive an email from them asking you to
register in order for them to be able to recognize your review on your new
profile page. Publons may use the Review Data to generate derivative metadata
for the benefit of Publons and you as a reviewer, carefully considering the
sensitivity of such information. For example, Publons may verify your record as
a reviewer by updating your profile published on its webservice if you have
registered for such service or help editors to identify candidate reviewers. Please
find the details of processing in Publons’ privacy policy
https://publons.com/about/terms
No
Declaration of competing interests
Please complete a declaration of competing
interests, considering the following questions:
1
. 
Have you in the past five years received reimbursements, fees, funding, or
salary from an organisation that may in any way gain or lose financially
from the publication of this manuscript, either now or in the future?
2
. 
Do you hold any stocks or shares in an organisation that may in any way
gain or lose financially from the publication of this manuscript, either now
or in the future?
3
. 
Do you hold or are you currently applying for any patents relating to the
content of the manuscript?
4
. 
Have you received reimbursements, fees, funding, or salary from an
organization that holds or has applied for patents relating to the content of
the manuscript?
5
. 
Do you have any other financial competing interests?
6
. 
Do you have any non-financial competing interests in relation to this
paper?
If you can answer no to all of the above, write 'I declare that I have no competing
interests' below. If your reply is yes to any, please give details below.
I declare that I have no competing interests.
Reviewer Publication Consent.
 I agree for my report to be made available
under an Open Access Creative Commons CC-BY License (
http://creativecommons.org/licenses/by/4.0
) if this manuscript is accepted for
publication. Any comments that I do not wish to be included in the published
report have been included as confidential comments to the editor, which will not
be published.
If you are not happy for us to publish this report, please contact the
editorial office before completing the review.
If you wish, you can include your
name in your published report. Please note you must decide whether to include
your name at the start of the process and confirm this decision whenever
prompted. If you change your decision later, we will not be able to publish your
name.
I agree to the terms of the CC-BY 4.0 license; please 
do not
 publish my name
with my report. (default)
Is the study design appropriate to answer the research question (including the use
of appropriate controls), and are the conclusions supported by the evidence
presented?
No
Are the methods sufficiently described to allow the study to be repeated?
Yes
Is the use of statistics and treatment of uncertainties appropriate?
Yes
Is the presentation of the work clear?
Yes
Are the images in this manuscript (including electrophoretic gels and blots) free
from apparent manipulation?
Yes
Please review this paper.
user
Reviewer’s report
Title: 
Genotype-Phenotype Associations of Polymorphisms within the Gene
Locus of NOD-like Receptor Pyrin Domain Containing 3 in Swiss inflammatory
bowel disease patients
Version: 
0 
Date: 
01 May 2021
Reviewer's report:
In their paper, Yoganathan et al describe the effects of three NLRP3-associated
SNPs on the clinical parameters of Swiss IBD patients. 
The authors describe that
the polymorphisms have opposite effects in Crohn's disease (less severe) vs
ulcerative colitis (more severe). 
The topic is of interest to the IBD field and the
manuscript is well written. 
However, some issues must be addressed before this
work is accepted for publication.
Major comments
1. Do authors have access to patient material? 
Would it be feasible to measure
NLRP3 function, or IL1b and/or IL18 protein levels from serum? 
Authors
comment quite extensively on how NLRP3-inflammasome activity influences
levels of these cytokines in the discussion and include one reference on how IL-
1b levels are decreased in one of the SNPs, but what about the other
polymorphisms? 
Is anything known about NLRP3 function and/or cytokine
levels in patients with multiple SNPs?
Without knowing NLRP3 function and IL-1b levels in this current IBD cohort
Authors should not draw conclusions on how SNPs in CD vs UC might alter
NLRP3 function and cytokine levels and how in turn these polymorphisms might
affect treatment decisions (Discussion, p13 line39 - p13 line 12). 
This work is
still very important without this patient data and thus I would rather emphasize,
as main conclusion, the need of proper analyses on how these SNPs influence
inflammasome function and downstream cytokine production.
2. Authors mention "major allele" several times throughout the paper, but it is
not clear to the reviewer whether they mean the major allele within the healthy
population, or within the examined cohort of patients. 
Please clarify.
3. Figure1: text states that "presence of the major (G) allele … was associated
with a significantly lower maximal CDAI value (p = 0.011)." 
However, this
significance is not indicated in the figure, please correct.
As authors find 2 other significant associations with CD (longer disease duration
and fewer operations due to stenosis), this should also be shown in a figure,
maybe added to Figure 1 as Figure 1C and D.
4. Similarly, the significant association with higher age at disease onset in UC
should be added to Figure2 (eg as Fig2C).
5. Although sometimes mentioned in the text very broadly (eg p10, line 53) there
is no information on the therapy patients received. 
If possible, please comment
on this, for example whether patients needed treatment intensification, need for
biological therapies etc.
Minor comments
1. Although the English is high quality throughout the manuscript, some typos
and comma mistakes do occur (eg "swiss" instead of "Swiss" in the title). 
The
manuscript should be carefully checked and these should be corrected.
2. Background, last paragraph: I would include at least one sentence on what the
findings are before starting the "Our findings…" sentence.
3. What is "last patient visit" on p7, line14 (time from diagnosis until last patient
visit)? 
Please clarify.
4. Authors report less operations as treatment of stenosis in CD (p7). 
Was the
frequency of stenosis also lower, or was the percentage of stenosis requiring
surgery lower?
5. Who do authors define as an "ordinary IBD patient" (p11, line 56)?
6. Table 2, rs4353135 vs rs55646866, TT (p20, line 59): total should be 317, not
217.
Publons Reviewer Recognition
. Springer Nature can send verification of this
review directly to Publons (a subsidiary of Clarivate Analytics). If you would
like to take advantage of this service, please click on the “Yes” option below.
Your name, email address, title of the reviewed manuscript, name of the journal,
and date of your review submission (the “Review Data”) will then be transmitted
to Publons after the final decision on the manuscript has been made. If you have
already registered at Publons, they will notify you of the receipt of this review
and update your profile 
as per your settings and their policy. If you are not
registered with Publons, you will receive an email from them asking you to
register in order for them to be able to recognize your review on your new
profile page. Publons may use the Review Data to generate derivative metadata
for the benefit of Publons and you as a reviewer, carefully considering the
sensitivity of such information. For example, Publons may verify your record as
a reviewer by updating your profile published on its webservice if you have
registered for such service or help editors to identify candidate reviewers. Please
find the details of processing in Publons’ privacy policy
https://publons.com/about/terms
No
Declaration of competing interests
Please complete a declaration of competing
interests, considering the following questions:
1
. 
Have you in the past five years received reimbursements, fees, funding, or
salary from an organisation that may in any way gain or lose financially
from the publication of this manuscript, either now or in the future?
2
. 
Do you hold any stocks or shares in an organisation that may in any way
gain or lose financially from the publication of this manuscript, either now
or in the future?
3
. 
Do you hold or are you currently applying for any patents relating to the
content of the manuscript?
4
. 
Have you received reimbursements, fees, funding, or salary from an
organization that holds or has applied for patents relating to the content of
the manuscript?
5
. 
Do you have any other financial competing interests?
6
. 
Do you have any non-financial competing interests in relation to this
paper?
If you can answer no to all of the above, write 'I declare that I have no competing
interests' below. If your reply is yes to any, please give details below.
I declare that I have no competing interests.
Reviewer Publication Consent.
 I agree for my report to be made available
under an Open Access Creative Commons CC-BY License (
http://creativecommons.org/licenses/by/4.0
) if this manuscript is accepted for
publication. Any comments that I do not wish to be included in the published
report have been included as confidential comments to the editor, which will not
be published.
If you are not happy for us to publish this report, please contact the
editorial office before completing the review.
If you wish, you can include your
name in your published report. Please note you must decide whether to include
your name at the start of the process and confirm this decision whenever
prompted. If you change your decision later, we will not be able to publish your
name.
I agree to the terms of the CC-BY 4.0 license; please 
do not
 publish my name
with my report. (default)
Is the study design appropriate to answer the research question (including the use
of appropriate controls), and are the conclusions supported by the evidence
presented?
No
Are the methods sufficiently described to allow the study to be repeated?
Yes
Is the use of statistics and treatment of uncertainties appropriate?
Yes
Is the presentation of the work clear?
Yes
Are the images in this manuscript (including electrophoretic gels and blots) free
from apparent manipulation?
Yes
assistant