Review for 10.1186/s12876-021-01880-9 (2021)

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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Is the study design appropriate to answer the research question (including the use
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