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Congratulations on the acceptance.
Yours,
Yoshi
Prof. Yoshinori Marunaka, M.D., Ph.D.
The authors answered all the comments and edited the manuscript accordingly. The manuscript is now suitable for publication.
No comment
No comment
No comment
Please revise your manuscript according to the reviewer's remaining comments.
Yours,
Yoshi
Prof. Yoshinori Marunaka, M.D., Ph.D.
The manuscript has been widely improved from its first version.
English is clear, references have been correctly added and addressed, and the manuscript is fluent and easy to follow.
In the attached revised manuscript, I pointed out several typos that are still present, and that should be fixed before publication.
The authors answered all the revisions; all the requested issues have been resolved. Hence, I do not have further comment on the study's experimental design.
The Authors answered all the requested revisions. Despite some typos, some concepts need to be clarified or rewritten for clarity, as pointed out in the revised version of the manuscript.
In the "Abstract" section, there are misleading references to some evaluated models (dominant, codominant and overdominant), which were clearer in the previous version of the manuscript.
All the sections are now easy to understand and clearer and need minimal adjustment, as reported in the revisions across the manuscript (attached PDF file).
The "Conclusion" section is now acceptable; however, it might benefit from an expansion of a couple of sentences related to the author's suggestion on how to address further research and/or regarding the target(s) to select, as well as the kind of study/studies to perform.
Dear Authors,
The manuscript has been extensively revised and fixed. The text is now clear and entirely understandable.
The effort in revising the manuscript has been widely appreciated.
Despite minimal adjustments, as reported in these comments and the attached revised manuscript, the research article could now be accepted for publication.
Please revise your manuscript according to the reviewers' comments.
Yours,
Yoshi
Prof. Yoshinori Marunaka, M.D., Ph.D.
The authors investigated the association of three TYK2 gene polymorphisms with the risk of microscopic polyangiitis in a Chinese population. While the findings the interesting I have several comments:
1. What is the justification of choosing these three SNPs of TYK2 gene?
2. The authors did not perform any sample size calculation. What is the effect size for this study?
3. In page 98-99 the authors wrote that they collected controls from the hospital. What is the reason behind that? As cases are from guanxi population so controls should also be randomly collected from guanxi population.
1. To calculate the odds ratio, multivariate logistic regression is the preferred method. Did the authors perform that?
2. Did the authors control for all significant demographic variables (age, ethnicity, DBP) in the logistic regression model?
3. The authors performed the analysis for three genetic models: dominant, recessive, and over dominant models. I suggest they do it for heterozygous, homozygous, and allelic models too.
4. The authors did not perform any correction for multiple comparison. I suggest they do Bonferroni correction for all the p values.
To validate the findings the authors may perform gene expression or protein expression analysis to elucidate the effects of the TYK2 gene SNPs.
The article by Yang, Fen, and colleagues reports an investigation of three single nucleotide polymorphisms and their associations with MPA in the Guangxi population.
The article presents the potential and the interest to advance genetic knowledge on MPA; however, in its current state, it presents several issues that should be addressed and considered for publication.
English must be revised. The manuscript presents several typos, such as missing spaces (for example, see lines 50 and 97), missing connectors (for example, see lines 56 and 58, which are missing "and"), and missing structural layout, such as missing bold sentence (see line 101) and clear but grammatically incorrect structure (see line 103 and 107).
Some technical words are missing or not properly used, for example: "locus were calculated" at line 110; "negative results" at line 138 (does it refer to not significant results?).
Some abbreviations should be reported in their extended version on the first appearance, such as Th1 and Th17 (lines 72-73). Moreover, some abbreviations are not adequately reported, such as type 1 interferon (IFN), which should be substituted for IFN1 (line 75).
The article does not present clear and proper sections in its current structure.
The abstract presents a too-short discussion section and lacks a conclusion; it should be strongly revised.
The Introduction presents an unclear presentation of the ANCA-associated autoantibodies (lines 39 to 41): proteinase 3 and myeloperoxidase are presented as PR3-ANCA and MPO-ANCA, which refers to their autoantibodies rather than to the proteins themselves. Hence, it should be rewritten. Moreover, given the genetic perspective of the paper and the little overview provided on the different ANCA-associated vasculitis, when introducing them, I suggest the authors reference the following articles: (1) Hunter RW et al., BMJ, 2020 (PMID: 32291255) on general AAV; Puéchal X, 2020, Joint Bone Spine (PMID: 32562697) on GPA; Treccani M et al., 2024, CIMB (PMID: 39057087) on EGPA.
Moreover, line 95 presents a numbered reference (18) that should be revised according to the journal instructions.
The discussion is not well organized and difficult to follow. Despite the reported concepts being precise and correct, they are not presented fluently, concisely and well-structured. For example, the population effect presented in lines 169-174 is interesting but unclear; the associations of TYK2 with immune-mediated diseases are repetitive and difficult to follow; the presentation of possible intronic-mediated effect is interesting but difficult to follow; moreover, the short conclusions reported in lines 194-195, 211-213, and 224-226 are disconnected and not too understandable.
The reported tables should be revised.
Table 1 reports multiple instances of age, gender and ethnicity: the subfields reported (e.g., age, age>56, age<56) should be graphically restructured for easy comprehension. Moreover, the table should report whether the presented P-value refers to a nominal or a corrected value. In the end, the caption should present the extended version of the abbreviated terms.
Table 2 should be revised regarding the caption, which is too synthetic. The word "polymorphisms" is lacking the final s. Moreover, I suggest preferring the decimal to the percentage annotation when reporting the MAF ratio. Moreover, could the author explain this ratio? Why is it important? Shouldn't it be better to report a single number (e.g. MAF cases=0.5; MAF control=0.3; MAF ratio=1.67) and explain the meaning using thresholds?
In Table 3 the number of cases and controls are not clear and thus should be specified (because they are differing from the number reported along the manuscript).
In Table 4, the word "variant" should present a starting capital letter. Moreover, the term "All subjects" should be explained.
Despite what is reported in the manuscript, Table S1 does not present information regarding the female subgroup, but it refers to ethnicity; moreover, Table S2 refers to age. Given a sex bias in the genetic association, the female table should be reported in the main tables and not as supplementary material.
In the manuscript, the authors present a clear objective and research question. However, the knowledge gap is questionable.
The author states that currently, no reports are available regarding the association between TYK2 mutations and AVV. However, Ortiz-Fernandez and colleagues (Clinical Experimental Rheumatology, 2020) reported the first hint of association between TYK2 and AAV, which the authors refer to in the Discussion section of this manuscript. So, despite the valid research question, the current knowledge gap should be revised or properly differentiated from Ortiz-Fernandez et al., 2020.
Among all the manuscripts, the main inconsistency and issue regards the investigated SNPs.
In the beginning, the SNPs investigated resulted in being three and are reported together with their rscode (from dbSNP) and their alleles (in the form A>C). However, despite the correctness of the provided rscode, the alleles are incorrectly reported, as checked on dbSNP and ClinVar. Hence, authors should provide proof of the utilised nomenclature and consider risk alleles for the reporting methodology and analysis. Moreover, these SNPs are inconsistently reported across the manuscripts: for example, in line 84, rs2304256 is reported with inverted alleles compared to its first appearance; hence, it should be clarified.
Furthermore, the Result section presents an additional SNP (rs2304255), which has not been presented in the previous pages, representing a novel element for the analysis. Given this fact, the authors should state since the initial part of the manuscript that the investigated SNPs are four (instead of three) and the results they obtained. Moreover, this SNP's exclusion criteria are unclear, given that they are addressed in terms of both MAF and statistical significance. Hence, it should be clarified.
The investigation follows the scientific community standard and is presented clearly. However, the Materials & Methods section lacks information: all the applied methods are not referenced; moreover, some information regarding references and releases should be provided, either in the methods (e.g., Annovar, BWA function) or the materials (e.g., the reference genome). At last, the DNA kit is not clearly stated and incorrectly referred to (e.g., "Thermo Scientific, USA").
The impact and novelty of the research paper are clear; in short, this paper represents the first real evidence of association between some TYK2 genotypes and MPA since this paper focuses only on MPA.
Despite its novelty, the authors should address the genotypes and risk alleles of the proposed variants, clarifying the correct allele under investigation and the effect of the associated genotypes; thus, an explanation should be provided regarding rs2304256A>C (or C>A), rs280519G>A (or A>G), and rs12720270A>G (or G>A).
Furthermore, the authors should provide information regarding the analysis conducted on the female subgroup, which is missing in the whole manuscript.
In terms of statistics, the authors should explicitly state whether the computed p-value is nominal or adjusted: in the first case, they should provide evidence supporting the lack of correction; in the second case, they should provide information regarding the adopted correction. Above all, the mathematical tests adopted are missing (e.g., Student's t-test, Fisher's test or others) and should be reported.
The Conclusion is too short for the research article. Together with the Discussion section, it should be deeply revised and restructured.
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