PONE-D-22-02849DR4/DQ2 haplotype confers susceptibility to T1DM with early clinical disease onset: a retrospective analysis in a tertiary-care hospital in ItalyPLOS ONE

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Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #2: No

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Reviewer #1: The authors present a hospital cohort of early clinical onset T1DM patients analyzed for genetic factors linked to HLA haplotypes with the aim of identifying specific regional haplotypes in addition to the prevalent ones. The cohort is not large and the authors correctly declare the need for further validations, the analysis is conducted with validated methodologies, the results show the presence of the DR4 / DQ2 haplotype significant for susceptibility to T1DM and not present in the Italian standard protocols. To support and clarity of the results presented and the consequent conclusions, the presentation of the demographic data of the cohort and DR4 / DQ2 patients is necessary in order to verify the clinical and geographic specificity of the variant.

Reviewer #2: 1) The abstract is not too much focused on the topic. Abstract: delete “factors” from the second line, there is a repeat. In materials and methods there is a “s”. “Familiarity” is a false friend; family history sounds better. It is better to say medical data or report than “medical files”. The % in the parentheses missed the number. The part with the comorbidities in the abstract is useless there. You should insert instead the p values of the HLA haplotypes found in DM1 population.

2) Introduction: You should underline the p values of the other studies done to evaluate the HLA-T1D correlation.

3) Materials and methods: not medical files, but medical data. You should specify how many people the control group consists of, average age, and if you are sure that we do not have the dm1. In the Italian donor register, do participants specify whether they are suffering from autoimmune diseases or is this an exclusion criterion?

4) HLA Class II typing: explain the methods of analysis of the different HLA in order or with a flowchart or table. Explaining here which HLAs give increased, intermediate, and low risk is not indicated. To put this data in the introduction, specifying the sources and p value. The figure 1 is good, but with p values.

5) Results: “5 patients did not have known autoantibody at disease onset”. Did you test them now? “the difference of frequency of anti IAA ………(Figure 1)”; what statistical test was used? Chi Quadro for 3 different variables? Regarding the onset, you should correlate them with HLA (e.g. onset 10-15 ys � HLA XXX)

6) HLA class II allele frequency in T1D: in the second line there is “and”.

7) You should put all the data of HLA correlations in the tables in the same table.

8) DR4/DQ2 haplotypes: “study population” is not accurate. You should use “the population with T1D”. There is also a repetition. “we compared -………DR4/DQ2- cohort” � there is or not the difference of this IA2 antybodies?

9) HLA and comorbidities: you should put the data in a table. You should correlate them with the HLA Haplotype.

10) References: you should correct the references, as not all written in Vancouver (after the authors does not go the point, the pages should be shortened e.g. 24-26 --> 24-6)

11) You should rewrite the data in a better way, more clear and short, without repeats.

12) In the figures, you should use them in English, not in Italian.

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Reviewer #1: No

Reviewer #2: No

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DR4/DQ2 haplotype confers susceptibility to T1DM with early clinical disease onset: a retrospective analysis in a tertiary-care hospital in Italy

PONE-D-22-02849R1

Dear Dr. Ricci,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Giuseppe Novelli

Academic Editor

PLOS ONE

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