PONE-D-20-36360

Interleukin-13 rs1800925/-1112C/T promoter single nucleotide polymorphism variant linked to anti-schistosomiasis adult males in Murehwa District, Zimbabwe.

PLOS ONE

Dear Ms Emilia Choto,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

• Specifically, questions about the methodology and study design should be addressed; explanations should be given for why numbers don't tally in your manuscript. 
  • ​You enrolled  366 participants but report SNP results for 356 participants (Page 12: Lines 284-285) and no reason(s) was/were given for the remaining one that was missing; probably due to unsuccessful genotyping.
  •  Of the 366 participants that were enrolled, IL-13 cytokine concentrations were reported for only 107 participants and no reason(s) was/were given for the remaining unreported results. In addition, the authors did not state how many participants out of the 107 had schistosomiasis and how many were uninfected.
• It was observed that certain data presented in this study had earlier been published by the authors [Choto et al. Infectious Agents and Cancer (2020) 15:59; PMID: 33042215], but no mention was made about this in the Results section (Page 12: Lines 281-282) so as to avoid any semblance of duplicate publishing
• You need to also clarify the connection between the stated aims of your study; not much attention was given to the prostate antigen aspect. The study looks like two different studies (one on the association between IL-13rs1800925/-1112C/T promoter SNPs and Schistosoma haematobium infection, and the other on association between IL-13rs1800925 polymorphism and prostate-specific antigen levels) but the nexus between the two does not come out clearly in the literature review and discussion.
• There are also grammatical errors that need to be edited.

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Chiaka Ijeoma Anumudu

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The study attempted to evaluate the IL-13 in susceptibility or resistance against schistosomiasis and association to risk of prostate cancer development. The study should provide promising information on understanding the role of the cytokine in host response to the disease schistosomiasis.

Introduction

Line 99-100 "Host genetic variability of encoding genes such as polymorphisms located in the promoter region modify gene transcription and cytokine production in parasitic and autoimmune diseases" is not explicit and appeared inconclusive, please rephrase

Line 108-110 add reference to the statement "Single nucleotide polymorphisms (SNPs) are the most common genetic variations..... sequences and protein structure (ref.)

Line 116- Isnard et al (2011)... and not Isnard et al., in 2011

Line 144- Remove schistosome from the statement "S. haematobium schistosome egg burden was associated"

Materials and Methods

Line 164- Inclusion criteria: Reason on focusing on adults aged 18 and above should be clearly stated

Line 174-175: Schistosome infected individuals were treated with praziquantel(PZQ) at the standard single oral dose of 40mg/kg per body weigh (ref.)

Line 162-163: Detailed description of study areas was not well provided in this study. Providing map, daily activities of the study population will help

Line 360-362: "Binomial logistic regression was used to predict the risk of prostate cancer development between participants with prostate specific antigen levels > 4 ng/mL and < 4ng/mL using IL362 13 cytokine concentrations and schistosomiasis status as the predictor value". The statement is more of methodology than results, rephrase.

Discussion: The discussion is well written but more recent literatures on study should be included to help support the outcome of the present study.

Reviewer #2: The manuscript is technically sound and the data support the conclusion. However, the study looks like two different studies (one on the association between IL-13rs1800925/-1112C/T promoter SNPs and Schistosoma haematobium infection, and the other on association between IL-13rs1800925 polymorphism and prostate-specific antigen levels) but the nexus between the two does not come out clearly in the literature review and discussion. The author should also consider and mention that adult humans do not shed S. haematobium eggs well in urine and urinary egg counts may therefore not be a good indicator of infection intensity or disease burden in adults. In addition it is noteworthy that although IL-13 is an important player in schistosomiasis carcinogenesis, there are other important players such as infiltrin which should have been mentioned in discussion. Being a cross-sectional study, no influence could have been detected and therefore the word "influence" in lines 34 and 152 should be changed to "association".

The analyses were performed appropriately and and rigorously. however, the power of the study could have been compromised by the small number of infected individuals (n=50). The data underlying the findings were made available but it would have been better if the age distribution of the subjects was also presented.

The manuscript is presented in an intelligible fashion and in standard English. However, there are several grammatical errors and omissions that should be corrected. For example, the term "schistosomiasis infected" should be changed to "S. haematobium-infected"

Reviewer #3: ABSTRACT

Page 2: Lines 32-34

The authors should correct "Our study evaluated the frequency of the IL-13 rs1800925/-1112 C/ T promoter single nucleotide polymorphisms (SNPs) and assessed the influence of the variants on IL-13 cytokine levels." to read "Our study evaluated the frequency of the IL-13 rs1800925/-1112 C/ T promoter single nucleotide polymorphisms (SNPs) among schistosomiasis infected individuals and assessed the influence of the variants on IL-13 cytokine levels."

Page 2: Lines 46-48

The authors should indicated whether the sentence "There were significantly (p<0.05) higher IL-13 cytokine levels among participants with the genotypes CC and CT; median 92.25 pg/mL and 106.5 pg/mL, respectively, compared to TT variant individuals; 44.78 pg/mL." is with respect to schistosomiasis infected individuals or uninfected.

INTRODUCTION

Page 4: Line 82

Please restructure "...Schistosomiasis is a neglected parasitic tropical disease" to read "...Schistosomiasis is a neglected tropical parasitic disease"

Page 4: Line 91

Please restructure "...Schistosomiasis acute infections" to read "...Acute schistosomiasis infections"

Page 4: Lines 98-101

Needs grammatical restructuring.

Page 5: Line 109

Please restructure "...located in the coding regions of the genes" to read "...located in the coding regions of genes"

Page 5: Lines 122-125

The sentence "In contrast, to the above findings recently Adedokun et al. in 2018 found no statistical difference in the IL-13 rs7719175 genotypic or allelic frequencies between schistosome-infected and uninfected controls or any association with disease [26]." would be better in the Discussion Section.

Page 5: Lines 125-127

The sentence "Furthermore, no association between IL-13 rs1800925 C/T and autoimmune diseases such as Graves’ disease risk [27] and rheumatoid arthritis [18] has been established." should be removed because it does not appear to have any relevance there.

Page 6: Lines 150 and 151

The sentence "Therefore, the aim of the study were..." should be corrected to read "Therefore, the aim of the study was...".

MATERIALS AND METHODS

Page 7: Lines 161

The authors should also give a description of the enrolment or case definition of participants with prostate cancer.

RESULTS

Page 12: Lines 281-282

It was observed that certain data presented in this study had earlier been published by the authors [Choto et al. Infectious Agents and Cancer (2020) 15:59; PMID: 33042215]. The authors should have made mention of this in this section.

Page 12: Lines 285-285

The authors had earlier indicated that 366 participants were enrolled but genotypic results for IL-13 -1112C/T polymorphism were given for only 356 participants. The authors should give reasons for this discrepancy.

Page 13: Line 308

The authors presented IL-13 cytokine concentrations results for only 107 participants out of the 366 participants that were enrolled. The authors should also give reasons for this discrepancy.

Page 15: Line 367

The authors should review this Table to ensure that the Title is a true reflection of the contents.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Dr. Segun Isaac OYEDEJI

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Interleukin-13 rs1800925/-1112C/T promoter single nucleotide polymorphism variant linked to anti-schistosomiasis in adult males in Murehwa District, Zimbabwe.

PONE-D-20-36360R1

Dear Ms Choto,

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.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Chiaka Ijeoma Anumudu

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #3: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #3: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #3: The initial comments have been addressed but there are few, though minor observations that needs to be addressed. The authors should please make the following minor corrections:

INTRODUCTION

Page 5: Line 128

Please insert a full stop (.) after et al

Page 6: Lines 129-130

Please remove the comma (,) after In contrast and place it after findings in line 130.

MATERIALS AND METHODS

Page 7: Lines 161 and 170

I think that it is better to start this section with Study design, study area and study population (as it was in the original

submission), rather than starting with Ethical approval.

Page 7: Lines 176-177

Please reconstruct the sentence "The District consists of more than 90 % of the area is..."

Page 8: Line 186

Please change "give" to "gave"

RESULTS

Page 13: Line 323

Please insert frequency after genotypic

Page 14: Line 331 (Table 1)

Please remove the semicolon in the parenthesis under Total.

DISCUSSION

Pages 17 and 18: Lines 403-404.

Please reconstruct the sentence "... to elucidate promoter gene polymorphisms on IL-13 cytokine levels, role to

susceptibility or protective against schistosomiasis..."

Page 21 Line 486.

Please insert "which" after (2010)

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #3: Yes: Segun Isaac OYEDEJI