Protective Role of Genetic Variants in HSP90 Genes-Complex in COPD Secondary to Biomass-Burning Smoke Exposure and Non-Severe COPD Forms in Tobacco Smoking Subjects

Round 1

Reviewer 1 Report

This is an interesting study aimed to evaluate an association between SNPs of the heat shock proteins HSP90 and COPD due to tobacco smoke or biomass-burning smoke exposure.

The study is well designed and results are straightforward and clearly presented. Overall, the manuscript is well written. However, I have following comments;

What is altitude of Oaxaca’s northern highlands and suburban areas in Tlalpan? Is there a significant altitude difference? If yes, it should be considered during the analysis.

Table 1: Please carefully check the data on lung function for their accuracy.

Please check the abbreviations for consistency (e.g., COPD-T, line 292, COPD-BS, line 294).

Author Response

We are grateful for the time spent and the prompt review of our article. Here are the responses to the comments and suggestions made:

Reviewer 1:

1. What is altitude of Oaxaca’s northern highlands and suburban areas in Tlalpan? Is there a significant altitude difference? If yes, it should be considered during the analysis.

First of all, We want to thank you for the comments made.

Altitude in Oaxaca’s highlands is between 2,000 and 3,200 meters above mean sea level. The participants of our study live between 2,000 and 2,500 meters above mean sea level (MAMSL). In Mexico City, Tlalpan county has a maximum altitude of 3,930 MAMSL, but the study participants are from zones where the altitude is around 2,300 MAMSL.

Differents authors discuss the effect of the altitude in COPD; the main point is the assessment of COPD patients travels to high altitudes (>2,500 MAMSL) from low altitudes (<1,500, or even sea level) and the decrease of exercise performed, partial O2 (pO2), blood pressure and lung function values. In our case, the study includes patients that had live all their life at high altitude. Also, the spirometry was done considering the altitude in each place; now, we have included this mention in the methods section.

1. Table 1: Please carefully check the data on lung function for their accuracy.

Thanks for the observations; we corrected this error. We wrongly assigned lung function values between FEV1 and FVC.

1. Please check the abbreviations for consistency (e.g., COPD-T, line 292, COPD-BS, line 294).

Thanks for the commentary. Abbreviations were checked in the full document.

Reviewer 2 Report

I have read the article by Ambrocio-Ortiz et al. with great interest. The authors investigated genetic background of biomass-induced COPD by analysing a selected group of SNPs.

Comments:

• Please remove brackets and put comma before emphysema which is not part of the lung remodelling.
• 2^nd paragraph. I am not sure if it is correct to assume that patients with biomass induced COPD have an “asthmatic” phenotype. The cited studies clearly do not suggest this. Please, revise.
• Lung function data are pre- or post-bronchodilator. Please, comment.
• Table 1. The median values for FEV1 and FVC in the COPD-S group unlikely to be true. Please check.
• It would be important to see markers of disease activity (i.e. symptoms scores, number of exacerbations) and if they were related to genotypes.
• “FEV1/FVC ratio was slightly higher in the BBES group compared with the SWOC group.” Please provide p values for comparisons between the two control groups.
• I notice that some of the controls in the smoker group had low lung volumes. Do you have any data on birth weight?

Author Response

Reviewer 2:

1. Please remove brackets and put comma before emphysema which is not part of the lung remodelling.

Thanks for your advice. Now is corrected

1. 2nd paragraph. I am not sure if it is correct to assume that patients with biomass induced COPD have an “asthmatic” phenotype. The cited studies clearly do not suggest this. Please, revise.

Thanks for your comment; we have reviewed the articles and corrected the interpretation

1. Lung function data are pre- or post-bronchodilator. Please, comment.

Lung function data is post-bronchodilator; it is shown in results and table 1.

1. Table 1. The median values for FEV1 and FVC in the COPD-S group unlikely to be true. Please check.

Thanks for the observations; we corrected this error. We wrongly assigned median lung function values between FEV1 and FVC.

1. It would be important to see markers of disease activity (i.e. symptoms scores, number of exacerbations) and if they were related to genotypes.

Thanks for your valuable comment. We presented inflammatory markers (TNF-α, IL-6, IL-8) and the relation with other SNPs in previous works (PMID: 30296713, 31964947). We have few patients reporting exacerbations, and we had not had enough data to get reliable results. Also, included patients were stable, without supplementary oxygen at the enrollment time, without a history of exacerbations, neither antibiotics nor systemic corticosteroid treatment in the last 3 months. Now, it is stated in the Material and Methods section.

1. “FEV1/FVC ratio was slightly higher in the BBES group compared with the SWOC group.” Please provide p values for comparisons between the two control groups.

We added the p-value in the Result section, but these results should be interpreted with care.

1. I notice that some of the controls in the smoker group had low lung volumes. Do you have any data on birth weight?

That’s an interesting comment; unfortunately, the information provided by participants is limited, among this, birth weight or perinatal exposure to indoor contaminants, particularly in the exposed to BBS group recruited from rural or suburban areas.

Round 2

Reviewer 2 Report

I am happy with the changes and suggest acceptance.