The Joint Contribution of Childhood Exposure to Parental Smoking and Genetic Susceptibility to Smoking to Epigenetic Age Acceleration in Late Adulthood: The Health and Retirement Study
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThe article provides information on a little-researched topic. One of the reasons for the lack of research is the difficulty of collecting the material. Nevertheless, the authors managed to collect such difficult material. And they were able to analyse it very well. The results of the study clearly show that one should not underestimate the impact of passive smoking in childhood on health in later life. I recommend the article for publication. It is not only a contribution to the study of a scientific problem, but also a contribution to public health.
Author Response
Thank you for the encouraging comments!
Reviewer 2 Report
Comments and Suggestions for AuthorsThe present article entitled "Joint contribution of childhood exposure to parental smoking and genetic susceptibility to smoking to epigenetic age acceleration in late adulthood: the Health and Retirement Study" aims to investigate genetic susceptibility to smoking. This paper has relevant information, but should be reviewed before acceptance:
Abstract
The section clearly describes the purpose of the study and the methods used, providing the reader with an overview of the research.
Introduction
This section would benefit from an exposition of previous studies on the impact of parental smoking specifically on epigenetic acceleration and the relevance of genetic heterogeneity in these effects
Methods
This section presents a solid and detailed design although it would be necessary to include how confounding variables were controlled. Likewise, the statistical analysis section should be reformulated for better understanding.
Discussion
It would also be interesting to add those results that were not significant and discuss them to see how they can affect the conclusions. In addition, a final paragraph should be added that discusses the limitations of the study.
Conclusion.
In this section, it would be advisable to add a sentence/paragraph with future research.
Author Response
Comments 1: Introduction -- This section would benefit from an exposition of previous studies on the impact of parental smoking specifically on epigenetic acceleration and the relevance of genetic heterogeneity in these effects.
Response 1: Thank you for the comments and suggestions. Few studies have explored the effect of childhood parental smoking exposure on EAAs due to scarce of data on the childhood exposure and/or EAAs. Our study is among the first few efforts to explore the topic. The relevance of genetic heterogeneity was based on many previous studies showing that the effect of lifestyle behaviors can be modified by genetic background. We have now added the following sentence in the introduction section. Please refer to lines 61-62.
"Many previous studies have demonstrated that the effect of lifestyle behaviors can be modified by genetic compositions.24-26"
Comments 2: Methods -- This section presents a solid and detailed design although it would be necessary to include how confounding variables were controlled. Likewise, the statistical analysis section should be reformulated for better understanding.
Responses: Thank you for the comments and suggestions. We have revised the statistical analyses section to explain our analyses more clearly. The new section now reads as follows with changes highlighted in yellow:
"Associations between childhood exposure to parental smoking and the five EAAs were evaluated using two multivariable linear regression models: a base model adjusting for age, sex, and race, and a full model additionally adjusting for education, smoking, drinking, BMI, CESD score, parental divorce, parental death, and separation from mother/father in the overall sample. The associations were then examined in White and Black participants separately using the same two models without race. To determine whether these associations differ by genetic susceptibility to smoking, we tested interactions between the childhood exposure to parental smoking and the PGS for smoking initiation, by adding an interaction term, exposure*PGS, along with individual variables of the term in the two models. For the purpose of illustration, participants were categorized into PGS tertiles, and associations between childhood exposure to parental smoking and each EAA were presented by these tertiles in each race group."
Comments 3: Discussion --It would also be interesting to add those results that were not significant and discuss them to see how they can affect the conclusions. In addition, a final paragraph should be added that discusses the limitations of the study.
Response 3: Thank you for the suggestions. We have now discussed the non-significant findings as follows.
"however, our study adds that parental smoking exposure was not linked to the other three EAA measures. The three EAA measures were developed using CpG sites related to chronological age or mortality. While GrimAA and DunedinAA involve CpG sites directly or indirectly related to smoking. Nevertheless, parental smoking exposure tended to show different effect on the three EAAs by levels of the PGS. Future studies examining interaction of genes with parental smoking exposure may identify individual groups who were particularly vulnerable to smoking. "
We also added the following limitations:
"However, there are limitations. First, childhood exposure to parental smoking was self-reported, which may introduce information bias. Nonetheless, such bias is likely non-differential, potentially biasing estimates toward the null and reducing statistical power to detect significant associations, thereby demonstrating the robustness of our findings. Second, the PRS was developed based on genome-wide association studies conducted predominantly among participants of European ancestry. Its performance in Black participants was less optimal. Future studies with a better PRS for Black participants are needed."
Comments 4: Conclusion -- In this section, it would be advisable to add a sentence/paragraph with future research.
Response 4: We have now added the following sentence suggesting future research.
"Future genome-wide studies testing interactions of genetic variants with childhood exposure to parental smoking may identify genes contributing to accelerated aging among. "
Reviewer 3 Report
Comments and Suggestions for Authors1. Highlight strengths and areas for improvement.
2. Be specific in your comments, suggesting how the authors can enhance their work.
3. Assess the scientific validity of the claims made.
4. Look for any biases or unsupported assertions.
5. The study utilizes data from the Health and Retirement Study, which is a robust and nationally representative dataset. The use of epigenetic clocks and polygenic risk scores is appropriate for addressing the research question. However, the methodology section would benefit from additional details on the calculation and validation of the polygenic risk scores and the epigenetic clocks used.
6. What is a home message?
7. The study uses data from the Health and Retirement Study (HRS) and employs epigenetic clocks and polygenic risk scores (PRS) to assess EAA. Evaluate whether the methods are adequately detailed and appropriate for the research question. Consider if the sample size and statistical analyses (e.g., regression models) are sufficient to support the study's conclusions.
8. Assess the study's scientific rigor, including the robustness of the methodology and the validity of the conclusions. Consider any potential biases or confounding factors that may affect the results.
Author Response
Comments 1: The study utilizes data from the Health and Retirement Study, which is a robust and nationally representative dataset. The use of epigenetic clocks and polygenic risk scores is appropriate for addressing the research question. However, the methodology section would benefit from additional details on the calculation and validation of the polygenic risk scores and the epigenetic clocks used.
Response 1: Thank you for the suggestion. We have now provided more details on the calculation and validation of the scores and clocks in the method section. Please refer to lines 107-115.
Comments 2: What is a home message?
Response 2: Thank you for the comment. Our take-home message is that childhood is a critical period during which smoking exposure may trigger lasting changes in the epigenome and accelerate aging till late adulthood, particularly among those with a high genetic susceptibility to smoking. We have now added the take-home message in the conclusion section of our manuscript. Please refer to lines 253-256.
Comments 3: The study uses data from the Health and Retirement Study (HRS) and employs epigenetic clocks and polygenic risk scores (PRS) to assess EAA. Evaluate whether the methods are adequately detailed and appropriate for the research question. Consider if the sample size and statistical analyses (e.g., regression models) are sufficient to support the study's conclusions.
Response 3: Thank you for the comment and suggestion. We have now provided more details on the PRS and EAAs in the methods section. Please refer to lines 107-115. The current study is the largest on this topic. We have followed similar regression models in previous studies. The sample size and statistical analyses should be sufficient to support the conclusions.
Comments 4: Assess the study's scientific rigor, including the robustness of the methodology and the validity of the conclusions. Consider any potential biases or confounding factors that may affect the results.
Response 4: Thank you for the comment. Childhood exposure to parental smoking was self-reported, which may introduce information bias. Nonetheless, such bias is likely non-differential between those with fast and slow aging, potentially biasing estimates toward the null and reducing statistical power to detect significant associations. Still, we detected significant associations of the exposure with EAAs, demonstrating the robustness of our findings. We have now discussed the information bias as a limitation. Please refer to lines 239-242. Another limitation is that the PRS was developed based on genome-wide association studies conducted predominantly among individuals of European ancestry. Its performance in Black participants was not optimal. Future studies with better PRS for Black participants are needed. We also included this as a limitation. Please refer to lines 242-246.
Round 2
Reviewer 3 Report
Comments and Suggestions for AuthorsThe Author responds to the comments.
