Chest
Volume 142, Issue 2, August 2012, Pages 425-431
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Original Research
Asthma
Methylated Genes in Sputum Among Older Smokers With Asthma

https://doi.org/10.1378/chest.11-2519Get rights and content

Objective

The epigenetic basis for human asthma is not well studied, particularly among older adults. This study investigated the methylation profiles in sputum DNA among older adults with asthma, using a population of smokers.

Methods

This was a cross-sectional study using the Lovelace Smokers Cohort, a population of former and current smokers aged ≥ 40 years in New Mexico. One hundred eighty-four smokers with asthma were compared with 511 smoker control subjects with a similar smoking history, after carefully excluding those with COPD. Environmental exposures were assessed by a standard questionnaire. Postbronchodilator spirometry was performed. Induced sputum was analyzed for the methylation prevalence of 12 selected asthma-related genes using nested methylation-specific polymerase chain reaction assay.

Results

Asthma was associated with a greater number of methylated genes and, specifically, with methylated protocadherin-20 gene in sputum DNA compared with control subjects with a similar smoking history. These associations remained significant after adjustment for covariates as well as Bonferroni correction. A synergistic interaction was noted between two methylated genes (protocadherin-20 and paired box protein transcription factor-5α) in sputum DNA on the odds for asthma (P = .009). Interestingly, the epigenetic-asthma associations were not explained by the environmental factors studied. Further, methylated genes in sputum DNA, including the protocadherin-20 gene, identified a symptomatically more severe asthma phenotype in a subgroup analysis.

Conclusions

Asthma is associated with methylation of selected genes, such as protocadherin-20 gene, in sputum DNA. If future studies establish causality, novel demethylating interventions to prevent and treat asthma among older smokers may be possible.

Section snippets

Study Population

In this cross-sectional study, subjects were drawn from 1,861 eligible participants enrolled between 2001 and 2007 in the Lovelace Smokers Cohort, a well-characterized cohort in New Mexico.12, 13 This large cohort disproportionately enrolled women who had ever smoked to study the susceptibility to the development of obstructive lung disease, since women are underrepresented in most studies of airflow obstruction in the United States.14 The catchment area was Albuquerque, New Mexico, and its

Results

Smokers with asthma were more likely to have higher SGRQ scores (ie, greater respiratory symptoms, activity difficulties, and impact on daily life); greater prevalence of postbronchodilator spirometric obstruction26; and lower absolute postbronchodilator FEV1/FVC ratio, as compared with smoker control subjects (Table 1). In addition, smokers with asthma were more likely to be obese than smoker control subjects, in both unadjusted and adjusted analyses (Table 1, Table 2). Of particular note, the

Discussion

Older adult smokers with asthma demonstrate epigenetic changes in sputum DNA, specifically PCDH20 methylation, when compared with control subjects with a similar smoking history. We further demonstrate a synergistic interaction between two methylated genes (PCDH20 and PAX5α) in sputum DNA on the odds for asthma in this population. Interestingly, the epigenetic-asthma associations are not explained by the environmental factors studied, nor are the obesity-asthma associations explained by the

Acknowledgments

Author contributions: Dr Sood: contributed to conception and design of the study, drafting the article or revising it critically for important intellectual content, and approving the version to be published.

Mr Petersen: contributed to acquisition of data or analysis and interpretation of data, drafting the article or revising it critically for important intellectual content, and approving the version to be published.

Dr Blanchette: contributed to acquisition of data or analysis and

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    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.

    Funding/Support: This study was supported by the State of New Mexico (appropriation from the Tobacco Settlement Fund) and from the National Institutes of Health [Grants K23 HL 094531-01 and CTSA 1ULRR031977-01 (A. S.), RO1 ES015482 (Y. T.), and R01 CA 097356 (S. B.)].

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