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Am J Respir Crit Care Med. 2020 Jan 29. doi: 10.1164/rccm.201902-0439OC. [Epub ahead of print]

DNA Methylation is Predictive of Mortality in Current and Former Smokers.

Author information

1
Brigham & Women's Hospital, Channing Division of Network Medicine, Boston, Massachusetts, United States; remdj@channing.harvard.edu.
2
National Jewish Health, Denver , Colorado, United States.
3
National Jewish Health, Department of Medicine, Denver, Colorado, United States.
4
University of Michigan, Internal Medicine, Ann Arbor, Michigan, United States.
5
Brigham and Women's Hospital, Channing Laboratory, Boston, Massachusetts, United States.
6
GlaxoSmithKline R&D, Collegeville, Pennsylvania, United States.
7
Dana Farber Cancer Institute, 1855, Boston, Massachusetts, United States.
8
Cornell University Joan and Sanford I Weill Medical College, 12295, New York, New York, United States.
9
Brigham and Women's Hospital, 1861, Channing Division of Network Medicine, Boston, Massachusetts, United States.
10
Brigham and Womens, Boston, Massachusetts, United States.

Abstract

RATIONALE:

Smoking results in at least a decade lower life expectancy. Mortality among current smokers is two to three times as high as never smokers. DNA methylation is an epigenetic modification of the human genome that has been associated with both cigarette smoking and mortality.

OBJECTIVES:

We sought to identify DNA methylation marks in blood predictive of mortality in a subset of the COPDGene study, representing 101 deaths among 667 current and former smokers.

METHODS:

We assayed genome-wide DNA methylation in non-Hispanic white smokers with and without COPD using blood samples from the COPDGene enrollment visit. We tested whether DNA methylation was associated with mortality in models adjusted for COPD status, age, sex, current-smoking status, and pack-years of cigarette smoking. Replication was performed in a subset of 231 individuals from the ECLIPSE study.

RESULTS:

We identified seven CpG sites associated with mortality (FDR < 20%) that replicated in the ECLIPSE cohort (p < 0.05). None of these marks were associated with longitudinal lung function decline in survivors, smoking history or current smoking status. However, differential methylation of two replicated PIK3CD sites were associated with lung function at enrollment (p < 0.05). We also observed associations between DNA methylation and gene expression for the PIK3CD sites.

CONCLUSIONS:

This study is the first to identify variable DNA methylation associated with all-cause mortality in smokers with and without COPD. Evaluating predictive epigenomic marks of smokers in peripheral blood may allow for targeted risk stratification and aid in delivery of future tailored therapeutic interventions.

KEYWORDS:

COPD; DNA methylation; all-cause mortality; epigenetics; survival analysis

PMID:
31995399
DOI:
10.1164/rccm.201902-0439OC

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