Jamaji C Nwanaji-Enwerem1, Andres Cardenas2, Peter R Chai3, Marc G Weisskopf4, Andrea A Baccarelli5, Edward W Boyer3. 1. Department of Environmental Health, Harvard T.H. Chan School of Public Health and MD-PhD Program, Harvard Medical School, Boston, MA. 2. Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim HealthCare Institute, Boston, MA. 3. Division of Medical Toxicology, Department of Emergency Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA. 4. Department of Environmental Health and Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA. 5. Department of Environmental Health Sciences, Columbia Mailman School of Public Health, New York, NY.
Abstract
INTRODUCTION: Currently, there is no widely accepted, non-self-report measure that simultaneously reflects smoking behaviors and is molecularly informative of general disease processes. Recently, researchers developed a smoking index (SI) using nucleated blood cells and a multi-tissue DNA methylation-based predictor of chronological age and disease (DNA methylation age [DNAm-age]). To better understand the utility of this novel SI in readily accessible cell types, we used buccal cell DNA methylation to examine SI relationships with long-term tobacco smoking and moist snuff consumption. METHODS: We used a publicly available dataset composed of buccal cell DNA methylation values from 120 middle-aged men (40 long-term smokers, 40 moist snuff consumers, and 40 nonsmokers). DNAm-age (353-CpGs) and SI (66-CpGs) were calculated using CpG sites measured using the Illumina HumanMethylation450 BeadChip. We estimated associations of tobacco consumption habits with both SI and DNAm-age using linear regression models adjusted for chronological age, race, and methylation technical covariates. RESULTS: In fully adjusted models with nonsmokers as the reference, smoking (β = 1.08, 95% CI = 0.82 to 1.33, p < .0001) but not snuff consumption (β = .06, 95% CI = -0.19 to 0.32, p = .63) was significantly associated with SI. SI was an excellent predictor of smoking versus nonsmoking (area under the curve = 0.92, 95% CI = 0.85 to 0.98). Four DNAm-age CpGs were differentially methylated between smokers and nonsmokers including cg14992253 [EIF3I], which has been previously shown to be differentially methylated with exposure to long-term fine-particle air pollution (PM2.5). CONCLUSIONS: The 66-CpG SI appears to be a useful tool for measuring smoking-specific behaviors in buccal cells. Still, further research is needed to broadly confirm our findings and SI relationships with DNAm-age. IMPLICATIONS: Our findings demonstrate that this 66-CpG blood-derived SI can reflect long-term tobacco smoking, but not long-term snuff consumption, in buccal cells. This evidence will be useful as the field works to identify an accurate non-self-report smoking biomarker that can be measured in an easily accessible tissue. Future research efforts should focus on (1) optimizing the relationship of the SI with DNAm-age so that the metric can maximize its utility as a tool for understanding general disease processes, and (2) determining normal values for the SI CpGs so that the measure is not as study sample specific.
INTRODUCTION: Currently, there is no widely accepted, non-self-report measure that simultaneously reflects smoking behaviors and is molecularly informative of general disease processes. Recently, researchers developed a smoking index (SI) using nucleated blood cells and a multi-tissue DNA methylation-based predictor of chronological age and disease (DNA methylation age [DNAm-age]). To better understand the utility of this novel SI in readily accessible cell types, we used buccal cell DNA methylation to examine SI relationships with long-term tobacco smoking and moist snuff consumption. METHODS: We used a publicly available dataset composed of buccal cell DNA methylation values from 120 middle-aged men (40 long-term smokers, 40 moist snuff consumers, and 40 nonsmokers). DNAm-age (353-CpGs) and SI (66-CpGs) were calculated using CpG sites measured using the Illumina HumanMethylation450 BeadChip. We estimated associations of tobacco consumption habits with both SI and DNAm-age using linear regression models adjusted for chronological age, race, and methylation technical covariates. RESULTS: In fully adjusted models with nonsmokers as the reference, smoking (β = 1.08, 95% CI = 0.82 to 1.33, p < .0001) but not snuff consumption (β = .06, 95% CI = -0.19 to 0.32, p = .63) was significantly associated with SI. SI was an excellent predictor of smoking versus nonsmoking (area under the curve = 0.92, 95% CI = 0.85 to 0.98). Four DNAm-age CpGs were differentially methylated between smokers and nonsmokers including cg14992253 [EIF3I], which has been previously shown to be differentially methylated with exposure to long-term fine-particle air pollution (PM2.5). CONCLUSIONS: The 66-CpG SI appears to be a useful tool for measuring smoking-specific behaviors in buccal cells. Still, further research is needed to broadly confirm our findings and SI relationships with DNAm-age. IMPLICATIONS: Our findings demonstrate that this 66-CpG blood-derived SI can reflect long-term tobacco smoking, but not long-term snuff consumption, in buccal cells. This evidence will be useful as the field works to identify an accurate non-self-report smoking biomarker that can be measured in an easily accessible tissue. Future research efforts should focus on (1) optimizing the relationship of the SI with DNAm-age so that the metric can maximize its utility as a tool for understanding general disease processes, and (2) determining normal values for the SI CpGs so that the measure is not as study sample specific.
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Authors: Jamaji C Nwanaji-Enwerem; Elena Colicino; Letizia Trevisi; Itai Kloog; Allan C Just; Jincheng Shen; Kasey Brennan; Alexandra Dereix; Lifang Hou; Pantel Vokonas; Joel Schwartz; Andrea A Baccarelli Journal: Environ Epigenet Date: 2016-06-12