Untargeted Metabolomics Reveals Multiple Metabolites influencing Smoking-Related DNA Methylation

Abstract

Aim: We conducted a joint metabolomic–epigenomic study to identify patterns of epigenetic associations with smoking-related metabolites. Patients & methods: We performed an untargeted metabolome-wide association study of smoking and epigenome-wide association studies of smoking-related metabolites among 180 male twins. We examined the patterns of epigenetic association linked to smoking-related metabolites using hierarchical clustering. Results: Among 12 annotated smoking-related metabolites identified from a metabolome-wide association study, we observed significant hypomethylation associated with increased level of N-acetylpyrrolidine, cotinine, 5-hydroxycotinine and nicotine and hypermethylation associated with increased level of 8-oxoguanine. Hierarchical clustering revealed common and unique epigenetic–metabolic associations related to smoking. Conclusion: Our study suggested that a joint metabolome–epigenome approach can reveal additional details in molecular responses to the environmental exposure to understand disease risk.

Keywords::

• epigenetic epidemiology
• epigenetics
• epigenome
• EWAS
• exposome
• metabolome
• metabolome-wide association study
• methylome
• metabolome-wide association study
• twin

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at www.tandfonline.com/doi/suppl/10.2217/epi-2017-0101

Acknowledgements

The authors thank the members of the VET Registry for their continued cooperation and participation.

Financial & competing interests disclosure

The United States Department of Veterans Affairs (VA) has provided financial support for the development and maintenance of the Vietnam Era Twin Registry. Numerous organizations have provided invaluable assistance, including VA Cooperative Study Program; Department of Defense; National Personnel Records Center; National Archives and Records Administration; the Internal Revenue Service; NIH; National Opinion Research Center; National Research Council, National Academy of Sciences; and the Institute for Survey Research, Temple University. This work was supported by the NIH (K24HL077506, R01 HL68630, R01 AG026255, R01 MH056120, R01 HL088726, R21 NS096455, R01 NR013520, P30 ES019776 and K24 MH076955); the National Institute of General Medical Sciences at the NIH (5K12 GM000680); the Emory University General Clinical Research Center (MO1-RR00039); and the American Heart Association (0245115N and 13GRNT17060002). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

The United States Department of Veterans Affairs (VA) has provided financial support for the development and maintenance of the Vietnam Era Twin Registry. Numerous organizations have provided invaluable assistance, including VA Cooperative Study Program; Department of Defense; National Personnel Records Center; National Archives and Records Administration; the Internal Revenue Service; NIH; National Opinion Research Center; National Research Council, National Academy of Sciences; and the Institute for Survey Research, Temple University. This work was supported by the NIH (K24HL077506, R01 HL68630, R01 AG026255, R01 MH056120, R01 HL088726, R21 NS096455, R01 NR013520, P30 ES019776 and K24 MH076955); the National Institute of General Medical Sciences at the NIH (5K12 GM000680); the Emory University General Clinical Research Center (MO1-RR00039); and the American Heart Association (0245115N and 13GRNT17060002). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.