Abstract
Altered DNA methylation (DNAm) might be a biological intermediary in the pathway from smoking to lung cancer. In this study, we investigated the contribution of differential blood DNAm to explain the association between smoking and lung cancer incidence. Blood DNAm was measured in 2321 Strong Heart Study (SHS) participants. Incident lung cancer was assessed as time to event diagnoses. We conducted mediation analysis, including validation with DNAm and paired gene expression data from the Framingham Heart Study (FHS). In the SHS, current versus never smoking and pack-years single-mediator models showed, respectively, 29 and 21 differentially methylated positions (DMPs) for lung cancer with statistically significant mediated effects (14 of 20 available, and five of 14 available, positions, replicated, respectively, in FHS). In FHS, replicated DMPs showed gene expression downregulation largely in trans, and were related to biological pathways in cancer. The multimediator model identified that DMPs annotated to the genes AHRR and IER3 jointly explained a substantial proportion of lung cancer. Thus, the association of smoking with lung cancer was partly explained by differences in baseline blood DNAm at few relevant sites. Experimental studies are needed to confirm the biological role of identified eQTMs and to evaluate potential implications for early detection and control of lung cancer.
| Original language | English |
|---|---|
| Article number | 122153 |
| Journal | Environmental Pollution |
| Volume | 334 |
| DOIs | |
| Publication status | Published - 1 Oct 2023 |
Bibliographical note
Funding Information:ADR was supported by a fellowship from “ la Caixa” Foundation (ID 100010434 ) (fellowship code “ LCF/BQ/DR19/11740016 ”).
Funding Information:
MTP was supported by the Strategic Action for Research in Health sciences (CP12/03080 and PI15/00071 ) , which are initiatives from Instituto de Salud Carlos III and the Spanish Ministry of Science and Innovation and co-funded with European Funds for Regional Development ( FEDER ), by the Third AstraZeneca Award for Spanish Young Researchers (AstraZeneca, Spain), and by the State Agency for Research ( PID2019-108973RB- C21 ). The opinions and views expressed in this article are those of the authors and do not necessarily represent the official position of the Instituto de Salud Carlos III (Spain).
Funding Information:
The Framingham Heart Study (FHS) is funded by National Institutes of Health contract N01-HC-25195 . The laboratory work for this investigation was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institutes , National Institutes of Health and an NIH Director's Challenge Award (D. Levy, Principal Investigator).
Funding Information:
The Strong Heart Study is funded by grants from the National Heart, Lung, and Blood Institute (NHLBI) (contract numbers 75N92019D00027 , 75N92019D00028 , 75N92019D00029 and 75N92019D00030 ) and previous grants ( R01HL090863 , R01HL109315 , R01HL109301 , R01HL109284 , R01HL109282 , and R01HL109319 and cooperative agreements: U01HL41642 , U01HL41652 , U01HL41654 , U01HL65520 and U01HL65521 ) and by the National Institute of Environmental Health Sciences (grant numbers R01ES021367 , R01ES025216 , P42ES033719 , P30ES009089 ).
Funding Information:
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ana Navas-Acien reports financial support was provided by National Heart Lung and Blood Institute. Ana Navas-Acien reports financial support was provided by National Institute of Environmental Health Sciences. Daniel Levy reports financial support was provided by National Institutes of Health. Arce Domingo-Relloso reports financial support was provided by La Caixa Foundation. Maria Tellez-Plaza reports financial support provided by AstraZeneca Spain, the Instituto de Salud Carlos III and the Spanish Ministry of Science and Innovation and co-funded with European Funds for Regional Development.The Strong Heart Study is funded by grants from the National Heart, Lung, and Blood Institute (NHLBI) (contract numbers 75N92019D00027, 75N92019D00028, 75N92019D00029 and 75N92019D00030) and previous grants (R01HL090863, R01HL109315, R01HL109301, R01HL109284, R01HL109282, and R01HL109319 and cooperative agreements: U01HL41642, U01HL41652, U01HL41654, U01HL65520 and U01HL65521) and by the National Institute of Environmental Health Sciences (grant numbers R01ES021367, R01ES025216, P42ES033719, P30ES009089). The Framingham Heart Study (FHS) is funded by National Institutes of Health contract N01-HC-25195. The laboratory work for this investigation was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institutes, National Institutes of Health and an NIH Director's Challenge Award (D. Levy, Principal Investigator). ADR was supported by a fellowship from “la Caixa” Foundation (ID 100010434) (fellowship code “LCF/BQ/DR19/11740016”). MTP was supported by the Strategic Action for Research in Health sciences (CP12/03080 and PI15/00071), which are initiatives from Instituto de Salud Carlos III and the Spanish Ministry of Science and Innovation and co-funded with European Funds for Regional Development (FEDER), by the Third AstraZeneca Award for Spanish Young Researchers (AstraZeneca, Spain), and by the State Agency for Research (PID2019-108973RB- C21). The opinions and views expressed in this article are those of the authors and do not necessarily represent the official position of the Instituto de Salud Carlos III (Spain).
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