德纳姆
肺癌
DNA甲基化
癌症
弗雷明翰心脏研究
医学
肿瘤科
全血
内科学
生物
基因
弗雷明翰风险评分
基因表达
遗传学
疾病
作者
Arce Domingo‐Relloso,Roby Joehanes,Zulema Rodriguez-Hernandez,Lies Lahousse,Karin Haack,M. Daniele Fallin,Miguel Herreros-Martinez,Jason G. Umans,Lyle G. Best,Tianxiao Huan,Chunyu Liu,Jiantao Ma,Chen Yao,Allan Jérolon,José D. Bermúdez,Shelley A. Cole,Dorothy A. Rhoades,Daniel Levy,Ana Navas‐Acien,María Téllez-Plaza
标识
DOI:10.1016/j.envpol.2023.122153
摘要
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.
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