Journal
INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
Volume 50, Issue 5, Pages 1482-1497Publisher
OXFORD UNIV PRESS
DOI: 10.1093/ije/dyab044
Keywords
Causal inference; EWAS; Mendelian randomization
Categories
Funding
- Faculty of Medicine and Health Sciences at NTNU
- Central Norway Regional Health Authority
- Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6]
- Scottish Funding Council [HR03006]
- Medical Research Council UK
- Wellcome Trust [104036/Z/14/Z]
- Wellcome Trust [104036/Z/14/Z] Funding Source: researchfish
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This study identified smoking-related DNA methylation sites in blood and assessed their causal role between smoking and lung cancer risk. While smoking was found to have a causal effect on DNA methylation, there was no evidence for a causal link between DNA methylation and the risk of lung cancer.
Background: It is unclear if smoking-related DNA methylation represents a causal pathway between smoking and risk of lung cancer. We sought to identify novel smoking-related DNA methylation sites in blood, with repeated measurements, and to appraise the putative role of DNA methylation in the pathway between smoking and lung cancer development. Methods: We derived a nested case-control study from the Trondelag Health Study (HUNT), including 140 incident patients who developed lung cancer during 2009-13 and 140 controls. We profiled 850 K DNA methylation sites (Illumina Infinium EPIC array) in DNA extracted from blood that was collected in HUNT2 (1995-97) and HUNT3 (2006-08) for the same individuals. Epigenome-wide association studies (EWAS) were performed for a detailed smoking phenotype and for lung cancer. Two-step Mendelian randomization (MR) analyses were performed to assess the potential causal effect of smoking on DNA methylation as well as of DNA methylation (13 sites as putative mediators) on risk of lung cancer. Results: The EWAS for smoking in HUNT2 identified associations at 76 DNA methylation sites (P<5 x 10(-8)), including 16 novel sites. Smoking was associated with DNA hypomethylation in a dose-response relationship among 83% of the 76 sites, which was confirmed by analyses using repeated measurements from blood that was collected at 11 years apart for the same individuals. Two-step MR analyses showed evidence for a causal effect of smoking on DNA methylation but no evidence for a causal link between DNA methylation and the risk of lung cancer. Conclusions: DNA methylation modifications in blood did not seem to represent a causal pathway linking smoking and the lung cancer risk.
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