Dataset Information

Appraising the causal relevance of DNA methylation for risk of lung cancer.

ABSTRACT:

Background

DNA methylation changes in peripheral blood have recently been identified in relation to lung cancer risk. Some of these changes have been suggested to mediate part of the effect of smoking on lung cancer. However, limitations with conventional mediation analyses mean that the causal nature of these methylation changes has yet to be fully elucidated.

Methods

We first performed a meta-analysis of four epigenome-wide association studies (EWAS) of lung cancer (918 cases, 918 controls). Next, we conducted a two-sample Mendelian randomization analysis, using genetic instruments for methylation at CpG sites identified in the EWAS meta-analysis, and 29 863 cases and 55 586 controls from the TRICL-ILCCO lung cancer consortium, to appraise the possible causal role of methylation at these sites on lung cancer.

Results

Sixteen CpG sites were identified from the EWAS meta-analysis [false discovery rate (FDR) < 0.05], for 14 of which we could identify genetic instruments. Mendelian randomization provided little evidence that DNA methylation in peripheral blood at the 14 CpG sites plays a causal role in lung cancer development (FDR?>?0.05), including for cg05575921-AHRR where methylation is strongly associated with both smoke exposure and lung cancer risk.

Conclusions

The results contrast with previous observational and mediation analysis, which have made strong claims regarding the causal role of DNA methylation. Thus, previous suggestions of a mediating role of methylation at sites identified in peripheral blood, such as cg05575921-AHRR, could be unfounded. However, this study does not preclude the possibility that differential DNA methylation at other sites is causally involved in lung cancer development, especially within lung tissue.

SUBMITTER: Battram T

PROVIDER: S-EPMC6857764 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Appraising the causal relevance of DNA methylation for risk of lung cancer.

Battram Thomas T Richmond Rebecca C RC Baglietto Laura L Haycock Philip C PC Perduca Vittorio V Bojesen Stig E SE Gaunt Tom R TR Hemani Gibran G Guida Florence F Carreras-Torres Robert R Hung Rayjean R Amos Christopher I CI Freeman Joshua R JR Sandanger Torkjel M TM Nøst Therese H TH Nordestgaard Børge G BG Teschendorff Andrew E AE Polidoro Silvia S Vineis Paolo P Severi Gianluca G Hodge Allison M AM Giles Graham G GG Grankvist Kjell K Johansson Mikael B MB Johansson Mattias M Davey Smith George G Relton Caroline L CL

International journal of epidemiology 20191001 5

<h4>Background</h4>DNA methylation changes in peripheral blood have recently been identified in relation to lung cancer risk. Some of these changes have been suggested to mediate part of the effect of smoking on lung cancer. However, limitations with conventional mediation analyses mean that the causal nature of these methylation changes has yet to be fully elucidated.<h4>Methods</h4>We first performed a meta-analysis of four epigenome-wide association studies (EWAS) of lung cancer (918 cases, 9 ...[more]

PMID: 31549173

Similar Datasets

Project description:ObjectivesTo develop a new methodology to systematically compare evidence across diverse risk markers for coronary heart disease and to compare this evidence with guideline recommendations.Design"Horizontal" systematic review incorporating different sources of evidence.Data sourcesElectronic search of Medline and hand search of guidelines. Study selection Two reviewers independently determined eligibility of studies across three sources of evidence (observational studies, genetic association studies, and randomised controlled trials) related to four risk markers: depression, exercise, C reactive protein, and type 2 diabetes. Data extraction For each risk marker, the largest meta-analyses of observational studies and genetic association studies, and meta-analyses or individual randomised controlled trials were analysed.ResultsMeta-analyses of observational studies reported adjusted relative risks of coronary heart disease for depression of 1.9 (95% confidence interval 1.5 to 2.4), for top compared with bottom fourths of exercise 0.7 (0.5 to 1.0), for top compared with bottom thirds of C reactive protein 1.6 (1.5 to 1.7), and for diabetes in women 3.0 (2.4 to 3.7) and in men 2.0 (1.8 to 2.3). Prespecified study limitations were more common for depression and exercise. Meta-analyses of studies that allowed formal Mendelian randomisation were identified for C reactive protein (and did not support a causal effect), and were lacking for exercise, diabetes, and depression. Randomised controlled trials were not available for depression, exercise, or C reactive protein in relation to incidence of coronary heart disease, but trials in patients with diabetes showed some preventive effect of glucose control on risk of coronary heart disease. None of the four randomised controlled trials of treating depression in patients with coronary heart disease reduced the risk of further coronary events. Comparisons of this horizontal evidence review with two guidelines published in 2007 showed inconsistencies, with depression prioritised more in the guidelines than in our review.ConclusionsThis horizontal systematic review pinpoints deficiencies and strengths in the evidence for depression, exercise, C reactive protein, and diabetes as unconfounded and unbiased causes of coronary heart disease. This new method could be used to develop a field synopsis and prioritise future development of guidelines and research.

Dataset Information

Appraising the causal relevance of DNA methylation for risk of lung cancer.

Background

Methods

Results

Conclusions

Publications

Appraising the causal relevance of DNA methylation for risk of lung cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets