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

Battram, Thomas; Richmond, Rebecca C; Baglietto, Laura; Haycock, Philip; Perduca, Vittorio; Bojesen, Stig E.; Gaunt, Tom R.; Hemani, Gibran; Guida, Florence; Carreras‐Torres, Robert; Hung, Rayjean J.; Amos, Christopher I.; Freeman, Jennifer B.; Sandanger, Torkjel M.; Nøst, Therese Haugdahl; Nordestgaard, Børge G.; Teschendorff, Andrew E.; Polidoro, Silvia; Víneis, Paolo; Severi, Gianluca; Hodge, Allison; Giles, Graham G.; Grankvist, Kjell; Johansson, Mikael; Johansson, Mattias; Smith, George Davey; Relton, Caroline L

doi:10.1093/ije/dyz190

Cited by 62 publications

(56 citation statements)

References 41 publications

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“…Our results, hence, do not support the hypothesis that smoking‐induced methylation changes mediate the effect of smoking on lung cancer risk. Similar conclusions were reached in a recent two‐step Mendelian randomization analysis …”

Section: Data Application: Smoking Dna Methylation and Lung Cancer supporting

confidence: 88%

Global test for high‐dimensional mediation: Testing groups of potential mediators

Djordjilović

Page

Gran

et al. 2019

Statistics in Medicine

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We address the problem of testing whether a possibly high-dimensional vector may act as a mediator between some exposure variable and the outcome of interest. We propose a global test for mediation, which combines a global test with the intersection-union principle. We discuss theoretical properties of our approach and conduct simulation studies that demonstrate that it performs equally well or better than its competitor. We also propose a multiple testing procedure, Screen-Min, that provides asymptotic control of either familywise error rate or false discovery rate when multiple groups of potential mediators are tested simultaneously. We apply our approach to data from a large Norwegian cohort study, where we look at the hypothesis that smoking increases the risk of lung cancer by modifying the level of DNA methylation. KEYWORDSfalse discovery rate, familywise error rate, high-dimensional data, multiple mediators 3346

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Section: Data Application: Smoking Dna Methylation and Lung Cancer supporting

confidence: 88%

Global test for high‐dimensional mediation: Testing groups of potential mediators

Djordjilović

Page

Gran

et al. 2019

Statistics in Medicine

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“…7 However, we found in MR analysis that there was no strong evidence for a causal effect of AHRR methylation on FEV 1 , indicating that it is unlikely to be mediating the effect of smoking on lung function. Similar conflicting findings have been observed between conventional mediation approaches and MR analysis aimed at determining epigenetic mediation in the context of smoking and lung cancer 49,50 and of prenatal famine and later-life metabolic profile. 51,52 Traditional mediation approaches are more susceptible to measurement error and potential reverse causation than MR, 53 meaning the proportion of the mediated effect reported by these studies is likely to be overestimated.…”

Section: Comparison With Other Studiesmentioning

confidence: 55%

Smoking, DNA Methylation, and Lung Function: a Mendelian Randomization Analysis to Investigate Causal Pathways

Jamieson

Korologou-Linden

Wootton

et al. 2020

The American Journal of Human Genetics

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Whether smoking-associated DNA methylation has a causal effect on lung function has not been thoroughly evaluated. We first investigated the causal effects of 474 smoking-associated CpGs on forced expiratory volume in 1 s (FEV 1) in UK Biobank (n ¼ 321,047) by using two-sample Mendelian randomization (MR) and then replicated this investigation in the SpiroMeta Consortium (n ¼ 79,055). Second, we used two-step MR to investigate whether DNA methylation mediates the effect of smoking on FEV 1. Lastly, we evaluated the presence of horizontal pleiotropy and assessed whether there is any evidence for shared causal genetic variants between lung function, DNA methylation, and gene expression by using a multiple-trait colocalization (''moloc'') framework. We found evidence of a possible causal effect for DNA methylation on FEV 1 at 18 CpGs (p < 1.2 3 10 À4). Replication analysis supported a causal effect at three CpGs (cg21201401 [LIME1 and ZGPAT], cg19758448 [PGAP3], and cg12616487 [EML3 and AHNAK] [p < 0.0028]). DNA methylation did not clearly mediate the effect of smoking on FEV 1 , although DNA methylation at some sites might influence lung function via effects on smoking. By using ''moloc'', we found evidence of shared causal variants between lung function, gene expression, and DNA methylation. These findings highlight potential therapeutic targets for improving lung function and possibly smoking cessation, although larger, tissue-specific datasets are required to confirm these results.

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“…In the population-based study by Bojesen et al of approximately 23% never smokers and current/former smokers with mean smoking histories of fewer than 40 pack years, an over four-fold increased risk of lung cancer for individuals in the lowest versus highest methylation quintiles (95% CI: 2.31–10.30) was observed after adjusting for smoking status, cigarettes per day, and pack years [ 9 ]. In four publications reporting on combinations of study populations from up to five nested case-control studies, with each individual nested case-control study comprised of 63 to 367 pairs, statistically significant 40–60% increased risks of lung cancer per standard deviation decrease in cg05575921 methylation were reported [ 4 , 19 , 21 , 22 ]. These results maintained statistical significance after adjustment for smoking for all but one study, which reported a statistically significant 63% increased risk that was attenuated and no longer statistically significant after controlling for smoking features (e.g., smoking status, pack years, comprehensive smoking index) [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

AHRR methylation in heavy smokers: associations with smoking, lung cancer risk, and lung cancer mortality

et al. 2020

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Background A low level of methylation at cg05575921 in the aryl-hydrocarbon receptor repressor (AHRR) gene is robustly associated with smoking, and some studies have observed associations between cg05575921 methylation and increased lung cancer risk and mortality. To prospectively examine whether decreased methylation at cg05575921 may identify high risk subpopulations for lung cancer screening among heavy smokers, and mortality in cases, we evaluated associations between cg05575921 methylation and lung cancer risk and mortality, by histotype, in heavy smokers. Methods The β-Carotene and Retinol Efficacy Trial (CARET) included enrollees ages 45–69 with ≥ 20 pack-year smoking histories and/or occupational asbestos exposure. A subset of CARET participants had cg05575921 methylation available from HumanMethylationEPIC assays of blood collected on average 4.3 years prior to lung cancer diagnosis in cases. Cg05575921 methylation β-values were treated continuously for a 10% methylation decrease and as quintiles, where quintile 1 (Q1, referent) represents high methylation and Q5, low methylation. We used conditional logistic regression models to examine lung cancer risk overall and by histotype in a nested case-control study including 316 lung cancer cases (diagnosed through 2005) and 316 lung cancer-free controls matched on age (±5 years), sex, race/ethnicity, enrollment year, current/former smoking, asbestos exposure, and follow-up time. Mortality analyses included 372 lung cancer cases diagnosed between 1985 and 2013 with available methylation data. We used Cox proportional hazards models to examine mortality overall and by histotype. Results Decreased cg05575921 methylation was strongly associated with smoking, even in our population of heavy smokers. We did not observe associations between decreased pre-diagnosis cg05575921 methylation and increased lung cancer risk, overall or by histotype. We observed linear increasing trends for lung cancer-specific mortality across decreasing cg05575921 methylation quintiles for adenocarcinoma and small cell carcinoma (P-trends = 0.01 and 0.04, respectively). Conclusions In our study of heavy smokers, decreased cg05575921 methylation was strongly associated with smoking but not increased lung cancer risk. The observed association between cg05575921 methylation and increased mortality in adenocarcinoma and small cell histotypes requires further examination. Our results do not support using decreased cg05575921 methylation as a biomarker for lung cancer screening risk stratification.

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

Cited by 62 publications

References 41 publications

Global test for high‐dimensional mediation: Testing groups of potential mediators

Global test for high‐dimensional mediation: Testing groups of potential mediators

Smoking, DNA Methylation, and Lung Function: a Mendelian Randomization Analysis to Investigate Causal Pathways

AHRR methylation in heavy smokers: associations with smoking, lung cancer risk, and lung cancer mortality

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