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

被引：49

作者：

Battram, Thomas ^{[1
,2
]}

Richmond, Rebecca C. ^{[1
,2
]}

Baglietto, Laura ^{[3
]}

Haycock, Philip C. ^{[1
,2
]}

Perduca, Vittorio ^{[4
]}

Bojesen, Stig E. ^{[5
,6
,7
]}

Gaunt, Tom R. ^{[1
,2
]}

Hemani, Gibran ^{[1
,2
]}

Guida, Florence ^{[8
]}

Carreras-Torres, Robert ^{[8
]}

Hung, Rayjean ^{[9
]}

Amos, Christopher, I ^{[10
]}

Freeman, Joshua R. ^{[11
]}

Sandanger, Torkjel M. ^{[12
]}

Nost, Therese H. ^{[12
]}

Nordestgaard, Borge G. ^{[5
,6
,7
]}

Teschendorff, Andrew E. ^{[13
,14
,15
]}

Polidoro, Silvia ^{[16
]}

Vineis, Paolo ^{[16
,17
]}

Severi, Gianluca ^{[18
,19
,20
]}

Hodge, Allison M. ^{[19
,20
]}

Giles, Graham G. ^{[19
,20
]}

Grankvist, Kjell ^{[21
]}

Johansson, Mikael B. ^{[22
]}

Johansson, Mattias ^{[8
]}

Smith, George Davey ^{[1
,2
]}

Relton, Caroline L. ^{[1
,2
]}

机构：

[1] Univ Bristol, MRC Integrat Epidemiol Unit, Bristol, Avon, England

[2] Univ Bristol, Populat Hlth Sci, Bristol, Avon, England

[3] Univ Pisa, Dept Clin & Expt Med, Pisa, Italy

[4] Univ Paris 05, Lab Math Appl, Paris, France

[5] Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Clin Biochem, Herlev, Denmark

[6] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark

[7] Copenhagen Univ Hosp, Frederiksberg Hosp, Copenhagen City Heart Study, Copenhagen, Denmark

[8] Int Agcy Res Canc, Genet Epidemiol Div, Lyon, France

[9] Sinai Hlth Syst, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada

[10] Dartmouth Coll, Biomed Data Sci, Geisel Sch Med, Hanover, NH 03755 USA

[11] Univ Massachusetts, Dept Biostat & Epidemiol, Amherst, MA 01003 USA

[12] Arctic Univ Norway, Dept Community Med, Tromso, Norway

[13] UCL, Inst Womens Hlth, Dept Womens Canc, London, England

[14] UCL, UCL Canc Inst, London, England

[15] Chinese Acad Sci, CAS Max Planck Gesell MPG Partner Inst Computat B, Key Lab Computat Biol, Shanghai, Peoples R China

[16] IIGM, Mol & Genet Epidemiol Unit, Turin, Italy

[17] Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England

[18] Univ Paris Saclay, Univ Paris Sud, CESP Inserm U1018, UVSQ,Fac Med, F-94805 Villejuif, France

[19] Canc Council Victoria, Canc Epidemiol & Intelligence Div, Melbourne, Vic, Australia

[20] Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne Sch Populat & Global Hlth, Melbourne, Vic, Australia

[21] Umea Univ, Dept Med Biosci Clin Chem, Umea, Sweden

[22] Umea Univ, Dept Radiat Sci, Umea, Sweden

来源：

INTERNATIONAL JOURNAL OF EPIDEMIOLOGY | 2019年 / 48卷 / 05期

基金：

英国生物技术与生命科学研究理事会; 芬兰科学院; 英国医学研究理事会; 英国惠康基金;

关键词：

Lung cancer; DNA methylation; Mendelian randomization; ALSPAC; ARIES; MENDELIAN RANDOMIZATION; SMOKING; ASSOCIATION; BIAS; INSTRUMENTS; EFFICIENT; DESIGN; LOCI;

D O I：

10.1093/ije/dyz190

中图分类号：

R1 [预防医学、卫生学];

学科分类号：

1004 ; 120402 ;

摘要：

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.

引用

页码：1493 / 1504

页数：12

共 40 条

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