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Hypomethylation of smoking-related genes is associated with future lung cancer in four prospective cohorts

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Hypomethylation of smoking-related genes is associated with future lung cancer in four prospective cohorts

Auteurs : Francesca Fasanelli [Italie] ; Laura Baglietto [France, Australie] ; Erica Ponzi [Italie] ; Florence Guida [Royaume-Uni] ; Gianluca Campanella [Royaume-Uni] ; Mattias Johansson [France, Suède] ; Kjell Grankvist [Suède] ; Mikael Johansson [Suède] ; Manuela Bianca Assumma [Italie] ; Alessio Naccarati [Italie] ; Marc Chadeau-Hyam [Royaume-Uni] ; Ugo Ala [Italie] ; Christian Faltus [Allemagne] ; Rudolf Kaaks [Allemagne] ; Angela Risch [Allemagne, Autriche] ; Bianca De Stavola [Royaume-Uni] ; Allison Hodge [Australie] ; Graham G. Giles [Australie] ; Melissa C. Southey [Australie] ; Caroline L. Relton [Royaume-Uni] ; Philip C. Haycock [Royaume-Uni] ; Eiliv Lund [Norvège] ; Silvia Polidoro [Italie] ; Torkjel M. Sandanger [Norvège] ; Gianluca Severi [Italie, France, Australie] ; Paolo Vineis [Italie, Royaume-Uni]

Source :

Nature Communications [ 2041-1723 ] ; 2015.

RBID : PMC:4682166

Abstract

DNA hypomethylation in certain genes is associated with tobacco exposure but it is unknown whether these methylation changes translate into increased lung cancer risk. In an epigenome-wide study of DNA from pre-diagnostic blood samples from 132 case–control pairs in the NOWAC cohort, we observe that the most significant associations with lung cancer risk are for cg05575921 in AHRR (OR for 1 s.d.=0.37, 95% CI: 0.31–0.54, P-value=3.3 × 10⁻¹¹) and cg03636183 in F2RL3 (OR for 1 s.d.=0.40, 95% CI: 0.31–0.56, P-value=3.9 × 10⁻¹⁰), previously shown to be strongly hypomethylated in smokers. These associations remain significant after adjustment for smoking and are confirmed in additional 664 case–control pairs tightly matched for smoking from the MCCS, NSHDS and EPIC HD cohorts. The replication and mediation analyses suggest that residual confounding is unlikely to explain the observed associations and that hypomethylation of these CpG sites may mediate the effect of tobacco on lung cancer risk.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4682166

DOI: 10.1038/ncomms10192
PubMed: 26667048
PubMed Central: 4682166

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<affiliation wicri:level="1"><nlm:aff id="a9"><institution>Department of Biobank Research, Umeå University</institution>
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<author><name sortKey="Ala, Ugo" sort="Ala, Ugo" uniqKey="Ala U" first="Ugo" last="Ala">Ugo Ala</name>
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<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Faltus, Christian" sort="Faltus, Christian" uniqKey="Faltus C" first="Christian" last="Faltus">Christian Faltus</name>
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<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Kaaks, Rudolf" sort="Kaaks, Rudolf" uniqKey="Kaaks R" first="Rudolf" last="Kaaks">Rudolf Kaaks</name>
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</nlm:aff>
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<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<affiliation wicri:level="1"><nlm:aff id="a14"><institution>Translational Lung Research Center Heidelberg, Member of the German Center for Lung Research (DZL)</institution>
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</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Risch, Angela" sort="Risch, Angela" uniqKey="Risch A" first="Angela" last="Risch">Angela Risch</name>
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, Heidelberg 69121,<country>Germany</country>
</nlm:aff>
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<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<affiliation wicri:level="1"><nlm:aff id="a14"><institution>Translational Lung Research Center Heidelberg, Member of the German Center for Lung Research (DZL)</institution>
, Heidelberg 69120,<country>Germany</country>
</nlm:aff>
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<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<affiliation wicri:level="1"><nlm:aff id="a15"><institution>Division of Cancer Research and Epigenetics, Department of Molecular Biology, University of Salzburg</institution>
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</nlm:aff>
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<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="De Stavola, Bianca" sort="De Stavola, Bianca" uniqKey="De Stavola B" first="Bianca" last="De Stavola">Bianca De Stavola</name>
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<author><name sortKey="Hodge, Allison" sort="Hodge, Allison" uniqKey="Hodge A" first="Allison" last="Hodge">Allison Hodge</name>
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<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<affiliation wicri:level="1"><nlm:aff id="a6"><institution>School of Population and Global Health, Centre for Epidemiology and Biostatistics, University of Melbourne</institution>
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</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Southey, Melissa C" sort="Southey, Melissa C" uniqKey="Southey M" first="Melissa C." last="Southey">Melissa C. Southey</name>
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</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Relton, Caroline L" sort="Relton, Caroline L" uniqKey="Relton C" first="Caroline L." last="Relton">Caroline L. Relton</name>
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 BS8 2BN,<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
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<author><name sortKey="Haycock, Philip C" sort="Haycock, Philip C" uniqKey="Haycock P" first="Philip C." last="Haycock">Philip C. Haycock</name>
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 BS8 2BN,<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Lund, Eiliv" sort="Lund, Eiliv" uniqKey="Lund E" first="Eiliv" last="Lund">Eiliv Lund</name>
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</nlm:aff>
<country xml:lang="fr">Norvège</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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</author>
<author><name sortKey="Polidoro, Silvia" sort="Polidoro, Silvia" uniqKey="Polidoro S" first="Silvia" last="Polidoro">Silvia Polidoro</name>
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</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
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<author><name sortKey="Sandanger, Torkjel M" sort="Sandanger, Torkjel M" uniqKey="Sandanger T" first="Torkjel M." last="Sandanger">Torkjel M. Sandanger</name>
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</nlm:aff>
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<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Severi, Gianluca" sort="Severi, Gianluca" uniqKey="Severi G" first="Gianluca" last="Severi">Gianluca Severi</name>
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</nlm:aff>
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</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a4"><institution>Paris-South University</institution>
, Villejuif 91450,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a5"><institution>Department of Genetic Epidemiology, Cancer Epidemiology Centre, Cancer Council of Victoria</institution>
, Melbourne, Victoria 3004,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a6"><institution>School of Population and Global Health, Centre for Epidemiology and Biostatistics, University of Melbourne</institution>
, Melbourne, Victoria 3010,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Vineis, Paolo" sort="Vineis, Paolo" uniqKey="Vineis P" first="Paolo" last="Vineis">Paolo Vineis</name>
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, Torino 10126,<country>Italy</country>
</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a7"><institution>MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Norfolk Place</institution>
, London W2 1PG,<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Hypomethylation of smoking-related genes is associated with future lung cancer in four prospective cohorts</title>
<author><name sortKey="Fasanelli, Francesca" sort="Fasanelli, Francesca" uniqKey="Fasanelli F" first="Francesca" last="Fasanelli">Francesca Fasanelli</name>
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, Torino 10126,<country>Italy</country>
</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a2"><institution>Unit of Cancer Epidemiology, Citta' della Salute e della Scienza Hospital-University of Turin, Center for Cancer Prevention</institution>
, Via Santena 7, Torino 10126,<country>Italy</country>
</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Baglietto, Laura" sort="Baglietto, Laura" uniqKey="Baglietto L" first="Laura" last="Baglietto">Laura Baglietto</name>
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, U1018, Team 9, 114 rue Edouard Vaillant, Villejuif 94805,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a4"><institution>Paris-South University</institution>
, Villejuif 91450,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a5"><institution>Department of Genetic Epidemiology, Cancer Epidemiology Centre, Cancer Council of Victoria</institution>
, Melbourne, Victoria 3004,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
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, Melbourne, Victoria 3010,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Ponzi, Erica" sort="Ponzi, Erica" uniqKey="Ponzi E" first="Erica" last="Ponzi">Erica Ponzi</name>
<affiliation wicri:level="1"><nlm:aff id="a1"><institution>Molecular end Epidemiology Unit, HuGeF, Human Genetics Foundation</institution>
, Torino 10126,<country>Italy</country>
</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Guida, Florence" sort="Guida, Florence" uniqKey="Guida F" first="Florence" last="Guida">Florence Guida</name>
<affiliation wicri:level="1"><nlm:aff id="a7"><institution>MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Norfolk Place</institution>
, London W2 1PG,<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Campanella, Gianluca" sort="Campanella, Gianluca" uniqKey="Campanella G" first="Gianluca" last="Campanella">Gianluca Campanella</name>
<affiliation wicri:level="1"><nlm:aff id="a7"><institution>MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Norfolk Place</institution>
, London W2 1PG,<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Johansson, Mattias" sort="Johansson, Mattias" uniqKey="Johansson M" first="Mattias" last="Johansson">Mattias Johansson</name>
<affiliation wicri:level="1"><nlm:aff id="a8"><institution>Genetic Epidemiology Division, International Agency for Research on Cancer</institution>
, Lyon 69008,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a9"><institution>Department of Biobank Research, Umeå University</institution>
, Umeå SE—90187,<country>Sweden</country>
</nlm:aff>
<country xml:lang="fr">Suède</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Grankvist, Kjell" sort="Grankvist, Kjell" uniqKey="Grankvist K" first="Kjell" last="Grankvist">Kjell Grankvist</name>
<affiliation wicri:level="1"><nlm:aff id="a9"><institution>Department of Biobank Research, Umeå University</institution>
, Umeå SE—90187,<country>Sweden</country>
</nlm:aff>
<country xml:lang="fr">Suède</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Johansson, Mikael" sort="Johansson, Mikael" uniqKey="Johansson M" first="Mikael" last="Johansson">Mikael Johansson</name>
<affiliation wicri:level="1"><nlm:aff id="a10"><institution>Department of Radiation Sciences, Umeå University</institution>
, Umeå SE—90187,<country>Sweden</country>
</nlm:aff>
<country xml:lang="fr">Suède</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Assumma, Manuela Bianca" sort="Assumma, Manuela Bianca" uniqKey="Assumma M" first="Manuela Bianca" last="Assumma">Manuela Bianca Assumma</name>
<affiliation wicri:level="1"><nlm:aff id="a1"><institution>Molecular end Epidemiology Unit, HuGeF, Human Genetics Foundation</institution>
, Torino 10126,<country>Italy</country>
</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Naccarati, Alessio" sort="Naccarati, Alessio" uniqKey="Naccarati A" first="Alessio" last="Naccarati">Alessio Naccarati</name>
<affiliation wicri:level="1"><nlm:aff id="a1"><institution>Molecular end Epidemiology Unit, HuGeF, Human Genetics Foundation</institution>
, Torino 10126,<country>Italy</country>
</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Chadeau Hyam, Marc" sort="Chadeau Hyam, Marc" uniqKey="Chadeau Hyam M" first="Marc" last="Chadeau-Hyam">Marc Chadeau-Hyam</name>
<affiliation wicri:level="1"><nlm:aff id="a7"><institution>MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Norfolk Place</institution>
, London W2 1PG,<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Ala, Ugo" sort="Ala, Ugo" uniqKey="Ala U" first="Ugo" last="Ala">Ugo Ala</name>
<affiliation wicri:level="1"><nlm:aff id="a11"><institution>Department of Molecular Biotechnology and Health Sciences, Università di Torino</institution>
, Torino 10126,<country>Italy</country>
</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Faltus, Christian" sort="Faltus, Christian" uniqKey="Faltus C" first="Christian" last="Faltus">Christian Faltus</name>
<affiliation wicri:level="1"><nlm:aff id="a12"><institution>Division of Epigenomics and Cancer Risk Factors, DKFZ—German Cancer Research Center</institution>
, Heidelberg 69121,<country>Germany</country>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Kaaks, Rudolf" sort="Kaaks, Rudolf" uniqKey="Kaaks R" first="Rudolf" last="Kaaks">Rudolf Kaaks</name>
<affiliation wicri:level="1"><nlm:aff id="a13"><institution>Division of Cancer Epidemiology, DKFZ—German Cancer Research Center</institution>
, Heidelberg 69121,<country>Germany</country>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a14"><institution>Translational Lung Research Center Heidelberg, Member of the German Center for Lung Research (DZL)</institution>
, Heidelberg 69120,<country>Germany</country>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Risch, Angela" sort="Risch, Angela" uniqKey="Risch A" first="Angela" last="Risch">Angela Risch</name>
<affiliation wicri:level="1"><nlm:aff id="a12"><institution>Division of Epigenomics and Cancer Risk Factors, DKFZ—German Cancer Research Center</institution>
, Heidelberg 69121,<country>Germany</country>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a14"><institution>Translational Lung Research Center Heidelberg, Member of the German Center for Lung Research (DZL)</institution>
, Heidelberg 69120,<country>Germany</country>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a15"><institution>Division of Cancer Research and Epigenetics, Department of Molecular Biology, University of Salzburg</institution>
, Salzburg 5020,<country>Austria</country>
</nlm:aff>
<country xml:lang="fr">Autriche</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="De Stavola, Bianca" sort="De Stavola, Bianca" uniqKey="De Stavola B" first="Bianca" last="De Stavola">Bianca De Stavola</name>
<affiliation wicri:level="1"><nlm:aff id="a16"><institution>Department of Medical Statistics, London School of Hygiene and Tropical Medicine</institution>
, London WC1E 7HT,<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Hodge, Allison" sort="Hodge, Allison" uniqKey="Hodge A" first="Allison" last="Hodge">Allison Hodge</name>
<affiliation wicri:level="1"><nlm:aff id="a5"><institution>Department of Genetic Epidemiology, Cancer Epidemiology Centre, Cancer Council of Victoria</institution>
, Melbourne, Victoria 3004,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Giles, Graham G" sort="Giles, Graham G" uniqKey="Giles G" first="Graham G." last="Giles">Graham G. Giles</name>
<affiliation wicri:level="1"><nlm:aff id="a5"><institution>Department of Genetic Epidemiology, Cancer Epidemiology Centre, Cancer Council of Victoria</institution>
, Melbourne, Victoria 3004,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a6"><institution>School of Population and Global Health, Centre for Epidemiology and Biostatistics, University of Melbourne</institution>
, Melbourne, Victoria 3010,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Southey, Melissa C" sort="Southey, Melissa C" uniqKey="Southey M" first="Melissa C." last="Southey">Melissa C. Southey</name>
<affiliation wicri:level="1"><nlm:aff id="a17"><institution>Genetic Epidemiology Laboratory, University of Melbourne</institution>
, Melbourne, Victoria 3010,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Relton, Caroline L" sort="Relton, Caroline L" uniqKey="Relton C" first="Caroline L." last="Relton">Caroline L. Relton</name>
<affiliation wicri:level="1"><nlm:aff id="a18"><institution>MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol</institution>
 BS8 2BN,<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Haycock, Philip C" sort="Haycock, Philip C" uniqKey="Haycock P" first="Philip C." last="Haycock">Philip C. Haycock</name>
<affiliation wicri:level="1"><nlm:aff id="a18"><institution>MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol</institution>
 BS8 2BN,<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Lund, Eiliv" sort="Lund, Eiliv" uniqKey="Lund E" first="Eiliv" last="Lund">Eiliv Lund</name>
<affiliation wicri:level="1"><nlm:aff id="a19"><institution>Department of Community Medicine UiT–The Arctic University of Norway</institution>
, Tromso 9019,<country>Norway</country>
</nlm:aff>
<country xml:lang="fr">Norvège</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Polidoro, Silvia" sort="Polidoro, Silvia" uniqKey="Polidoro S" first="Silvia" last="Polidoro">Silvia Polidoro</name>
<affiliation wicri:level="1"><nlm:aff id="a1"><institution>Molecular end Epidemiology Unit, HuGeF, Human Genetics Foundation</institution>
, Torino 10126,<country>Italy</country>
</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Sandanger, Torkjel M" sort="Sandanger, Torkjel M" uniqKey="Sandanger T" first="Torkjel M." last="Sandanger">Torkjel M. Sandanger</name>
<affiliation wicri:level="1"><nlm:aff id="a19"><institution>Department of Community Medicine UiT–The Arctic University of Norway</institution>
, Tromso 9019,<country>Norway</country>
</nlm:aff>
<country xml:lang="fr">Norvège</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Severi, Gianluca" sort="Severi, Gianluca" uniqKey="Severi G" first="Gianluca" last="Severi">Gianluca Severi</name>
<affiliation wicri:level="1"><nlm:aff id="a1"><institution>Molecular end Epidemiology Unit, HuGeF, Human Genetics Foundation</institution>
, Torino 10126,<country>Italy</country>
</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a3"><institution>Inserm (Institut National de la Santé et de la Recherche Médicale), Centre for Research in Epidemiology and Population Health</institution>
, U1018, Team 9, 114 rue Edouard Vaillant, Villejuif 94805,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a4"><institution>Paris-South University</institution>
, Villejuif 91450,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a5"><institution>Department of Genetic Epidemiology, Cancer Epidemiology Centre, Cancer Council of Victoria</institution>
, Melbourne, Victoria 3004,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a6"><institution>School of Population and Global Health, Centre for Epidemiology and Biostatistics, University of Melbourne</institution>
, Melbourne, Victoria 3010,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Vineis, Paolo" sort="Vineis, Paolo" uniqKey="Vineis P" first="Paolo" last="Vineis">Paolo Vineis</name>
<affiliation wicri:level="1"><nlm:aff id="a1"><institution>Molecular end Epidemiology Unit, HuGeF, Human Genetics Foundation</institution>
, Torino 10126,<country>Italy</country>
</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a7"><institution>MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Norfolk Place</institution>
, London W2 1PG,<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
</analytic>
<series><title level="j">Nature Communications</title>
<idno type="eISSN">2041-1723</idno>
<imprint><date when="2015">2015</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p>DNA hypomethylation in certain genes is associated with tobacco exposure but it is unknown whether these methylation changes translate into increased lung cancer risk. In an epigenome-wide study of DNA from pre-diagnostic blood samples from 132 case–control pairs in the NOWAC cohort, we observe that the most significant associations with lung cancer risk are for cg05575921 in <italic>AHRR</italic>
 (OR for 1 s.d.=0.37, 95% CI: 0.31–0.54, <italic>P</italic>
-value=3.3 × 10<sup>−11</sup>
) and cg03636183 in <italic>F2RL3</italic>
 (OR for 1 s.d.=0.40, 95% CI: 0.31–0.56, <italic>P</italic>
-value=3.9 × 10<sup>−10</sup>
), previously shown to be strongly hypomethylated in smokers. These associations remain significant after adjustment for smoking and are confirmed in additional 664 case–control pairs tightly matched for smoking from the MCCS, NSHDS and EPIC HD cohorts. The replication and mediation analyses suggest that residual confounding is unlikely to explain the observed associations and that hypomethylation of these CpG sites may mediate the effect of tobacco on lung cancer risk.</p>
</div>
</front>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
  <front><journal-meta><journal-id journal-id-type="nlm-ta">Nat Commun</journal-id>
<journal-id journal-id-type="iso-abbrev">Nat Commun</journal-id>
<journal-title-group><journal-title>Nature Communications</journal-title>
</journal-title-group>
<issn pub-type="epub">2041-1723</issn>
<publisher><publisher-name>Nature Publishing Group</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">26667048</article-id>
<article-id pub-id-type="pmc">4682166</article-id>
<article-id pub-id-type="pii">ncomms10192</article-id>
<article-id pub-id-type="doi">10.1038/ncomms10192</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Hypomethylation of smoking-related genes is associated with future lung cancer in four prospective cohorts</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Fasanelli</surname>
<given-names>Francesca</given-names>
</name>
<xref ref-type="aff" rid="a1">1</xref>
<xref ref-type="aff" rid="a2">2</xref>
<xref ref-type="author-notes" rid="n1">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Baglietto</surname>
<given-names>Laura</given-names>
</name>
<xref ref-type="aff" rid="a3">3</xref>
<xref ref-type="aff" rid="a4">4</xref>
<xref ref-type="aff" rid="a5">5</xref>
<xref ref-type="aff" rid="a6">6</xref>
<xref ref-type="author-notes" rid="n1">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ponzi</surname>
<given-names>Erica</given-names>
</name>
<xref ref-type="aff" rid="a1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Guida</surname>
<given-names>Florence</given-names>
</name>
<xref ref-type="aff" rid="a7">7</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Campanella</surname>
<given-names>Gianluca</given-names>
</name>
<xref ref-type="aff" rid="a7">7</xref>
<contrib-id contrib-id-type="orcid">http://orcid.org/0000-0002-5411-6338</contrib-id>
</contrib>
<contrib contrib-type="author"><name><surname>Johansson</surname>
<given-names>Mattias</given-names>
</name>
<xref ref-type="aff" rid="a8">8</xref>
<xref ref-type="aff" rid="a9">9</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Grankvist</surname>
<given-names>Kjell</given-names>
</name>
<xref ref-type="aff" rid="a9">9</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Johansson</surname>
<given-names>Mikael</given-names>
</name>
<xref ref-type="aff" rid="a10">10</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Assumma</surname>
<given-names>Manuela Bianca</given-names>
</name>
<xref ref-type="aff" rid="a1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Naccarati</surname>
<given-names>Alessio</given-names>
</name>
<xref ref-type="aff" rid="a1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Chadeau-Hyam</surname>
<given-names>Marc</given-names>
</name>
<xref ref-type="aff" rid="a7">7</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ala</surname>
<given-names>Ugo</given-names>
</name>
<xref ref-type="aff" rid="a11">11</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Faltus</surname>
<given-names>Christian</given-names>
</name>
<xref ref-type="aff" rid="a12">12</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kaaks</surname>
<given-names>Rudolf</given-names>
</name>
<xref ref-type="aff" rid="a13">13</xref>
<xref ref-type="aff" rid="a14">14</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Risch</surname>
<given-names>Angela</given-names>
</name>
<xref ref-type="aff" rid="a12">12</xref>
<xref ref-type="aff" rid="a14">14</xref>
<xref ref-type="aff" rid="a15">15</xref>
<contrib-id contrib-id-type="orcid">http://orcid.org/0000-0002-8026-5505</contrib-id>
</contrib>
<contrib contrib-type="author"><name><surname>De Stavola</surname>
<given-names>Bianca</given-names>
</name>
<xref ref-type="aff" rid="a16">16</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hodge</surname>
<given-names>Allison</given-names>
</name>
<xref ref-type="aff" rid="a5">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Giles</surname>
<given-names>Graham G.</given-names>
</name>
<xref ref-type="aff" rid="a5">5</xref>
<xref ref-type="aff" rid="a6">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Southey</surname>
<given-names>Melissa C.</given-names>
</name>
<xref ref-type="aff" rid="a17">17</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Relton</surname>
<given-names>Caroline L.</given-names>
</name>
<xref ref-type="aff" rid="a18">18</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Haycock</surname>
<given-names>Philip C.</given-names>
</name>
<xref ref-type="aff" rid="a18">18</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lund</surname>
<given-names>Eiliv</given-names>
</name>
<xref ref-type="aff" rid="a19">19</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Polidoro</surname>
<given-names>Silvia</given-names>
</name>
<xref ref-type="aff" rid="a1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Sandanger</surname>
<given-names>Torkjel M.</given-names>
</name>
<xref ref-type="aff" rid="a19">19</xref>
<xref ref-type="author-notes" rid="n2">†</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Severi</surname>
<given-names>Gianluca</given-names>
</name>
<xref ref-type="aff" rid="a1">1</xref>
<xref ref-type="aff" rid="a3">3</xref>
<xref ref-type="aff" rid="a4">4</xref>
<xref ref-type="aff" rid="a5">5</xref>
<xref ref-type="aff" rid="a6">6</xref>
<xref ref-type="author-notes" rid="n2">†</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Vineis</surname>
<given-names>Paolo</given-names>
</name>
<xref ref-type="corresp" rid="c1">a</xref>
<xref ref-type="aff" rid="a1">1</xref>
<xref ref-type="aff" rid="a7">7</xref>
<xref ref-type="author-notes" rid="n2">†</xref>
</contrib>
<aff id="a1"><label>1</label>
<institution>Molecular end Epidemiology Unit, HuGeF, Human Genetics Foundation</institution>
, Torino 10126,<country>Italy</country>
</aff>
<aff id="a2"><label>2</label>
<institution>Unit of Cancer Epidemiology, Citta' della Salute e della Scienza Hospital-University of Turin, Center for Cancer Prevention</institution>
, Via Santena 7, Torino 10126,<country>Italy</country>
</aff>
<aff id="a3"><label>3</label>
<institution>Inserm (Institut National de la Santé et de la Recherche Médicale), Centre for Research in Epidemiology and Population Health</institution>
, U1018, Team 9, 114 rue Edouard Vaillant, Villejuif 94805,<country>France</country>
</aff>
<aff id="a4"><label>4</label>
<institution>Paris-South University</institution>
, Villejuif 91450,<country>France</country>
</aff>
<aff id="a5"><label>5</label>
<institution>Department of Genetic Epidemiology, Cancer Epidemiology Centre, Cancer Council of Victoria</institution>
, Melbourne, Victoria 3004,<country>Australia</country>
</aff>
<aff id="a6"><label>6</label>
<institution>School of Population and Global Health, Centre for Epidemiology and Biostatistics, University of Melbourne</institution>
, Melbourne, Victoria 3010,<country>Australia</country>
</aff>
<aff id="a7"><label>7</label>
<institution>MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Norfolk Place</institution>
, London W2 1PG,<country>UK</country>
</aff>
<aff id="a8"><label>8</label>
<institution>Genetic Epidemiology Division, International Agency for Research on Cancer</institution>
, Lyon 69008,<country>France</country>
</aff>
<aff id="a9"><label>9</label>
<institution>Department of Biobank Research, Umeå University</institution>
, Umeå SE—90187,<country>Sweden</country>
</aff>
<aff id="a10"><label>10</label>
<institution>Department of Radiation Sciences, Umeå University</institution>
, Umeå SE—90187,<country>Sweden</country>
</aff>
<aff id="a11"><label>11</label>
<institution>Department of Molecular Biotechnology and Health Sciences, Università di Torino</institution>
, Torino 10126,<country>Italy</country>
</aff>
<aff id="a12"><label>12</label>
<institution>Division of Epigenomics and Cancer Risk Factors, DKFZ—German Cancer Research Center</institution>
, Heidelberg 69121,<country>Germany</country>
</aff>
<aff id="a13"><label>13</label>
<institution>Division of Cancer Epidemiology, DKFZ—German Cancer Research Center</institution>
, Heidelberg 69121,<country>Germany</country>
</aff>
<aff id="a14"><label>14</label>
<institution>Translational Lung Research Center Heidelberg, Member of the German Center for Lung Research (DZL)</institution>
, Heidelberg 69120,<country>Germany</country>
</aff>
<aff id="a15"><label>15</label>
<institution>Division of Cancer Research and Epigenetics, Department of Molecular Biology, University of Salzburg</institution>
, Salzburg 5020,<country>Austria</country>
</aff>
<aff id="a16"><label>16</label>
<institution>Department of Medical Statistics, London School of Hygiene and Tropical Medicine</institution>
, London WC1E 7HT,<country>UK</country>
</aff>
<aff id="a17"><label>17</label>
<institution>Genetic Epidemiology Laboratory, University of Melbourne</institution>
, Melbourne, Victoria 3010,<country>Australia</country>
</aff>
<aff id="a18"><label>18</label>
<institution>MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol</institution>
 BS8 2BN,<country>UK</country>
</aff>
<aff id="a19"><label>19</label>
<institution>Department of Community Medicine UiT–The Arctic University of Norway</institution>
, Tromso 9019,<country>Norway</country>
</aff>
</contrib-group>
<author-notes><corresp id="c1"><label>a</label>
<email>p.vineis@imperial.ac.uk</email>
</corresp>
<fn id="n1"><label>*</label>
<p>These authors contributed equally to this work.</p>
</fn>
<fn id="n2"><label>†</label>
<p>These authors jointly supervised this work.</p>
</fn>
</author-notes>
<pub-date pub-type="epub"><day>15</day>
<month>12</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="collection"><year>2015</year>
</pub-date>
<volume>6</volume>
<elocation-id>10192</elocation-id>
<history><date date-type="received"><day>27</day>
<month>02</month>
<year>2015</year>
</date>
<date date-type="accepted"><day>16</day>
<month>11</month>
<year>2015</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.</copyright-statement>
<copyright-year>2015</copyright-year>
<copyright-holder>Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.</copyright-holder>
<license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/4.0/"><pmc-comment>author-paid</pmc-comment>
          <license-p>This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>
</license-p>
</license>
</permissions>
<abstract><p>DNA hypomethylation in certain genes is associated with tobacco exposure but it is unknown whether these methylation changes translate into increased lung cancer risk. In an epigenome-wide study of DNA from pre-diagnostic blood samples from 132 case–control pairs in the NOWAC cohort, we observe that the most significant associations with lung cancer risk are for cg05575921 in <italic>AHRR</italic>
 (OR for 1 s.d.=0.37, 95% CI: 0.31–0.54, <italic>P</italic>
-value=3.3 × 10<sup>−11</sup>
) and cg03636183 in <italic>F2RL3</italic>
 (OR for 1 s.d.=0.40, 95% CI: 0.31–0.56, <italic>P</italic>
-value=3.9 × 10<sup>−10</sup>
), previously shown to be strongly hypomethylated in smokers. These associations remain significant after adjustment for smoking and are confirmed in additional 664 case–control pairs tightly matched for smoking from the MCCS, NSHDS and EPIC HD cohorts. The replication and mediation analyses suggest that residual confounding is unlikely to explain the observed associations and that hypomethylation of these CpG sites may mediate the effect of tobacco on lung cancer risk.</p>
</abstract>
<abstract abstract-type="web-summary"><p><inline-graphic id="i1" xlink:href="ncomms10192-i1.jpg"></inline-graphic>
Smoking tobacco is known to alter DNA methylation. Here, the authors show that hypomethylation of smoke-related genes is associated with future increase in lung cancer risk.</p>
</abstract>
</article-meta>
</front>
<floats-group><fig id="f1"><label>Figure 1</label>
<caption><title>NOWAC cohort.</title>
<p>Associations between smoking cessation (years since quitting on horizontal axis) and methylation levels (vertical axis).</p>
</caption>
<graphic xlink:href="ncomms10192-f1"></graphic>
</fig>
<fig id="f2"><label>Figure 2</label>
<caption><title>MCCS and NSHDS cohorts.</title>
<p>Associations between duration of smoking and time since smoking cessation and methylation levels in <italic>AHRR</italic>
-cg05575921 and <italic>F2RL3</italic>
-cg03636183.</p>
</caption>
<graphic xlink:href="ncomms10192-f2"></graphic>
</fig>
<fig id="f3"><label>Figure 3</label>
<caption><title>Mediation analysis: graphical representation.</title>
<p>In model A, the percentage of the effect mediated by <italic>AHRR</italic>
-cg05575921 is ∼31% of the total effect of smoking on lung cancer risk, whereas in model B, the percentage mediated by <italic>F2RL3-</italic>
cg03636183 is ∼32%. The joint mediation effect of these two CpGs is 37% if the two mediators are included together in the model with separate pathways (model C).</p>
</caption>
<graphic xlink:href="ncomms10192-f3"></graphic>
</fig>
<table-wrap position="float" id="t1"><label>Table 1</label>
<caption><title>Top-ranked CpG sites for the locus-by-locus risk analysis in NOWAC data (discovery set): CpGs in the <italic>AHRR</italic>
 and <italic>F2RL3</italic>
 genes display the most significant inverse associations with risk (hypomethylation in cases).</title>
</caption>
<table frame="hsides" rules="groups" border="1"><colgroup><col align="left"></col>
<col align="center"></col>
<col align="char" char="."></col>
<col align="center"></col>
<col align="center"></col>
<col align="char" char="."></col>
<col align="center"></col>
<col align="center"></col>
<col align="center"></col>
</colgroup>
<thead valign="bottom"><tr><th align="left" valign="top" charoff="50"><bold>Probe name</bold>
</th>
<th align="center" valign="top" charoff="50"><bold>Gene name</bold>
</th>
<th align="center" valign="top" char="." charoff="50"><bold>Chromosome</bold>
</th>
<th align="center" valign="top" charoff="50"><bold>Position</bold>
</th>
<th align="center" valign="top" charoff="50"><bold>Region</bold>
</th>
<th align="center" valign="top" char="." charoff="50"><bold>OR for 1 s.d.</bold>
</th>
<th align="center" valign="top" charoff="50"><bold>95% CI</bold>
</th>
<th align="center" valign="top" charoff="50"><italic><bold>P</bold>
</italic>
<bold>-value</bold>
</th>
<th align="center" valign="top" charoff="50"><italic><bold>P</bold>
</italic>
<bold>-value Bonferroni</bold>
</th>
</tr>
</thead>
<tbody valign="top"><tr><td align="left" valign="top" charoff="50">cg05575921</td>
<td align="center" valign="top" charoff="50"><italic>AHRR</italic>
</td>
<td align="char" valign="top" char="." charoff="50">5</td>
<td align="center" valign="top" charoff="50">373378</td>
<td align="center" valign="top" charoff="50">N_Shore</td>
<td align="char" valign="top" char="." charoff="50">0.37</td>
<td align="center" valign="top" charoff="50">0.31–0.54</td>
<td align="center" valign="top" charoff="50">3.33 × 10<sup>−11</sup>
</td>
<td align="center" valign="top" charoff="50">1.36 × 10<sup>−5</sup>
</td>
</tr>
<tr><td align="left" valign="top" charoff="50">cg03636183</td>
<td align="center" valign="top" charoff="50"><italic>F2RL3</italic>
</td>
<td align="char" valign="top" char="." charoff="50">19</td>
<td align="center" valign="top" charoff="50">17000585</td>
<td align="center" valign="top" charoff="50">N_Shore</td>
<td align="char" valign="top" char="." charoff="50">0.40</td>
<td align="center" valign="top" charoff="50">0.31–0.56</td>
<td align="center" valign="top" charoff="50">3.86 × 10<sup>−10</sup>
</td>
<td align="center" valign="top" charoff="50">1.58 × 10<sup>−4</sup>
</td>
</tr>
<tr><td align="left" valign="top" charoff="50">cg21566642</td>
<td align="center" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50">2</td>
<td align="center" valign="top" charoff="50">233283329</td>
<td align="center" valign="top" charoff="50">Island</td>
<td align="char" valign="top" char="." charoff="50">0.36</td>
<td align="center" valign="top" charoff="50">0.23–0.48</td>
<td align="center" valign="top" charoff="50">1.33 × 10<sup>−9</sup>
</td>
<td align="center" valign="top" charoff="50">5.43 × 10<sup>−4</sup>
</td>
</tr>
<tr><td align="left" valign="top" charoff="50">cg06126421</td>
<td align="center" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50">6</td>
<td align="center" valign="top" charoff="50">233284934</td>
<td align="center" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50">0.41</td>
<td align="center" valign="top" charoff="50">0.25–0.49</td>
<td align="center" valign="top" charoff="50">1.52 × 10<sup>−9</sup>
</td>
<td align="center" valign="top" charoff="50">6.21 × 10<sup>−4</sup>
</td>
</tr>
<tr><td align="left" valign="top" charoff="50">cg25305703</td>
<td align="center" valign="top" charoff="50"><italic>CASC21</italic>
</td>
<td align="char" valign="top" char="." charoff="50">8</td>
<td align="center" valign="top" charoff="50">233284402</td>
<td align="center" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50">0.45</td>
<td align="center" valign="top" charoff="50">0.35–0.60</td>
<td align="center" valign="top" charoff="50">3.28 × 10<sup>−8</sup>
</td>
<td align="center" valign="top" charoff="50">1.34 × 10<sup>−2</sup>
</td>
</tr>
<tr><td align="left" valign="top" charoff="50">cg21161138</td>
<td align="center" valign="top" charoff="50"><italic>AHRR</italic>
</td>
<td align="char" valign="top" char="." charoff="50">5</td>
<td align="center" valign="top" charoff="50">399360</td>
<td align="center" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50">0.46</td>
<td align="center" valign="top" charoff="50">0.36–0.62</td>
<td align="center" valign="top" charoff="50">5.01 × 10<sup>−8</sup>
</td>
<td align="center" valign="top" charoff="50">2.04 × 10<sup>−2</sup>
</td>
</tr>
<tr><td align="left" valign="top" charoff="50">cg01940273</td>
<td align="center" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50">2</td>
<td align="center" valign="top" charoff="50">26578098</td>
<td align="center" valign="top" charoff="50">Island</td>
<td align="char" valign="top" char="." charoff="50">0.44</td>
<td align="center" valign="top" charoff="50">0.33–0.60</td>
<td align="center" valign="top" charoff="50">5.21 × 10<sup>−8</sup>
</td>
<td align="center" valign="top" charoff="50">2.13 × 10<sup>−2</sup>
</td>
</tr>
<tr><td align="left" valign="top" charoff="50">cg02451831</td>
<td align="center" valign="top" charoff="50"><italic>KIAA0087</italic>
</td>
<td align="char" valign="top" char="." charoff="50">7</td>
<td align="center" valign="top" charoff="50">30720080</td>
<td align="center" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50">0.43</td>
<td align="center" valign="top" charoff="50">0.29–0.57</td>
<td align="center" valign="top" charoff="50">6.55 × 10<sup>−8</sup>
</td>
<td align="center" valign="top" charoff="50">2.67 × 10<sup>−2</sup>
</td>
</tr>
<tr><td align="left" valign="top" charoff="50">cg05951221</td>
<td align="center" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50">2</td>
<td align="center" valign="top" charoff="50">233284661</td>
<td align="center" valign="top" charoff="50">Island</td>
<td align="char" valign="top" char="." charoff="50">0.41</td>
<td align="center" valign="top" charoff="50">0.30–0.58</td>
<td align="center" valign="top" charoff="50">8.59 × 10<sup>−8</sup>
</td>
<td align="center" valign="top" charoff="50">3.51 × 10<sup>−2</sup>
</td>
</tr>
<tr><td align="left" valign="top" charoff="50">cg04884171</td>
<td align="center" valign="top" charoff="50"><italic>BOLA2</italic>
</td>
<td align="char" valign="top" char="." charoff="50">16</td>
<td align="center" valign="top" charoff="50">128378218</td>
<td align="center" valign="top" charoff="50">S_Shelf</td>
<td align="char" valign="top" char="." charoff="50">0.33</td>
<td align="center" valign="top" charoff="50">0.15–0.41</td>
<td align="center" valign="top" charoff="50">1.18 × 10<sup>−8</sup>
</td>
<td align="center" valign="top" charoff="50">4.82 × 10<sup>−2</sup>
</td>
</tr>
<tr><td align="left" valign="top" charoff="50">cg03898802</td>
<td align="center" valign="top" charoff="50"><italic>DOPEY2</italic>
</td>
<td align="char" valign="top" char="." charoff="50">21</td>
<td align="center" valign="top" charoff="50">37617652</td>
<td align="center" valign="top" charoff="50">Island</td>
<td align="char" valign="top" char="." charoff="50">0.37</td>
<td align="center" valign="top" charoff="50">0.29–0.57</td>
<td align="center" valign="top" charoff="50">1.20 × 10<sup>−7</sup>
</td>
<td align="center" valign="top" charoff="50">4.90 × 10<sup>−2</sup>
</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn id="t1-fn1"><p>CI, confidence interval; OR, odds ratio.</p>
</fn>
<fn id="t1-fn2"><p>Unconditional logistic regression models were used with DNA methylation levels included as an independent variable and were adjusted for matching variables, micro-array, position of the sample on the micro-array and blood cell composition differentials.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap position="float" id="t2"><label>Table 2</label>
<caption><title>Results of the lung cancer risk analysis for the <italic>AHRR</italic>
 and <italic>F2RL3</italic>
 gene probes after strict adjustment for smoking in the discovery set and in the validation sets.</title>
</caption>
<table frame="hsides" rules="groups" border="1"><colgroup><col align="char" char=""></col>
<col align="center"></col>
<col align="center"></col>
<col align="center"></col>
<col align="center"></col>
<col align="center"></col>
<col align="center"></col>
<col align="center"></col>
<col align="center"></col>
<col align="center"></col>
<col align="center"></col>
</colgroup>
<thead valign="bottom"><tr><th align="char" valign="top" charoff="50"> </th>
<th colspan="5" align="center" valign="top" charoff="50"><bold>NOWAC</bold>
</th>
<th colspan="5" align="center" valign="top" charoff="50"><bold>MCCS</bold>
</th>
</tr>
</thead>
<tbody valign="top"><tr><td align="char" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"><bold>ca</bold>
</td>
<td align="center" valign="top" charoff="50"><bold>co</bold>
</td>
<td align="center" valign="top" charoff="50"><bold>OR</bold>
</td>
<td align="center" valign="top" charoff="50"><bold>95% CI</bold>
</td>
<td align="center" valign="top" charoff="50"><italic><bold>P</bold>
</italic>
<bold>-value</bold>
</td>
<td align="center" valign="top" charoff="50"><bold>ca</bold>
</td>
<td align="center" valign="top" charoff="50"><bold>co</bold>
</td>
<td align="center" valign="top" charoff="50"><bold>OR</bold>
</td>
<td align="center" valign="top" charoff="50"><bold>95% CI</bold>
</td>
<td align="center" valign="top" charoff="50"><italic><bold>P</bold>
</italic>
<bold>-value</bold>
</td>
</tr>
<tr><td colspan="11" align="left" valign="top" charoff="50"><italic>AHRR cg05575921</italic>
</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Unadjusted</td>
<td align="char" valign="top" char="." charoff="50">125</td>
<td align="char" valign="top" char="." charoff="50">125</td>
<td align="char" valign="top" char="." charoff="50">0.37</td>
<td align="center" valign="top" charoff="50">0.31–0.54</td>
<td align="center" valign="top" charoff="50">3.33 × 10<sup>−11</sup>
</td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Adjusted<xref ref-type="fn" rid="t2-fn2">*</xref>
</td>
<td align="char" valign="top" char="." charoff="50">124</td>
<td align="char" valign="top" char="." charoff="50">122</td>
<td align="char" valign="top" char="." charoff="50">0.39</td>
<td align="center" valign="top" charoff="50">0.24–0.61</td>
<td align="center" valign="top" charoff="50">2.55 × 10<sup>−05</sup>
</td>
<td align="char" valign="top" char="." charoff="50">367</td>
<td align="char" valign="top" char="." charoff="50">367</td>
<td align="char" valign="top" char="." charoff="50">0.62</td>
<td align="center" valign="top" charoff="50">0.50–0.78</td>
<td align="center" valign="top" charoff="50">2.91 × 10<sup>−5</sup>
</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Never</td>
<td align="char" valign="top" char="." charoff="50">11</td>
<td align="char" valign="top" char="." charoff="50">54</td>
<td align="char" valign="top" char="." charoff="50">0.90</td>
<td align="center" valign="top" charoff="50">0.26–3.10</td>
<td align="center" valign="top" charoff="50">8.70 × 10<sup>−01</sup>
</td>
<td align="char" valign="top" char="." charoff="50">43</td>
<td align="char" valign="top" char="." charoff="50">43</td>
<td align="char" valign="top" char="." charoff="50">0.63</td>
<td align="center" valign="top" charoff="50">0.24–1.64</td>
<td align="center" valign="top" charoff="50">3.47 × 10<sup>−1</sup>
</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Former<xref ref-type="fn" rid="t2-fn3">†</xref>
</td>
<td align="char" valign="top" char="." charoff="50">41</td>
<td align="char" valign="top" char="." charoff="50">33</td>
<td align="char" valign="top" char="." charoff="50">0.23</td>
<td align="center" valign="top" charoff="50">0.10–0.56</td>
<td align="center" valign="top" charoff="50">1.00 × 10<sup>−02</sup>
</td>
<td align="char" valign="top" char="." charoff="50">153</td>
<td align="char" valign="top" char="." charoff="50">153</td>
<td align="char" valign="top" char="." charoff="50">0.48</td>
<td align="center" valign="top" charoff="50">0.31–0.75</td>
<td align="center" valign="top" charoff="50">1.45 × 10<sup>−3</sup>
</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Current<xref ref-type="fn" rid="t2-fn4">‡</xref>
</td>
<td align="char" valign="top" char="." charoff="50">72</td>
<td align="char" valign="top" char="." charoff="50">35</td>
<td align="char" valign="top" char="." charoff="50">0.46</td>
<td align="center" valign="top" charoff="50">0.24–0.88</td>
<td align="center" valign="top" charoff="50">1.90 × 10<sup>−02</sup>
</td>
<td align="char" valign="top" char="." charoff="50">164</td>
<td align="char" valign="top" char="." charoff="50">164</td>
<td align="char" valign="top" char="." charoff="50">0.75</td>
<td align="center" valign="top" charoff="50">0.56–0.99</td>
<td align="center" valign="top" charoff="50">4.13 × 10<sup>−2</sup>
</td>
</tr>
<tr><td align="char" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
</tr>
<tr><td colspan="11" align="left" valign="top" charoff="50"><italic>F2RL3 cg03636183</italic>
</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Unadjusted</td>
<td align="char" valign="top" char="." charoff="50">125</td>
<td align="char" valign="top" char="." charoff="50">125</td>
<td align="char" valign="top" char="." charoff="50">0.40</td>
<td align="center" valign="top" charoff="50">0.31–0.56</td>
<td align="center" valign="top" charoff="50">3.86 × 10<sup>−10</sup>
</td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Adjusted<xref ref-type="fn" rid="t2-fn2">*</xref>
</td>
<td align="char" valign="top" char="." charoff="50">124</td>
<td align="char" valign="top" char="." charoff="50">122</td>
<td align="char" valign="top" char="." charoff="50">0.51</td>
<td align="center" valign="top" charoff="50">0.35–0.73</td>
<td align="center" valign="top" charoff="50">4.19 × 10<sup>−04</sup>
</td>
<td align="char" valign="top" char="." charoff="50">367</td>
<td align="char" valign="top" char="." charoff="50">367</td>
<td align="char" valign="top" char="." charoff="50">0.70</td>
<td align="center" valign="top" charoff="50">0.58–0.85</td>
<td align="center" valign="top" charoff="50">2.21 × 10<sup>−4</sup>
</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Never</td>
<td align="char" valign="top" char="." charoff="50">11</td>
<td align="char" valign="top" char="." charoff="50">54</td>
<td align="char" valign="top" char="." charoff="50">1.07</td>
<td align="center" valign="top" charoff="50">0.29–4.00</td>
<td align="center" valign="top" charoff="50">9.20 × 10<sup>−01</sup>
</td>
<td align="char" valign="top" char="." charoff="50">43</td>
<td align="char" valign="top" char="." charoff="50">43</td>
<td align="char" valign="top" char="." charoff="50">0.78</td>
<td align="center" valign="top" charoff="50">0.44–1.36</td>
<td align="center" valign="top" charoff="50">3.73 × 10<sup>−1</sup>
</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Former<xref ref-type="fn" rid="t2-fn3">†</xref>
</td>
<td align="char" valign="top" char="." charoff="50">41</td>
<td align="char" valign="top" char="." charoff="50">33</td>
<td align="char" valign="top" char="." charoff="50">0.25</td>
<td align="center" valign="top" charoff="50">0.35–0.55</td>
<td align="center" valign="top" charoff="50">1.00 × 10<sup>−03</sup>
</td>
<td align="char" valign="top" char="." charoff="50">153</td>
<td align="char" valign="top" char="." charoff="50">153</td>
<td align="char" valign="top" char="." charoff="50">0.70</td>
<td align="center" valign="top" charoff="50">0.50–0.98</td>
<td align="center" valign="top" charoff="50">3.81 × 10<sup>−2</sup>
</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Current<xref ref-type="fn" rid="t2-fn4">‡</xref>
</td>
<td align="char" valign="top" char="." charoff="50">72</td>
<td align="char" valign="top" char="." charoff="50">35</td>
<td align="char" valign="top" char="." charoff="50">0.55</td>
<td align="center" valign="top" charoff="50">0.32–0.94</td>
<td align="center" valign="top" charoff="50">3.00 × 10<sup>−02</sup>
</td>
<td align="char" valign="top" char="." charoff="50">164</td>
<td align="char" valign="top" char="." charoff="50">164</td>
<td align="char" valign="top" char="." charoff="50">0.81</td>
<td align="center" valign="top" charoff="50">0.61–1.06</td>
<td align="center" valign="top" charoff="50">1.18 × 10<sup>−1</sup>
</td>
</tr>
</tbody>
</table>
<table frame="hsides" rules="groups" border="1"><colgroup><col align="left"></col>
<col align="char" char="."></col>
<col align="char" char="."></col>
<col align="char" char="."></col>
<col align="center"></col>
<col align="center"></col>
<col align="char" char="."></col>
<col align="char" char="."></col>
<col align="char" char="."></col>
<col align="center"></col>
<col align="center"></col>
</colgroup>
<thead valign="bottom"><tr><th align="left" valign="top" charoff="50"> </th>
<th colspan="5" align="center" valign="top" char="." charoff="50"><bold>NSHDS</bold>
<hr></hr>
</th>
<th colspan="5" align="center" valign="top" char="." charoff="50"><bold>EPIC HEIDELBERG</bold>
<hr></hr>
</th>
</tr>
<tr><th align="left" valign="top" charoff="50"> </th>
<th align="center" valign="top" char="." charoff="50"><bold>ca</bold>
</th>
<th align="center" valign="top" char="." charoff="50"><bold>co</bold>
</th>
<th align="center" valign="top" char="." charoff="50"><bold>OR</bold>
</th>
<th align="center" valign="top" charoff="50"><bold>95% CI</bold>
</th>
<th align="center" valign="top" charoff="50"><italic><bold>P</bold>
</italic>
<bold>-value</bold>
</th>
<th align="center" valign="top" char="." charoff="50"><bold>ca</bold>
</th>
<th align="center" valign="top" char="." charoff="50"><bold>co</bold>
</th>
<th align="center" valign="top" char="." charoff="50"><bold>OR</bold>
</th>
<th align="center" valign="top" charoff="50"><bold>95% CI</bold>
</th>
<th align="center" valign="top" charoff="50"><italic><bold>P</bold>
</italic>
<bold>-value</bold>
</th>
</tr>
</thead>
<tbody valign="top"><tr><td colspan="11" align="center" valign="top" charoff="50"><italic>AHRR cg05575921</italic>
</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Unadjusted</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Adjusted<xref ref-type="fn" rid="t2-fn2">*</xref>
</td>
<td align="char" valign="top" char="." charoff="50">234</td>
<td align="char" valign="top" char="." charoff="50">234</td>
<td align="char" valign="top" char="." charoff="50">0.42</td>
<td align="center" valign="top" charoff="50">0.30–0.58</td>
<td align="center" valign="top" charoff="50">2.06 × 10<sup>−7</sup>
</td>
<td align="char" valign="top" char="." charoff="50">63</td>
<td align="char" valign="top" char="." charoff="50">63</td>
<td align="char" valign="top" char="." charoff="50">0.45</td>
<td align="center" valign="top" charoff="50">0.22–0.92</td>
<td align="center" valign="top" charoff="50">2.95 × 10<sup>−02</sup>
</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Never</td>
<td align="char" valign="top" char="." charoff="50">26</td>
<td align="char" valign="top" char="." charoff="50">26</td>
<td align="char" valign="top" char="." charoff="50">1.96</td>
<td align="center" valign="top" charoff="50">0.40–9.68</td>
<td align="center" valign="top" charoff="50">1.10 × 10<sup>−1</sup>
</td>
<td align="center" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Former<xref ref-type="fn" rid="t2-fn3">†</xref>
</td>
<td align="char" valign="top" char="." charoff="50">70</td>
<td align="char" valign="top" char="." charoff="50">70</td>
<td align="char" valign="top" char="." charoff="50">0.27</td>
<td align="center" valign="top" charoff="50">0.12–0.61</td>
<td align="center" valign="top" charoff="50">1.70 × 10<sup>−3</sup>
</td>
<td align="char" valign="top" char="." charoff="50">16</td>
<td align="char" valign="top" char="." charoff="50">16</td>
<td align="char" valign="top" char="." charoff="50">0.06</td>
<td align="center" valign="top" charoff="50">0.00–2.23</td>
<td align="center" valign="top" charoff="50">1.26 × 10<sup>−01</sup>
</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Current<xref ref-type="fn" rid="t2-fn4">‡</xref>
</td>
<td align="char" valign="top" char="." charoff="50">120</td>
<td align="char" valign="top" char="." charoff="50">120</td>
<td align="char" valign="top" char="." charoff="50">0.47</td>
<td align="center" valign="top" charoff="50">0.31–0.72</td>
<td align="center" valign="top" charoff="50">5.40 × 10<sup>−4</sup>
</td>
<td align="char" valign="top" char="." charoff="50">47</td>
<td align="char" valign="top" char="." charoff="50">47</td>
<td align="char" valign="top" char="." charoff="50">0.56</td>
<td align="center" valign="top" charoff="50">0.27–1.16</td>
<td align="center" valign="top" charoff="50">1.16 × 10<sup>−01</sup>
</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
</tr>
<tr><td colspan="11" align="center" valign="top" charoff="50"><italic>F2RL3 cg03636183</italic>
</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Unadjusted</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Adjusted<xref ref-type="fn" rid="t2-fn2">*</xref>
</td>
<td align="char" valign="top" char="." charoff="50">234</td>
<td align="char" valign="top" char="." charoff="50">234</td>
<td align="char" valign="top" char="." charoff="50">0.61</td>
<td align="center" valign="top" charoff="50">0.47–0.79</td>
<td align="center" valign="top" charoff="50">1.56 × 10<sup>−4</sup>
</td>
<td align="char" valign="top" char="." charoff="50">63</td>
<td align="char" valign="top" char="." charoff="50">63</td>
<td align="char" valign="top" char="." charoff="50">0.62</td>
<td align="center" valign="top" charoff="50">0.38–1.04</td>
<td align="center" valign="top" charoff="50">7.02 × 10<sup>−02</sup>
</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Never</td>
<td align="char" valign="top" char="." charoff="50">26</td>
<td align="char" valign="top" char="." charoff="50">26</td>
<td align="char" valign="top" char="." charoff="50">1.38</td>
<td align="center" valign="top" charoff="50">0.51–3.73</td>
<td align="center" valign="top" charoff="50">5.20 × 10<sup>−1</sup>
</td>
<td align="center" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Former<xref ref-type="fn" rid="t2-fn2">†</xref>
</td>
<td align="char" valign="top" char="." charoff="50">70</td>
<td align="char" valign="top" char="." charoff="50">70</td>
<td align="char" valign="top" char="." charoff="50">0.45</td>
<td align="center" valign="top" charoff="50">0.26–0.80</td>
<td align="center" valign="top" charoff="50">6.60 × 10<sup>−3</sup>
</td>
<td align="char" valign="top" char="." charoff="50">16</td>
<td align="char" valign="top" char="." charoff="50">16</td>
<td align="char" valign="top" char="." charoff="50">0.29</td>
<td align="center" valign="top" charoff="50">0.03–3.24</td>
<td align="center" valign="top" charoff="50">3.17 × 10<sup>−01</sup>
</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Current<xref ref-type="fn" rid="t2-fn4">‡</xref>
</td>
<td align="char" valign="top" char="." charoff="50">120</td>
<td align="char" valign="top" char="." charoff="50">120</td>
<td align="char" valign="top" char="." charoff="50">0.70</td>
<td align="center" valign="top" charoff="50">0.49–0.98</td>
<td align="center" valign="top" charoff="50">3.70 × 10<sup>−2</sup>
</td>
<td align="char" valign="top" char="." charoff="50">47</td>
<td align="char" valign="top" char="." charoff="50">47</td>
<td align="char" valign="top" char="." charoff="50">0.64</td>
<td align="center" valign="top" charoff="50">0.36–1.12</td>
<td align="center" valign="top" charoff="50">1.17 × 10<sup>−01</sup>
</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn id="t2-fn1"><p>ca, case; CI, confidence interval; co, control; MCCS, Melbourne Collaborative Cohort Study; OR, odds ratio.</p>
</fn>
<fn id="t2-fn2"><p><sup>*</sup>
In NOWAC, the estimates are from the unconditional logistic regression models adjusted for smoking status coded as never, former, current; in MCCS, the estimates are from the conditional logistic regression models where controls were matched on age, sex, date of blood collection, country of birth, type of biospecimen and smoking status as described in the text; in NSHDS, estimates are from conditional logistic regression models where cases and controls were matched on age, sex, smoking status and smoking quantity; in EPIC HD, the estimates are from conditional regression models where cases and controls were matched on smoking status and packyears of smoking.</p>
</fn>
<fn id="t2-fn3"><p><sup>†</sup>
In MCCS and EPIC HD, the estimates are also adjusted for number of cigarettes smoked, duration of smoking and time since quitting smoking; in NSHDS, estimates are also adjusted for duration of smoking and time since quitting smoking.</p>
</fn>
<fn id="t2-fn4"><p><sup>‡</sup>
In MCCS and EPIC HD, the estimates are also adjusted for number of cigarettes smoked and duration of smoking; in NSHDS, estimates are also adjusted for duration of smoking.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap position="float" id="t3"><label>Table 3</label>
<caption><title>Mediation analysis of the NOWAC cohort based on g-formula.</title>
</caption>
<table frame="hsides" rules="groups" border="1"><colgroup><col align="left"></col>
<col align="char" char="."></col>
<col align="char" char="."></col>
<col align="center"></col>
<col align="center"></col>
</colgroup>
<thead valign="bottom"><tr><th align="left" valign="top" charoff="50"> </th>
<th align="center" valign="top" char="." charoff="50"><bold>Log OR</bold>
</th>
<th align="center" valign="top" char="." charoff="50"><bold>s.e.</bold>
</th>
<th align="center" valign="top" charoff="50"><italic><bold>P-</bold>
</italic>
<bold>value</bold>
</th>
<th align="center" valign="top" charoff="50"><bold>95% CI</bold>
</th>
</tr>
</thead>
<tbody valign="top"><tr><td colspan="5" align="center" valign="top" charoff="50"><italic>AHRR-cg05575921</italic>
</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> TCE</td>
<td align="char" valign="top" char="." charoff="50">1.83</td>
<td align="char" valign="top" char="." charoff="50">0.29</td>
<td align="center" valign="top" charoff="50"><0.001</td>
<td align="center" valign="top" charoff="50">(1.37–2.64)</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> NDE</td>
<td align="char" valign="top" char="." charoff="50">1.26</td>
<td align="char" valign="top" char="." charoff="50">0.31</td>
<td align="center" valign="top" charoff="50"><0.001</td>
<td align="center" valign="top" charoff="50">(0.75–2.08)</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> NIE</td>
<td align="char" valign="top" char="." charoff="50">0.56</td>
<td align="char" valign="top" char="." charoff="50">0.08</td>
<td align="center" valign="top" charoff="50"><0.001</td>
<td align="center" valign="top" charoff="50">(0.39–0.73)</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Effect mediated</td>
<td align="char" valign="top" char="." charoff="50">0.31</td>
<td align="char" valign="top" char="." charoff="50">0.08</td>
<td align="center" valign="top" charoff="50"><0.001</td>
<td align="center" valign="top" charoff="50">(0.18–0.46)</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
</tr>
<tr><td colspan="5" align="center" valign="top" charoff="50"><italic>F2RL3-cg03636183</italic>
</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> TCE</td>
<td align="char" valign="top" char="." charoff="50">1.82</td>
<td align="char" valign="top" char="." charoff="50">0.30</td>
<td align="center" valign="top" charoff="50"><0.001</td>
<td align="center" valign="top" charoff="50">(1.29–2.48)</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> NDE</td>
<td align="char" valign="top" char="." charoff="50">1.23</td>
<td align="char" valign="top" char="." charoff="50">0.33</td>
<td align="center" valign="top" charoff="50"><0.001</td>
<td align="center" valign="top" charoff="50">(0.63–1.93)</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> NIE</td>
<td align="char" valign="top" char="." charoff="50">0.59</td>
<td align="char" valign="top" char="." charoff="50">0.09</td>
<td align="center" valign="top" charoff="50"><0.001</td>
<td align="center" valign="top" charoff="50">(0.43–0.80)</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Effect mediated</td>
<td align="char" valign="top" char="." charoff="50">0.32</td>
<td align="char" valign="top" char="." charoff="50">0.08</td>
<td align="center" valign="top" charoff="50"><0.001</td>
<td align="center" valign="top" charoff="50">(0.20–0.53)</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
</tr>
<tr><td colspan="5" align="center" valign="top" charoff="50"><italic>AHRR-cg05575921 and F2RL3-cg03636183</italic>
</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> TCE</td>
<td align="char" valign="top" char="." charoff="50">1.79</td>
<td align="char" valign="top" char="." charoff="50">0.30</td>
<td align="center" valign="top" charoff="50"><0.001</td>
<td align="center" valign="top" charoff="50">(1.28–2.53)</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> NDE</td>
<td align="char" valign="top" char="." charoff="50">1.13</td>
<td align="char" valign="top" char="." charoff="50">0.34</td>
<td align="center" valign="top" charoff="50">0.001</td>
<td align="center" valign="top" charoff="50">(0.49–1.86)</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> NIE</td>
<td align="char" valign="top" char="." charoff="50">0.66</td>
<td align="char" valign="top" char="." charoff="50">0.15</td>
<td align="center" valign="top" charoff="50"><0.001</td>
<td align="center" valign="top" charoff="50">(0.42–1.09)</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Effect mediated</td>
<td align="char" valign="top" char="." charoff="50">0.37</td>
<td align="char" valign="top" char="." charoff="50">0.11</td>
<td align="center" valign="top" charoff="50">0.001</td>
<td align="center" valign="top" charoff="50">(0.19–0.66)</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn id="t3-fn1"><p>CI, confidence interval; NDE, natural direct effect; NIE, natural indirect effect; OR, odds ratio; TCE, total causal effect.</p>
</fn>
<fn id="t3-fn2"><p>TCE, NDE and NIE for the cg05575921 probe in <italic>AHRR</italic>
, for the cg03636183 probe in <italic>F2RL3</italic>
 and for the two probes combined: 31% of the total effect of smoking on lung cancer risk is mediated by <italic>AHRR</italic>
 site-specific methylation, 32% of the total effect of smoking on lung cancer risk is mediated by <italic>F2RL3</italic>
 site-specific methylation and 37% of the total effect of smoking on lung cancer risk is mediated by the combined contribution of <italic>AHRR</italic>
 and <italic>F2RL3</italic>
 methylation (separate pathways for the two probes).</p>
</fn>
</table-wrap-foot>
</table-wrap>
</floats-group>
</pmc>
</record>

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	Serveur d'exploration sur les relations entre la France et l'Australie
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Hypomethylation of smoking-related genes is associated with future lung cancer in four prospective cohorts

Hypomethylation of smoking-related genes is associated with future lung cancer in four prospective cohorts

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