Genetic polymorphisms in 15q25 and 19q13 loci, cotinine levels, and risk of lung cancer in EPIC

Maria N. Timofeeva, James D. McKay, George Davey Smith, Mattias Johansson, Graham B. Byrnes, Amélie Chabrier, Caroline Relton, Per Magne Ueland, Stein Emil Vollset, Øivind Midttun, Ottar Nygård, Nadia Slimani, Isabelle Romieu, Françoise Clavel-Chapelon, Marie Christine Boutron-Ruault, Guy Fagherazzi, Rudolf Kaaks, Birgit Teucher, Heiner Boeing, Cornelia WeikertH. Bas Bueno-de-Mesquita, Carla Van Gils, Petra H.M. Peeters, Antonio Agudo, Aurelio Barricarte, Jose Maria Huerta, Laudina Rodríguez, Maria José Sánchez, Nerea Larrañaga, Kay Tee Khaw, Nick Wareham, Naomi E. Allen, Ruth C. Travis, Valentina Gallo, Teresa Norat, Vittorio Krogh, Giovanna Masala, Salvatore Panico, Carlotta Sacerdote, Rosario Tumino, Antonia Trichopoulou, Pagona Lagiou, Dimitrios Trichopoulos, Torgny Rasmuson, Göran Hallmans, Elio Riboli, Paolo Vineis, Paul Brennan*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

58 Citations (Scopus)


Backgrounds: Multiple polymorphisms affecting smoking behavior have been identified through genomewide association studies. Circulating levels of the nicotine metabolite cotinine is a marker of recent smoking exposure. Hence, genetic variants influencing smoking behavior are expected to be associated with cotinine levels. Methods: We conducted an analysis in a lung cancer case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. We investigated the effects of singlenucleotide polymorphisms (SNP) previously associated with smoking behavior on (i) circulating cotinine and (ii) lung cancer risk. A total of 894 cases and 1,805 controls were analyzed for cotinine and genotyped for 10 polymorphisms on 7p14, 8p11, 10q23, 15q25, and 19q13. Results: Two variants in the nicotinic acetylcholine receptor subunit genes CHRNA5 and CHRNA3 on 15q25, rs16969968 and rs578776, were associated with cotinine (P = 0.001 and 0.03, respectively) in current smokers and with lung cancer risk (P < 0.001 and P = 0.001, respectively). Two 19q13 variants, rs7937 and rs4105144, were associated with increased cotinine (P = 0.003 and P < 0.001, respectively) but decreased lung cancer risk (P = 0.01 for both, after adjusting for cotinine). Variants in 7p14, 8p11, and 10q23 were not associated with cotinine or lung cancer risk.Conclusions: 15q25 and 19q13 SNPs were associated with circulating cotinine. The directions of association for 15q25 variants with cotinine were in accordance with that expected of lung cancer risk, whereas SNPs on 19q13 displayed contrasting associations of cotinine and lung cancer that require further investigation. Impact: This study is the largest to date investigating the effects of polymorphisms affecting smoking behavior on lung cancer risk using circulating cotinine measures as proxies for recent smoking behavior.

Original languageEnglish
Pages (from-to)2250-2261
Number of pages12
JournalCancer Epidemiology Biomarkers and Prevention
Issue number10
Publication statusPublished - Oct 2011
Externally publishedYes


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