Association between a 15q25 gene variant, smoking quantity and tobacco-related cancers among 17 000 individuals

Esther H Lips, Valerie Gaborieau, James D McKay, Amelie Chabrier, Rayjean J Hung, Paolo Boffetta, Mia Hashibe, David Zaridze, Neonilia Szeszenia-Dabrowska, Jolanta Lissowska, Peter Rudnai, Eleonora Fabianova, Dana Mates, Vladimir Bencko, Lenka Foretova, Vladimir Janout, John K Field, Triantafillos Liloglou, George Xinarianos, John McLaughlinGeoffrey Liu, Frank Skorpen, Maiken Bratt Elvestad, Kristian Hveem, Lars Vatten, Epic Study, Simone Benhamou, Pagona Lagiou, Ivana Holcátová, Franco Merletti, Kristina Kjaerheim, Antonio Agudo, Xavier Castellsagué, Tatiana V Macfarlane, Luigi Barzan, Cristina Canova, Ray Lowry, David I Conway, Ariana Znaor, Claire Healy, Maria Paula Curado, Sergio Koifman, Jose Eluf-Neto, Elena Matos, Ana Menezes, Leticia Fernandez, Andres Metspalu, Simon Heath, Mark Lathrop, Paul Brennan

Research output: Contribution to journalArticle (journal)peer-review

112 Citations (Scopus)


BACKGROUND: Genetic variants in 15q25 have been identified as potential risk markers for lung cancer (LC), but controversy exists as to whether this is a direct association, or whether the 15q variant is simply a proxy for increased exposure to tobacco carcinogens.

METHODS: We performed a detailed analysis of one 15q single nucleotide polymorphism (SNP) (rs16969968) with smoking behaviour and cancer risk in a total of 17 300 subjects from five LC studies and four upper aerodigestive tract (UADT) cancer studies.

RESULTS: Subjects with one minor allele smoked on average 0.3 cigarettes per day (CPD) more, whereas subjects with the homozygous minor AA genotype smoked on average 1.2 CPD more than subjects with a GG genotype (P < 0.001). The variant was associated with heavy smoking (>20 CPD) [odds ratio (OR) = 1.13, 95% confidence interval (CI) 0.96-1.34, P = 0.13 for heterozygotes and 1.81, 95% CI 1.39-2.35 for homozygotes, P < 0.0001]. The strong association between the variant and LC risk (OR = 1.30, 95% CI 1.23-1.38, P = 1 x 10(-18)), was virtually unchanged after adjusting for this smoking association (smoking adjusted OR = 1.27, 95% CI 1.19-1.35, P = 5 x 10(-13)). Furthermore, we found an association between the variant allele and an earlier age of LC onset (P = 0.02). The association was also noted in UADT cancers (OR = 1.08, 95% CI 1.01-1.15, P = 0.02). Genome wide association (GWA) analysis of over 300 000 SNPs on 11 219 subjects did not identify any additional variants related to smoking behaviour.

CONCLUSIONS: This study confirms the strong association between 15q gene variants and LC and shows an independent association with smoking quantity, as well as an association with UADT cancers.

Original languageEnglish
Pages (from-to)563-77
Number of pages15
JournalInternational Journal of Epidemiology
Issue number2
Publication statusPublished - 1 Apr 2010


  • Aged
  • Chromosomes, Human, Pair 15/genetics
  • Female
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Lung Neoplasms/genetics
  • Male
  • Middle Aged
  • Odds Ratio
  • Polymorphism, Single Nucleotide
  • Receptors, Nicotinic/genetics
  • Smoking/adverse effects
  • Tobacco Use Disorder/genetics


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