Abstract
Metabolism of nicotine by cytochrome P450 2A6 (CYP2A6) is a suspected determinant of smoking dose and, consequently, lung cancer risk. We conducted a genome wide association study (GWAS) of CYP2A6 activity, as measured by the urinary ratio of trans 30 hydroxycotinine and its glucuronide conjugate over cotinine (total 3HCOT/COT), among 2,239 smokers in the Multiethnic Cohort (MEC) study. We identified 248 CYP2A6 variants associated with CYP2A6 activity (P < 5 × 10-8). CYP2A6 activity was correlated (r = 0.32; P < 0.0001) with total nicotine equivalents (a measure of nicotine uptake). When we examined the effect of these variants on lung cancer risk in the Transdisciplinary Research in Cancer of the Lung (TRICL) consortium GWAS dataset (13,479 cases and 43,218 controls), we found that the vast majority of these individual effects were directionally consistent and associated with an increased lung cancer risk. Two hundred and twenty-six of the 248 variants associated with CYP2A6 activity in the MEC were available in TRICL. Of them, 81% had directionally consistent risk estimates, and six were globally significantly associated with lung cancer. When conditioning on nine known functional variants and two deletions, the top two SNPs (rs56113850 in MEC and rs35755165 in TRICL) remained significantly associated with CYP2A6 activity in MEC and lung cancer in TRICL. The present data support the hypothesis that a greater CYP2A6 activity causes smokers to smoke more extensively and be exposed to higher levels of carcinogens, resulting in an increased risk for lung cancer. Although the variants identified in these studies may be used as risk prediction markers, the exact causal variants remain to be identified.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 5768-5776 |
| Number of pages | 9 |
| Journal | Cancer Research |
| Volume | 76 |
| Issue number | 19 |
| DOIs | |
| State | Published - Oct 1 2016 |
Bibliographical note
Funding Information:This MEC study was funded by NIH grants 5P01CA138338 (principal investigator, S. Hecht; project leaders, L. Le Marchand, S. Murphy). This study is also supported by U01 CA164973 (Contact PIs: L. Le Marchand). The TRICL Study was supported by NIH grant U19-CA148127 as part of the Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative. The SLRI study was supported by Canadian Cancer Society Research Institute (020214), Ontario Institute of Cancer and Cancer Care Ontario Chair Award to R. Hung. The ICR study was supported by Cancer Research UK (C1298/A8780 and C1298/A8362 - Bobby Moore Fund for Cancer Research UK) and NCRN, HEAL, and Sanofi-Aventis. Additional funding was obtained from NIH grants (5R01CA055769, 5R01CA127219, 5R01CA133996, and 5R01CA121197). The Liverpool Lung Project (LLP) was supported by The Roy Castle Lung Cancer Foundation, UK. The ICR and LLP studies made use of genotyping data from the Wellcome Trust Case Control Consortium 2 (WTCCC2); a full list of the investigators who contributed to the generation of the data is available at www.wtccc.org.uk. Sample collection for the Heidelberg lung cancer study was in part supported by a grant (70-2919) from the Deutsche Krebshilfe. The work was additionally supported by a Helmholtz-DAAD fellowship (A/07/97379 to MNT) and by the NIH (U19CA148127). The KORA Surveys were financed by the GSF, which is funded by the German Federal Ministry of Education, Science, Research and Technology and the State of Bavaria. The LUng Cancer in the Young study (LUCY) was funded in part by the National Genome Research Network (NGFN), the DFG (BI 576/2-1; BI 576/2-2), the Helmholtzgemeinschaft (HGF), and the Federal office for Radiation Protection (BfS: STSch4454). Genotyping was performed in the Genome Analysis Center (GAC) of the Helmholtz ZentrumMuenchen. Support for the Central Europe, HUNT2/Tromsø, and CARET genome-wide studies was provided by Institut National du Cancer, France. Support for the HUNT2/Tromsø genome-wide study was also provided by the European Community (Integrated Project DNA repair, LSHG-CT- 2005-512113), the Norwegian Cancer Association, and the Functional Genomics Programme of Research Council of Norway. Support for the Central Europe study, Czech Republic, was also provided by the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101). Support for the CARET genome-wide study was also provided by grants from the US NCI, NIH (R01 CA111703 and UO1 CA63673), and by funds from the Fred Hutchinson Cancer Research Center. Additional funding for study coordination, genotyping of replication studies and statistical analysis was provided by the US NCI (R01 CA092039). The lung cancer GWAS from Estonia was partly supported by a FP7 grant (REGPOT 245536), by the Estonian Government (SF0180142s08), by EU RDF in the frame of Centre of Excellence in Genomics and Estoinian Research Infrastructure's Roadmap, and by University of Tartu (SP1GVARENG). The work reported in this paper was partly undertaken during the tenure of a Postdoctoral Fellowship from the IARC (for MNT). The Environment and Genetics in Lung Cancer Etiology (EAGLE), the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC), and the Prostate, Lung, Colon, Ovary Screening Trial (PLCO) studies and the genotyping of ATBC, the Cancer Prevention Study II Nutrition Cohort (CPS-II), and part of PLCO were supported by the Intramural Research Program of NIH, NCI, Division of Cancer Epidemiology and Genetics. ATBC was also supported by US Public Health Service contracts (N01-CN-45165, N01-RC-45035 and N01-RC-37004) from the NCI. PLCO was also supported by individual contracts from the NCI to the University of Colorado Denver (NO1-CN-25514), Georgetown University (NO1-CN- 25522), Pacific Health Research Institute (NO1-CN-25515), Henry Ford Health System (NO1-CN-25512), University of Minnesota (NO1-CN- 25513), Washington University (NO1-CN-25516), University of Pittsburgh (NO1-CN-25511), University of Utah (NO1-CN-25524), Marshfield Clinic Research Foundation (NO1-CN-25518), University of Alabama at Birmingham (NO1-CN-75022, Westat, Inc. NO1-CN-25476), University of California, Los Angeles (NO1-CN-25404). Approval for the deCODE study was granted by the Icelandic National Bioethics Committee (ref. 12-122-V7) and the Icelandic Data Protection Authority (refs. 2001/25 and 2006/518). The Cancer Prevention Study II Nutrition Cohort was supported by the American Cancer Society. The NIH Genes, Environment and Health Initiative (GEI) partly funded DNA extraction and statistical analyses (HG-06-033- NCI-01 and RO1HL091172-01), genotyping at the Johns Hopkins University Center for Inherited Disease Research (U01HG004438 and NIHHHSN268200782096C), and study coordination at the GENEVA Coordination Center (U01 HG004446) for EAGLE and part of PLCO studies. Funding for the MD Anderson Cancer Study was provided by NIH grants (P50 CA70907, R01CA121197, R01 CA127219, U19 CA148127, R01 CA55769, and K07CA160753) and CPRIT grant (RP100443). Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is funded through a federal contract from the NIH to The Johns Hopkins University (HHSN268200782096C). The Harvard Lung Cancer Study was supported by the NIH (NCI) grants CA092824, CA090578, and CA074386.
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