Genetic polymorphisms in 15q25 and 19q13 loci, cotinine levels, and risk of lung cancer in EPIC.
- Authors
- Timofeeva, Maria N; McKay, James D; Smith, George Davey; Johansson, Mattias; Byrnes, Graham B; Chabrier, Amélie; Relton, Caroline; Ueland, Per Magne; Vollset, Stein Emil; Midttun, Øivind; Nygård, Ottar; Slimani, Nadia; Romieu, Isabelle; Clavel-Chapelon, Françoise; Boutron-Ruault, Marie-Christine; Fagherazzi, Guy; Kaaks, Rudolf; Teucher, Birgit; Boeing, Heiner; Weikert, Cornelia; Bueno-de-Mesquita, H Bas; van Gils, Carla; Peeters, Petra H M; Agudo, Antonio; Barricarte, Aurelio; Huerta, Jose-Maria; Rodríguez, Laudina; Sánchez, Maria-José; Larrañaga, Nerea; Khaw, Kay-Tee; Wareham, Nick; Allen, Naomi E; Travis, Ruth C; Gallo, Valentina; Norat, Teresa; Krogh, Vittorio; Masala, Giovanna; Panico, Salvatore; Sacerdote, Carlotta; Tumino, Rosario; Trichopoulou, Antonia; Lagiou, Pagona; Trichopoulos, Dimitrios; Rasmuson, Torgny; Hallmans, Göran; Riboli, Elio; Vineis, Paolo; Brennan, Paul
- Year
- 2011
- Journal
- Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
- PMID
- 21862624
- DOI
- 10.1158/1055-9965.EPI-11-0496
- PMCID
- PMC5697736
BACKGROUNDS: Multiple polymorphisms affecting smoking behavior have been identified through genome-wide 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 single-nucleotide 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.
ORs for the Risk of Lung Cancer by CPD (a.) and Cotinine Level (b.)a. ORs for the risk of lung cancer for deciles of CPD are presented before adjustment (Ptrend=2*10−53) and after adjustment for cotinine level (Ptrend=4.5*10−20). Corresponding mean cotinine level for each percentile of CPD is given. Non smokers were used as reference group. Corresponding ORs and 95%CIs are presented in the Supplementary Table 1. The analysis includes only individuals with available cotinine and CPD measurements.b. ORs for the risk of lung cancer for 200nmol/L intervals of cotinine level before Ptrend=3*10−73) and after correction for RDR and adjustment for CPD (Ptrend=1.5*10−29) are presented. Reference group for the cotinine level – individuals with less then 75nmol/L. Corresponding ORs and 95%CIs are presented in the Supplementary Table 2.
Effect of 15q25 Locus (rs16969968 and rs57876) and 19q13 Locus (rs7937 and rs4105144) on the Risk of Lung CancerORs and 95%CIs for the risk of lung cancer are calculated applying conditional logistic regression adjusted for quintiles of cotinine levels/CPD/duration of smoking. Effect of SNPs in smoking strata (current, former and never smokers) was calculated using unconditional logistic regression adjusted for matching variables (date of birth, country, date of blood collection and gender).
| Name | Type |
|---|---|
| 10q23 local | variant |
| 10q23 locus local | variant |
| 10q23 SNPs local | variant |
| 15q25 locus | variant |
| 15q25 locus variants local | variant |
| 15q25 missense variant local | variant |
| 19q13 local | variant |
| 19q13 locus local | variant |
| 19q13 SNPs local | variant |
| 7p14 local | variant |
| 7p14 locus local | variant |
| 7p14 locus variants local | variant |
| 7p14 SNPs local | variant |
| 8p11 local | variant |
| 8p11 locus local | variant |
| 8p11 SNPs local | variant |
| age at smoking cessation local | phenotype |
| age at smoking initiation | phenotype |
| cases | cohort |
| Chrna3 | gene |
| CHRNA5 | gene |
| Chrna6 | gene |
| Chrnb3 | gene |
| CHRNB3-CHRNA6 locus variants local | variant |
| Chrnb4 | gene |
| cigarettes | phenotype |
| cigarettes per day local | drug |
| circulating cotinine local | phenotype |
| controls | cohort |
| COT local | drug |
| cotinine | drug |
| cotinine levels | drug |
| CPD | phenotype |
| current smoking | phenotype |
| CYP2A6 | gene |
| CYP2A6-CYP2B6 locus variants local | variant |
| CYP2B6 | gene |
| duration of smoking | phenotype |
| EPIC | cohort |
| EPIC-lung | cohort |
| EPIC Lung study local | cohort |
| ever smoking | phenotype |
| former smokers | phenotype |
| genetic variants | cohort |
| lung cancer | phenotype |
| lung cancer risk | phenotype |
| never smokers | phenotype |
| nicotine | drug |
| nicotine addiction | phenotype |
| nicotine metabolites local | drug |
| nicotine metabolites local | phenotype |
| Pack-year local | phenotype |
| pack-years | phenotype |
| risk | phenotype |
| rs16969968 | variant |
| rs4105144 | variant |
| rs578776 | variant |
| rs7937 local | variant |
| smoking | phenotype |
| smoking behavior | phenotype |
| Smoking cases local | cohort |
| smoking interruptions local | phenotype |
| smoking status | phenotype |
| SNP | cohort |
| SNPs on 15q25 local | variant |
| SNPs on 19q13 local | variant |
| subjects | cohort |
| Swedish cohort | cohort |
| tobacco dependence | phenotype |
| tobacco use | phenotype |
| trans-3′-hydroxycotinine local | drug |
| variant | cohort |
| WENBIT local | cohort |
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