Nicotinic acetylcholine receptor polymorphism, smoking history, and tobacco-related cancer in the general population.

Abstract

1530 Background: Smokers often develop lung and bladder cancer; however, not all smokers develop these diseases. We examined whether the nicotinic acetylcholine receptor gene (CHRNA3) rs1051730 polymorphism can identify smokers in the general population at genetically high risk of tobacco-related cancer, that is, at higher risk than that explained by detailed smoking history alone. Methods: We genotyped 10,322 participants from the Danish general population, the Copenhagen City Heart Study. Detailed smoking history was obtained and validated at baseline. End-points during the following 18 years were lung and bladder cancer from the Danish cancer registry. Follow-up was 100% complete. Results: Among the 7831 ever smokers, CHRNA3 non-carriers (44%) and homozygotes (11%) had daily tobacco consumption of 16 and 18 g/day (Wilcoxon: p = 0.000004), cumulative tobacco consumption of 28 to 31 packyears (p = 0.001), and smoking inhalation of 72% and 78% (chi- square: p = 0.0002). As expected increasing baseline packyears smoked associated with increasing risk of lung and bladder cancer during the following 18 years (trend-tests: p = 4*10-47 and p = 0.0002); the hazard ratios for lung and bladder cancer in those with baseline > 40 packyears smoked vs. never-smokers were 44 (95% CI:14-105) and 2.9 (1.4-5.9) after multifactorial adjustment including genotype. In addition, CHRNA3 homozygotes vs. non-carriers had hazard ratios for lung and bladder cancer of 1.65 (1.18-2.30) and 1.79 (1.05-3.06) after multifactorial adjustment including detailed smoking history. The highest absolute 10-year risks were 11.4% for lung cancer and 4.4% for bladder cancer for homozygous smokers above 60 years who had smoked > 30 packyears at baseline. Conclusions: The nicotinic acetylcholine receptor rs1051730 polymorphism identifies 11% of smokers in the general population at excessive high risk of tobacco-related cancer, even after considering a full smoking history. No significant financial relationships to disclose.