Association of alcohol with lung cancer risk in men with different growth hormone receptor genotypes

Abstract

Objective: To test whether genetic variants of the growth hormone receptor gene (GHR) modulate the effect of lifestyle variables on lung cancer (LC) risk.

Materials and methods: This population-based cohort study involved 6,439 men from the Japan-Hawaii Cancer study drawn from the Kuakini Honolulu Heart Program who were cancer-free at baseline examination (1965-1968; age 45-68 years) and followed-up until December 1999. We determined the association of GHR SNP rs4130113 genotypes GHR-AA (common allele A homozygotes) and GHR-G (minor allele G carriage) with alcohol drinking, BMI, physical activity and cigarette smoking in relation to LC and non-small cell LC (NSCLC). Results were expressed as hazard ratios and 95 % CIs estimated from Cox proportional hazard models.

Results: Over mean 26.7 ± 7.4 SD years follow-up, 190 LC cases, including 133 NSCLC cases, were diagnosed. After adjusting for age, education, alcohol intake, BMI, physical activity, cigarette smoking, green tea consumption and dietary saturated fat, main-effect Cox models showed that compared with GHR-AA, GHR-G was associated with protection against LC: HR = 0.75 (95 % CI, 0.56-1.00). Full Cox models showed GHR-G interacted with alcohol intake only (β = 1.171; p = 0.0003; drinks per week: β = 0.279; P = 0.0024). Stratified analyses showed that for GHR-AA, drinkers had reduced LC risk (HR = 0.54; 95 % CI, 0.35-0.85), and that <2 drinks/week had the strongest protection (HR = 0.38; 95 % CI, 0.18-0.83). In contrast, for GHR-G, alcohol drinkers had increased LC risk (HR = 1.70; 95 % CI, 1.07-2.69) which was dose-dependent (P for trend = 0.005). Results for NSCLC were similar.

Conclusion: In men with the GHR-AA genotype, alcohol drinking at a low dose poses significantly less risk of LC compared with non-drinkers and higher alcohol consumption., the overall relationship being U-shaped. In contrast, in GHR minor allele carriers, alcohol posed a progressively greater risk of LC as amount consumed increased.

Keywords: Alcohol; Gene-environment interaction; Growth hormone receptor genotype; Lifestyle; Lung cancer; Non-small-cell lung cancer.