Role of Nicotine Dependence on the Relationship between Variants in the Nicotinic Receptor Genes and Risk of Lung Adenocarcinoma

Abstract

Several variations in the nicotinic receptor genes have been identified to be associated with both lung cancer risk and smoking in the genome-wide association (GWA) studies. However, the relationships among these three factors (genetic variants, nicotine dependence, and lung cancer) remain unclear. In an attempt to elucidate these relationships, we applied mediation analysis to quantify the impact of nicotine dependence on the association between the nicotinic receptor genetic variants and lung adenocarcinoma risk. We evaluated 23 single nucleotide polymorphisms (SNPs) in the five nicotinic receptor related genes (CHRNB3, CHRNA6, and CHRNA5/A3/B4) previously reported to be associated with lung cancer risk and smoking behavior and 14 SNPs in the four ‘control’ genes (TERT, CLPTM1L, CYP1A1, and TP53), which were not reported in the smoking GWA studies. A total of 661 lung adenocarcinoma cases and 1,347 controls with a smoking history, obtained from the Environment and Genetics in Lung Cancer Etiology case-control study, were included in the study. Results show that nicotine dependence is a mediator of the association between lung adenocarcinoma and gene variations in the regions of CHRNA5/A3/B4 and accounts for approximately 15% of this relationship. The top two CHRNA3 SNPs associated with the risk for lung adenocarcinoma were rs1051730 and rs12914385 (p-value = 1.9×10−10 and 1.1×10−10, respectively). Also, these two SNPs had significant indirect effects on lung adenocarcinoma risk through nicotine dependence (p = 0.003 and 0.007). Gene variations rs2736100 and rs2853676 in TERT and rs401681 and rs31489 in CLPTM1L had significant direct associations on lung adenocarcinoma without indirect effects through nicotine dependence. Our findings suggest that nicotine dependence plays an important role between genetic variants in the CHRNA5/A3/B4 region, especially CHRNA3, and lung adenocarcinoma. This may provide valuable information for understanding the pathogenesis of lung adenocarcinoma and for conducting personalized smoking cessation interventions.

Associations between smoking behavior-related alleles and the risk of melanoma

“…Various meta-analyses based on subjects of European ancestry identified robust associations for rs16969968 in the gene CHRNA5 and rs1051730 in the CHRNA3 with smoking quantity (number of cigarettes smoked per day) [7, 14, 15, 17]. Especially, rs16969968, a nonsynonymous variant, was indicated with functions of altering nicotinic receptor conductance in vitro by amino acid change in the CHRNA5 [7, 18, 19]. Those two loci have been found to be associated with lung cancer, chronic obstructive pulmonary disease and body mass index in never smokers [13, 20–23].…”

Genetic polymorphisms associated with smoking behaviour predict the risk of surgery in patients with Crohn's disease

“…In addition, validated questionnaires for nicotine dependence or biomarkers for nicotine consumption such as cotinine are not available within the SIBDCS data set. As such, though there is an extensive body of literature supporting the association of these smoking quantity‐associated SNPs with variables other than number of cigarettes per day: patient cotinine and carbon monoxide levels and nicotine dependence . However, without these data we cannot distinguish, whether the interaction of genetic risk with smoking in IBD patients is mediated via the number of cigarettes per day or in addition via a different smoking topography (ie deeper inhalation, number of puffs per cigarette).…”

Germline mutations predisposing to non-small cell lung cancer

“…In a study of variants of the nicotinic receptor genes and the association with both smoking dependence and adenocarcinoma of the lung, two CHRNA3 SNPs were most associated with nicotine dependence and adenocarcinoma of the lung [35]. They demonstrated that variations in these genes significantly affect the risk for adenocarcinoma of the lung.…”