title: 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.
authors.affiliation: Behavioral and Community Health Sciences, School of Public Health and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, United States of America.
authors.forename: Tung-Sung
authors.initials: TS
authors.lastname: Tseng
authors.affiliation: Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States of America.
authors.forename: Jong Y
authors.initials: JY
authors.lastname: Park
authors.affiliation: Department of Pediatrics and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, United States of America.
authors.forename: Jovanny
authors.initials: J
authors.lastname: Zabaleta
authors.affiliation: Behavioral and Community Health Sciences, School of Public Health and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, United States of America.
authors.forename: Sarah
authors.initials: S
authors.lastname: Moody-Thomas
authors.affiliation: Behavioral and Community Health Sciences, School of Public Health and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, United States of America.
authors.forename: Melinda S
authors.initials: MS
authors.lastname: Sothern
authors.affiliation: Department of Global Community Health and Behavioral Sciences, Tulane University, New Orleans, LA, United States of America.
authors.forename: Ted
authors.initials: T
authors.lastname: Chen
authors.affiliation: Department of Health Outcomes and Behavior, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States of America.
authors.forename: David E
authors.initials: DE
authors.lastname: Evans
authors.affiliation: Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States of America.
authors.forename: Hui-Yi
authors.initials: HY
authors.lastname: Lin
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011978:Receptors, Nicotinic / Q000235:genetics*; D012307:Risk Factors; D012907:Smoking / Q000235:genetics*; D014029:Tobacco Use Disorder / Q000235:genetics*
chemical_list: D011978:Receptors, Nicotinic