Gene variance in the nicotinic receptor cluster (CHRNA5‐CHRNA3‐CHRNB4) predicts death from cardiopulmonary disease and cancer in smokers

Abstract

BackgroundGenetic variation in the cluster on chromosome 15, encoding the nicotinic acetylcholine receptor subunits (CHRNA5‐CHRNA3‐CHRNB4), has shown strong associations with tobacco consumption and an additional risk increase in smoking‐related diseases such as chronic obstructive pulmonary disease (COPD), peripheral artery disease and lung cancer.ObjectivesTo test whether rs1051730 (C/T), a tag for multiple variants in the CHRNA5‐CHRNA3‐CHRNB3 cluster, is associated with a change in risk of smoking‐related mortality and morbidity in the Malmö Diet and Cancer study, a population‐based prospective cohort study.MethodsAt baseline participants were classified as current (n = 6951), previous (n = 8426) or never (n = 9417) smokers. Cox‐proportional hazards models were used to determine the correlation between rs1051730 and incidence of first COPD, tobacco‐related cancer, other cancer and cardiovascular disease (CVD), and total mortality due to these causes, during approximately 14 years of follow‐up.ResultsAmongst current smokers there were 480 first incident COPD events, 852 tobacco‐related cancers, 810 other cancers and 1022 CVD events. A total of 1508 deaths occurred, including 500 due to CVD, 102 due to respiratory diseases and 677 due to cancer. In adjusted additive models, an increasing number of T alleles were associated with a gradual increase in total mortality, incident COPD and tobacco‐related cancer, even after adjustment for smoking quantity. No significant associations were observed amongst never smokers.ConclusionOur data suggest that gene variance in the CHRNA5‐CHRNA3‐CHRNB4 cluster is associated with an increased risk of death, incidence of COPD and tobacco‐related cancer in smokers. These findings indicate an individual susceptibility to tobacco use and its complications; this may be important when targeting and designing smoking cessation therapies.

α5‐nAChR contributes to epithelial‐mesenchymal transition and metastasis by regulating Jab1/Csn5 signalling in lung cancer

“…The role of nAChRs has been intensely studied in the growth, angiogenesis and metastasis of lung cancer . The reason for this trend is due to GWAS studies showing genetic variations in α5‐α3‐β4 nAChR cluster (CHRNA5‐CHRNA3‐CHRNB4) associated with increased risk of death from lung cancer, COPD and tobacco‐related cancers . Conventionally, the α7‐nAChR is thought to mediate the proliferative, pro‐angiogenic and pro‐metastatic activity of nicotine in lung cancer .…”

“…13,30 The reason for this trend is due to GWAS studies showing genetic variations in α5-α3-β4 nAChR cluster (CHRNA5-CHRNA3-CHRNB4) associated with increased risk of death from lung cancer, COPD and tobacco-related cancers. 14,31 Conventionally, the α7-nAChR is thought to mediate the proliferative, pro-angiogenic and pro-metastatic activity of nicotine in lung cancer. 32 Other genomic variances near CHRNA2 gene were correlated to increased overall risk for developing lung cancer.…”

Metabolic Disorder in Chronic Obstructive Pulmonary Disease (COPD) Patients: Towards a Personalized Approach Using Marine Drug Derivatives

“…However, these variants account for only 1%–2% of all COPD cases [5]. Genetic variations in the cluster on chromosome 15, encoding the nicotinic acetylcholine receptor subunits (CHRNA5-CHRNA3-CHRNB4), are correlated with tobacco addiction and increased risk of COPD, peripheral artery disease, lung cancer and obesity [6,7,8]. Different studies on lung tissue and peripheral blood identified increased expression of genes related to inflammatory pathways and immune regulation [9].…”

Phenome-Wide Association Study for Alcohol and Nicotine Risk Alleles in 26394 Women

“…As both drinking and smoking behaviors are strongly associated with numerous health consequences, many studies have sought to link genes implicated in risk for smoking and drinking behaviors to the adverse health consequences of these behaviors, obtaining consistent results (Druesne-Pecollo et al, 2009;Li et al, 2011Li et al, , 2012Chen et al, 2015;Hallden et al, 2015). However, owing to the potent effects that nicotine, alcohol, and their metabolites have on the human body (Guo and Ren, 2010;Drug Therapeutics Bulletin, 2014), smoking and drinking behaviors and their associated genes (with large effects on nicotine response and acetaldehyde metabolism, respectively) might be involved in a much wider range of health conditions and human behaviors than is currently recognized.…”