title: Gene variance in the nicotinic receptor cluster (CHRNA5-CHRNA3-CHRNB4) predicts death from cardiopulmonary disease and cancer in smokers.
abstract: BACKGROUND
  Genetic 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.
  
  
  OBJECTIVE
  To 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.
  
  
  METHODS
  At 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.
  
  
  RESULTS
  Amongst 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.
  
  
  CONCLUSIONS
  Our 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.
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.|Department of Internal Medicine, Skåne University Hospital Malmö, Malmö, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Halldén
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Sjögren
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: B
authors.initials: B
authors.lastname: Hedblad
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: G
authors.initials: G
authors.lastname: Engström
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.|Department of Medical Imaging and Physiology, Skåne University Hospital, Malmö, Sweden.
authors.forename: V
authors.initials: V
authors.lastname: Hamrefors
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.|Department of Reconstructive Surgery, Skåne University Hospital Malmö, Malmö, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Manjer
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.|Department of Internal Medicine, Skåne University Hospital Malmö, Malmö, Sweden.
authors.forename: O
authors.initials: O
authors.lastname: Melander
mesh_terms: D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D005810:Multigene Family / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics*; D058729:Peripheral Arterial Disease / Q000401:mortality*; D011110:Polymorphism, Genetic; D016016:Proportional Hazards Models; D011446:Prospective Studies; D029424:Pulmonary Disease, Chronic Obstructive / Q000401:mortality*; D011978:Receptors, Nicotinic / Q000235:genetics*; D012907:Smoking / Q000009:adverse effects*
chemical_list: D009419:Nerve Tissue Proteins; D011978:Receptors, Nicotinic; C447158:CHRNA5 protein, human; C447159:CHRNB4 protein, human
keywords: CHRNA; COPD; epidemiology; smoking genetics; tobacco-related cancer