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.
Link to publicationCitation for published version (APA): Halldén, S., Sjögren, M., Hedblad, B., Engström, G., Narkiewicz, K., Hoffmann, M., ... Melander, O. (2013). Smoking and obesity associated BDNF gene variance predicts total and cardiovascular mortality in smokers. Heart, 99(13), 949-953. DOI: 10.1136949-953. DOI: 10. /heartjnl-2013 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal SMOKING AND OBESITY ASSOCIATED BDNF GENE VARIANCE PREDICTS TOTAL AND CARDIOVASCULAR MORTALITY IN SMOKERS DesignCox proportional hazards models were used to relate the BDNF rs4923461(A/G) polymorphisms to all-cause, cancer and cardiovascular mortality and CVD incidence adjusted for age, sex, BMI and smoking quantity. SettingThe Malmö Diet and Cancer Study (MDCS), a population based prospective cohort study (n=30 447). PatientsWe obtained complete data of 25 071 subjects of whom 6507 were current smokers and 18 564 non smokers who underwent a baseline examination 1991-1996. Main Outcome MeasuresDuring a mean follow-up time of 12 years, 1049 deaths (346 cardiovascular deaths and 492 cancer deaths) and 802 incident CVD events occurred among current smokers. ResultsThe major allele (A) of rs4923461was significantly associated with ever having smoked (P=0.03) and high BMI (P=0.001). The A-allele was associated with risk of all-cause (HR=1.12, 95% CI 1.00-1.25, P<0.05) and CVD (HR=1.23, 95% CI 1.01-1.49, P=0.04) mortality. There was no significant association between the rs4923461 and cancer mortality or CVD incidence. ConclusionsOur data suggests that smoking-and obesity-associated variation of the BDNF gene affects the risk of death, especially due to cardiovascular causes, in smokers. Determination of BDNF genotype in smokers may guide the intensity of smoke cessation interventions needed.
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