Interplay of Genetic Risk Factors (CHRNA5-CHRNA3-CHRNB4) and Cessation Treatments in Smoking Cessation Success
Publication: American Journal of Psychiatry
Abstract
Objective:
Smoking is highly intractable, and the genetic influences on cessation are unclear. Identifying the genetic factors affecting smoking cessation could elucidate the nature of tobacco dependence, enhance risk assessment, and support development of treatment algorithms. This study tested whether variants in the nicotinic receptor gene cluster CHRNA5-CHRNA3-CHRNB4 predict age at smoking cessation and relapse after an attempt to quit smoking.
Method:
In a community-based, cross-sectional study (N=5,216) and a randomized comparative effectiveness smoking cessation trial (N=1,073), the authors used Cox proportional hazard models and logistic regression to model the relationships of smoking cessation (self-reported quit age in the community study and point-prevalence abstinence at the end of treatment in the clinical trial) to three common haplotypes in the CHRNA5-CHRNA3-CHRNB4 region defined by rs16969968 and rs680244.
Results:
The genetic variants in the CHRNA5-CHRNA3-CHRNB4 region that predict nicotine dependence also predicted a later age at smoking cessation in the community sample. In the smoking cessation trial, haplotype predicted abstinence at end of treatment in individuals receiving placebo but not among individuals receiving active medication. Haplotype interacted with treatment in affecting cessation success.
Conclusions:
Smokers with the high-risk haplotype were three times as likely to respond to pharmacologic cessation treatments as were smokers with the low-risk haplotype. The high-risk haplotype increased the risk of cessation failure, and this increased risk was ameliorated by cessation pharmacotherapy. By identifying a high-risk genetic group with heightened response to smoking cessation pharmacotherapy, this work may support the development of personalized cessation treatments.
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History
Received: 20 October 2011
Revision received: 7 February 2012
Accepted: 5 March 2012
Published online: 1 July 2012
Published in print: July 2012
Authors
Funding Information
Drs. Bierut, Goate, and Wang are listed as inventors on issued U.S. patent 8,080,371, “Markers for Addiction,” which covers the use of certain SNPs in determining the diagnosis, prognosis, and treatment of addiction; no product is on the market, and no commercial interest presently exists for this patent. Dr. Goate also reports research funding for Alzheimer's disease research from AstraZeneca ($75,000 for the last 3 years), Genentech (total $120,000), and Pfizer ($200,000 over 3 years) and an honorarium ($1,000) from Pfizer for a presentation at Pfizer on Alzheimer's disease. The remaining authors report no financial relationships with commercial interests.Supported by grants P01 CA-089392 (Dr. Bierut) and P50 CA-84724 and K05 CA-139871 (Dr. Baker) from the National Cancer Institute; grants P50 DA-19706 (Dr. Baker), R01 DA-026911 (Dr. Saccone), K02 DA-021237 (Dr. Bierut), and K08 DA-030398 (Dr. Chen) from the National Institute on Drug Abuse; grant U01 HG-004422 (Dr. Bierut) from the National Human Genome Research Institute; and subaward KL2 RR-024994 (Dr. Chen) from the National Center for Research Resources. Genotyping services for the University of Wisconsin study group were provided by the Center for Inherited Disease Research at Johns Hopkins University, and funding support for the center was provided by grant U01 HG-004438 from the National Human Genome Research Institute and NIH contract HHSN268200782096C to Johns Hopkins University. Assistance with genotype cleaning was provided by the Gene Environment Association Studies Coordinating Center, supported by grant U01 HG-004446 from the National Human Genome Research Institute. The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01 HC-55015, N01 HC-55016, N01 HC-55018, N01 HC-55019, N01 HC-55020, N01 HC-55021, N01 HC-55022, R01 HL-087641, R01 HL-59367, and R01 HL-086694; by National Human Genome Research Institute contract U01 HG-004402; and by NIH contract HHSN268200625226C. Infrastructure was partly supported by grant UL1 RR-025005 from the NIH Division of Research Resources and NIH Roadmap for Medical Research. Glaxo Wellcome provided bupropion at no cost in the University of Wisconsin Transdisciplinary Tobacco Use Research Center clinical trial.
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