Monday, October 1, 2012

The Genetics of Smoking Cessation

Molecular Model of Nicotine
Research studies support a significant genetic contribution to alcohol, drug and nicotine dependence.  There may be some genetic factors that contribute to a general substance dependence vulnerability.  Additionally, some genetic factors may increase risk to specific substances of abuse.

A recent review of studies of European descent subjects found a link between cigarette consumption level (number of cigarettes smoked per day) and a region on chromosome 15.  This link has biological plausibility because it contains genes related to the cholingergic nicotinic receptor (CHRN).

Genetic factors related to nicotine dependence may act in several ways.  They may contribute to smoking risk through increasing risk for initiation, increasing risk for heavy smoking and increasing risk for persistence of smoking.  Persistent smoking risk may present with failure to respond to smoking cessation interventions.

Chen and colleagues from Washington University School of Medicine and the University of Wisconsin recently published an informative study on genetic risk factors and smoking cessation success in the American Journal of Psychiatry.

The key elements of the design for this studied included two major components:

  • Smoking Phenotype and Genotype:  Over 16,000 U.S. subjects between the ages of 45 and 64 participated in a prospective study of the epidemiology of atherosclerosis.  This study included assessment of smoking behavior and genotyping
  • Randomized Clinical Smoking Cessation Trial: Over 1,000 U.S. subjects participated in a clinical trial where they were randomized to one of six interventions: placebo, nicotine patch, nicotine lozenge, sustained release bupropion, nicotine patch plus nicotine lozenge, sustained release bupropion plus nicotine lozenge.  All subjects received brief indvidual counseling sessions

The research findings from this study were:

  • Smoking Phenotype and Genotype: Specific cholinergic nicotinic receptor haplotypes involving the A5, A3 and B4 receptors were linked to number of daily cigarettes smoked and to the age of smoking cessation.  Smoking more cigarettes on a daily basis was associated with a later age at smoking cessation.
  • Randomized Clinical Smoking Cessation Trial: 47.3% of subjects were abstinent from smoking at 8 weeks and receiving any active intervention increased abstinence rates by 87% compared to the placebo group.  Pharmacological treatment increased abstinence in the heavy smoking risk genotype but did not increase abstinence in subjects without the heavy risk genotype.  The heavy risk genotype subject group had the lowest abstinence rates in those receiving placebo indicating a "resistance" to a placebo effect

The authors note clinical implications of their findings "suggest that the biological effects of these haplotypes affect both smoking heaviness and a decreased ability to quit and that the interaction suggests that pharmacologic treatments are more effective for individuals who are biologically predisposed to have difficulty quitting". 

The randomized controlled trial in this study did not include the newest U.S. FDA approved smoking cessation drug varenicline.  Varenicline is a nicotine receptor partial agonist suggesting it's effectiveness may interact with nicotinic receptor genotype.

This study supports the evolution of a more personalized approach to smoking cessation and other drug dependence treatment.  Genotyping individual patients holds promise as a way to determine each individual's best treatment approach.

Molecular model of the drug nicotine is in the public domain from Wikipedia Commons authored by Esquilo.

Tobacco and Genetics Consortium (2010). Genome-wide meta-analyses identify multiple loci associated with smoking behavior. Nature genetics, 42 (5), 441-7 PMID: 20418890

Chen LS, Baker TB, Piper ME, Breslau N, Cannon DS, Doheny KF, Gogarten SM, Johnson EO, Saccone NL, Wang JC, Weiss RB, Goate AM, & Bierut LJ (2012). Interplay of genetic risk factors (CHRNA5-CHRNA3-CHRNB4) and cessation treatments in smoking cessation success. The American journal of psychiatry, 169 (7), 735-42 PMID: 22648373


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