Using the Genetics of Smoking Behavior to Optimize Selection of Cessation Technique

Jacquelyn K. Beals, PhD

Disclosures

June 23, 2010

If you are among the thousands of people who have tried to quit smoking, you may have done an Internet search on "smoking cessation" and "techniques." The approaches seem endless (> 500,000 results), and the promised outcomes questionable. But at least one of them should work for you, right?

Neurolinguistic programming claims to remove the psychological craving to smoke, and aversion therapy conditions smokers to associate smoking with unpleasant stimuli. A hypnotherapy site promises that clients will leave after an hour as "happy nonsmokers," while an acupuncturist more modestly says that treatment will "decrease withdrawal symptoms and the desire for cigarettes." And the list goes on.

The common factor in these claims is behavior modification. But is the tendency to smoke, to become nicotine-addicted, and to have difficulty quitting primarily behavioral -- a product of social surroundings and custom -- or is it genetic? Studies in twins have shown that between 40% and 60% of differences in smoking cessation are genetic.[1] Are some smokers, no matter how sincere their attempts to quit, doomed to failure, whereas others can go "cold turkey" with relative ease?

Where There's Smoke, There's CHRNA

Persistent smokers, whether clinicians or patients, may be interested in 3 studies published in the May 2010 issue of Nature Genetics.[2,3,4] The first report, from the Tobacco and Genetics Consortium,[2] is a meta-analysis of genetic results from more than 74,000 individuals and focused on the "15 most significant regions" associated with smoking. Their results identify 3 gene variants highly associated with cigarettes smoked per day (CPD) -- a recognized measure of nicotine addiction.

Chief among these is a variant of the nicotinic receptor gene CHRNA3. Three other single-nucleotide polymorphisms (SNPs) demonstrate much lower genome-wide significance; among them, EGLN2 codes for an enzyme involved in hypoxia-inducible factor degradation, the activity of which varies with oxygen availability.

Eight SNPs were associated with smoking initiation. The most significant is BDNF, a gene variously implicated in adult synaptic plasticity and in the effectiveness of antidepressants. A lone SNP near DBH (whose product catalyzes conversion of dopamine to norepinephrine) was associated with smoking cessation.

The second study, by the Oxford-GlaxoSmithKline study group,[3] reported a genome-wide meta-analysis of SNPs associated with behavioral traits related to smoking, using a study population of 41,150. CPD was tightly associated with several CHRNA genes, including CHRNA3. The study's search for genetic variants associated with establishing a smoking habit, or with past smoking but successful quitting, found no genome-wide significance or inconsistent results, respectively.

Finally, a group headed by deCODE Genetics[4] focused its study on CPD and smoking initiation. Their genome-wide meta-analysis found strong associations between CPD and SNPs in the region containing members of the CHRN gene family. CPD was also significantly associated with SNPs on chromosomes 19 and 8, including genes encoding enzymes that metabolize nicotine.

I'd Walk a Mile for Some Dopamine

It's all very well to note the prominent and consistently replicated association between CPD and variants encoding nicotinic receptors, but how can these findings guide clinical practice? A glance at earlier studies that focus on "addictive personalities" suggests some potential applications.

A 2007 study in Science[5] linked reduced dopamine receptor density and high dopamine levels with a poor ability to learn from errors. Specifically, reduced density of dopamine receptor D2 is associated with addictive behaviors; individuals with a genetic polymorphism that reduces D2 receptor density show less avoidance learning and relatively more learning from positive reinforcement.

Thus, failure to quit smoking may not always be caused by "needy" nicotinic receptors, but it could also reflect an inability to learn from negative outcomes. Perhaps it is not a coincidence that in the 3 recent studies the only SNP to be associated with smoking cessation lies near DBH, the product of which catalyzes dopamine conversion to norepinephrine.

A second study with even greater clinical relevance appeared in 2008 in Archives of General Psychiatry.[6] Smokers between 18 and 65 years of age were placed in one of several clinical smoking cessation trials evaluating bupropion vs placebo, nicotine nasal spray vs nicotine patch, nicotine patch vs placebo, or bupropion vs placebo.

Genetic analyses searched for SNPs associated with successful abstention throughout the trials. Although the investigators identified a long list of genes with variants that distinguished between successful and unsuccessful quitters, they concluded that the genetic factors involved in smoking cessation were different for the dopamine transporter blocker bupropion than for any of the nicotine replacement therapies.

I Screen, You Screen, We All Screen for ... What?

The complexity of human smoking behavior will probably never be reduced to a game where nicotine trumps dopamine or vice versa. However, as researchers continue to find gene variants associated with establishing a smoking habit, CPD, and successful or unsuccessful cessation, clinicians can use this information to accommodate patients' individual differences.

For example, if a patient's genomic profile shows CHRNA variants associated with high CPD, nicotine craving is probably a strong factor and nicotine replacement therapy may help that patient quit smoking. By contrast, a patient whose genomic screening reveals the variant that reduces dopamine receptor density probably learns poorly from negative feedback but relatively better through positive reinforcement. For this patient, the "carrots" of a positive reinforcement program may be more effective than the "sticks" of aversion therapy -- and unquestionably healthier than the carcinogen-laden "sticks" that they replace.

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