Quitting Smoking – A Matter of DNA?

Genes may play a role in determining why smokers can or cannot quit, according to a new study published online by Neuropsychopharmacology and reported by MedPage Today on 30 August 2005.

The report comprises results from two clinical trials that examined responses to Zyban (bupropion), transdermal nicotine patches and nicotine nasal spray.

Responsiveness to specific smoking-cessation therapies was associated with differences in genetic variants. According to researcher Caryn Lerman, PhD, of the Abramson Cancer Center of the University of Pennsylvania, these differences may explain why various smoking-cessation treatments work for some people and not others.

For example, smokers with two copies of the “Ins C” variant of the dopamine D2-receptor gene responded better to Zyban (bupropion) therapy, compared with smokers who had one or more copies of the “Del C” variant of the same gene.

Smokers with the “Del C” variant responded better than the other group to nicotine-replacement treatments such as a nicotine nasal spray or patch, compared to smokers with two copies of the “Inc C” gene.

Study Conduct & Results

The report covers two randomized clinical studies of about 400 participants each, with a six-month follow-up. One study was a double-blind, placebo-controlled Zyban trial; the other was an open-label study that compared a nicotine nasal spray with a transdermal nicotine patch.

In both studies, researchers examined the effect on treatment success of variations in the dopamine D2 receptor, which is known to be involved in the brain’s reward pathways. On this gene, at location 141 of the promoter sequence, two variants exist: “Ins C” and “Del C”. The “Ins C” allele is more common and is associated with greater gene-transcriptional efficiency.

Results of the Zyban trial showed that 35% of smokers who had two copies of (i.e., were homozygous for) “Ins C” continued to abstain from smoking at six months, compared with 20% of smokers with who had one or two copies of “Del C”.

Conversely, results of the nicotine replacement study showed that 46% of smokers carrying the “Del C” allele continued to abstain from smoking at six months, versus only 31% of smoker who were homozygous for “Ins C”.

The researchers suggested that smokers who are homozygous for “Ins C” may have more D2 receptors to bind dopamine. For these smokers, smoking may be more rewarding, and quitting more difficult. Zyban may work better than nicotine-replacement therapy for these people, because Zyban inhibits dopamine reuptake, resulting in higher dopamine levels that may act as a substitute for the pleasurable effects of smoking.

Side effects and withdrawal symptoms seemed to have to no significant differences based on genotype, suggesting that these events may be related to other mechanisms. The study was limited by the homogeneity of participants’ ethnic backgrounds - all were of European origin. The researchers concluded, "Larger scale pharmacogenetic trials confirming the findings of the present study in different ethnic groups may allow for genotype-based selection of pharmacotherapy for nicotine dependence."

Sources:

Posted: September 2005


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