The "Stop Smoking" Gene, DRD2
Smoking is a habit
that can cost you your life. According to the CDC, "Tobacco use is the
leading preventable cause of death in the United States. Cigarette smoking
causes an estimated 440,000 deaths, or about 1 of every 5 deaths, each
year. This estimate includes 35,000 deaths from secondhand smoke exposure."
In addition, "More deaths are caused each year by tobacco use than by all
deaths from human immunodeficiency virus (HIV), illegal drug use, alcohol
use, motor vehicle injuries, suicides, and murders combined." It is obvious
to see why researchers are looking for ways to help those who want to quit
smoking. Recently there have been reports in the popular press that if
you have a specific type of a gene, you may be able to quit smoking easier
than someone who lacks this specific type of gene.
DRD2 is the gene that
codes for dopamine D2 receptor. It is located on chromosome 11 (see figure
below for exact location). Those who carry certain alleles of the gene
DRD2 have been shown to be more prone to alcoholism, drug use, and other
addictive behaviors. Recently, researchers have found that those with these
alleles may be more prone to smoking as well. DRD2 is made up of two alleles,
A1 and A2. Therefore you can have three different genotypes if you carry
the DRD2 gene (A1/A1, A1/A2, A2/A2).
Figure 1. Location of DRD2 on Chromosome
11. DRD2 is located between 11q22-23 (Shaded area)
For a more detailed look at DRD2's location on Chromosome 11 click here
According to a CNN.com article published in 2001, Dr. Paul Cinciripini, the director of the Tobacco Research and Treatment Center at M.D. Anderson conducted a study in which the participants were all given counseling and a nicotine patch (CNN.com 2001). However, some of the subjects were given placebo's while the others were given antidepressants. During the 18 weeks of the study, 25% of those on placebo were able to abstain from smoking while 37% of those on the antidepressants were able to abstain from smoking. Dr. Cinciripini also found that "participants with a certain type of the DRD2 gene were more likely to start smoking again after the 18 weeks." He further stated that, "If you have the A1 allele, you quit (smoking) less often" while those who had the A2 allele responded well to the antidepressants and were able to abstain from smoking more often and for a longer period of time.
A study published in the American Journal of Psychiatry in 2004 looked at trends of smoking progression in adolescents. Audrain-McGovern et al.studied the effects of SLC6A3 and DRD2 but only the effects of DRD2 will be examined here. In addition to examining the smoking progression of the subjects, Audrain-McGovern et al. rated each subject for depression symptoms using the CES-D Scale. They found "of the 615 participants, 412 (67%) had no DRD2 A1 alleles (A2/A2), 184 (30%) had one DRD2 A1 allele (A1/A2), and 19 (3%) had two DRD2 A1 alleles (A1/A1)." They found that "smoking status was not significantly associated with DRD2 genotype." However, when looking at the depression scores there was "a highly significant dose response effect of DRD2 A1 alleles on depressions symptoms." For those adolescents with the A2/A2 genotype their score was 12.4, those with the A1/A2 genotype scored 15.1, and those with the A1/A1 genotype scored the highest on the scale with 16.7. They also found that the number of A1 alleles effected smoking progression, "each A1 allele nearly doubled the odds of smoking progression."
While Dr. Cinciripini's
findings are important, the popular article fails to articulate several
key features of Dr. Cinciripini's research. A report on Dr. Cinciripini's
unpublished data states that the antidepressant venlafaxine was used. Dr.
Cinciripini suggested that while there was a more consistent result on
smoking cessation using venlafaxine among those with the A2 genotype, some
A1 participants also responded positively. Dr. Cinciripini also noted that
there is a higher rate of smoking in those that have the A1 allele. He
hypothesized that the reason for this higher rate might be that "People
with the A1 allele may have lower receptor number or lower binding affinity
for dopamine; those with the A1 genotype might be less affected by changes
in dopamine availability...If A1 people have deficits in their responsiveness
to dopamine, they might compensate for this by using nicotine and other
substances more" (Zucker 2001).
While the popular press article is easy to understand and provides hope for those wishing to quit smoking, it is misleading in some respects. The article does not detail the statistical data of the study, nor does it state what form of antidepressants were used and what led researchers to choose antidepressants in the first place. More information needs to be provided as to the roots of using antidepressants. With the scientific paper it was shown that those adolescents with at least one A1 allele were significantly more depressed than those with the A2/A2 genotype. Did Dr. Cinciripini's research look at the depressed state of the adults? Were antidepressants used because it is known that those with the A1 allele are more likely to be depressed? And if so, is the depression the cause of the smoking or is the smoking the cause of depression? These questions were not addressed and are extremely important in deciphering the data.
the article states that those with the A2 genotype responded better to
the antidepressant than those with the A1 genotype it does not state that
the A2 genotype is the most prevalent in the population. In addition, the
article fails to address that those with the A1 genotype are more likely
to continue smoking. While the findings are important they do not address
what can be done for those with the A1 genotype, the group that is more
likely to continue smoking.
Audrain-McGovern, et al. 2004 July. Interacting Effects of Genetic Predisposition and Depression on Adolescent Smoking Progression. Am J Psychiatry. 161(7): 1224-1230.
McKusick, Victor A.
2004 June 30. Susceptibility to Tobacco Addiction. OMIM.
< http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=188890 > Accessed 2004 August 30.
Zucker, Mimi. 2001
July. Smoking Cessation Success May Depend on Genetics. PulmonaryReviews.com.
< http://www.pulmonaryreviews.com/jul01/pr_jul01_cessation.html > Accessed 2004 September 14.
1995 May 10. Nicotine
Gene & Smoking Behavior. Accessexcellence.org.
< http://www.accessexcellence.org/WN/SUA01/nicotine.html> Accessed 2004 August 30.
2001 April 23. Gene
may determine success of smoking cessation. CNN.com/Health.
< http://www.cnn.com/2001/HEALTH/04/23/smoking.cessation/index.html> Accessed 2004 August 30.
2004 February. Tobacco-Related
Mortality. Fact sheet. CDC.gov.
< http://www.cdc.gov/tobacco/factsheets/Tobacco_Related_Mortality_factsheet.htm> Accessed 2004 September 14.