Genetic Variation in Serotonin System May Play Role in Smoking Initiation

Each day more than 3,000 young people smoke their first cigarette, and the likelihood of becoming addicted to nicotine is higher for these young smokers than for those who begin later in life. A number of biological, social, and environmental factors combine to influence smoking initiation, and NIDA-supported research suggests that genetic factors play a role in determining a smoker's susceptibility to nicotine addiction. (See "Evidence Builds That Genes Influence Cigarette Smoking".) Now, researchers at the University of Pennsylvania in Philadelphia and Virginia Commonwealth University in Richmond have found an association between smoking initiation and variations in a gene related to the brain's serotonin system, which is involved in mood and behavior.

Researchers at the University of Pennsylvania have found that women and men who inherit the "A" form (allele) of the tryptophan hydroxylase gene from both parents and who become smokers are likely to begin smoking at an earlier age than women and men who inherit the "C" allele.

At the NIDA-supported Transdisciplinary Tobacco Use Research Center at the University of Pennsylvania, Dr. Caryn Lerman and her colleagues investigated the possible relationship between smoking behavior and different forms (alleles) -- designated 779A and 779C -- of a gene that regulates tryptophan hydroxylase (TPH), an enzyme involved in the synthesis of serotonin. "There is evidence from previous studies linking the less common 779A allele with behaviors related to poor impulse control," Dr. Lerman says. "Because of the association of tobacco and other substance use with poor impulse control, we speculated that the TPH gene may play a role in smoking initiation as well."

To investigate this possibility, the researchers recruited 249 smokers (smoked at least 5 cigarettes per day for the past year) and 202 nonsmokers (smoked fewer than 100 cigarettes in their lifetime). All the participants were white; their average age was 44 years, and slightly more than half (56 percent) were women. All participants completed written questionnaires that provided information on their age, education, marital status, and certain psychological traits. Smokers provided smoking histories, including the age when they started smoking at least one cigarette per day.

The researchers tested samples of the participants' blood to determine whether they had the 779A or 779C alleles for the TPH gene. The overall allele frequency was 42 percent for the THP 779A allele and 58 percent for the 779C allele. There was no significant association of the presence or absence of the 779A allele with becoming a regular smoker, Dr. Lerman says. But among participants who did become smokers, the 779A allele was associated with the age at which they began smoking. Those who inherited copies of 779A from both parents started smoking at age 15.6 years, those with one A and one C allele began smoking at 17.1, and those with two copies of 779C began smoking at 17.3 years.

"In light of other findings that 779A is associated with poor impulse control, one interpretation of this study is that individuals with that allele may be prone to engage in risky behavior such as smoking initiation at an earlier age," Dr. Lerman says.

Dr. Lerman discussed her research results with Dr. Patrick Sullivan at Virginia Commonwealth University. Dr. Sullivan and his colleagues then developed a study to look for possible associations between the TPH 779A allele and smoking initiation in a group of 740 participants who had previously been enrolled in research dealing with genetic influences on a range of behaviors, including drug abuse and addiction. As part of the earlier study, the participants had completed extensive questionnaires that included information about smoking, including age at which smoking began, age at which smokers first became dependent on nicotine (suffered withdrawal if they tried to quit), and the severity of their dependence -- measured by a standard tool called the Fagerstrom Tolerance Questionnaire (FTQ). For the TPH study, the participants were divided into three categories: those who had never smoked, regular smokers who had a low degree of dependence (scores of 0 to 3 on the 11-point FTQ), and regular smokers with a high degree of dependence (FTQ scores of 7 or higher). Dr. Sullivan and his colleagues analyzed the participants' TPH genes and found that the 779A allele was strongly associated with whether participants initiated smoking, but, unlike the University of Pennsylvania study, not strongly associated with an early age of smoking initiation.

"The fact that there is not complete agreement is not surprising," Dr. Sullivan says. "The two studies used different populations of subjects and were not designed to test the same hypothesis. Nonetheless, the two studies appear to have captured a similar influence that plays a role in the web of factors that underlies smoking initiation."

"It is rare to find confirmation of a candidate gene related to addiction, and these studies make a good case for an association between the TPH gene variant and smoking initiation," says Dr. Rebekah Rasooly of NIDA's Division of Neuroscience and Behavioral Research. "This kind of association helps us to better understand the factors that influence young potential smokers. They are the most vulnerable to becoming regular smokers and need to clearly understand all the risks associated with smoking that first cigarette."

Sources

• Lerman, C., et al. Tryptophan hydroxylase gene variant and smoking behavior. American Journal of Medical Genetics 105(6):518-520, 2001. [Abstract]
• Sullivan, P.F., et al. Association of the tryptophan hydroxylase gene with smoking initiation but not progression to nicotine dependence. American Journal of Medical Genetics 105(5):479-484, 2001. [Abstract]