Although Americans are bombarded with antismoking messages, at least 65 million continue to light up. Genetic factors play an important role in this continuing addiction to cigarettes, School of Medicine scientists suggest.
In two studies in the January 2007 issue of Human Molecular Genetics, the scientists show that certain genetic variations can influence smoking behaviors and contribute to a person’s risk for nicotine dependence.
The smoking-related genes identified facilitate communication between nerve cells in the brain. One gene in particular, the alpha-5 nicotinic cholinergic receptor (CHRNA5) gene, was a strong indicator of risk for nicotine dependence. Individuals with a specific variation in the gene seemed to have a two-fold increase of developing nicotine dependence once exposed to cigarette smoking. CHRNA5 is from a class of receptors that plays a role in dopamine pathways in the brain, which are linked to a person’s experience of pleasure.
The researchers also identified genes related to gamma aminobutyric acid (GABA) receptors, another set of proteins vital to nerve cell function. Both GABA and nicotinic receptors had been suspected of involvement in nicotine addiction, but these findings strengthen those suspicions.
The studies also identified a gene not previously known to be involved with nicotine dependence. Called the Neurexin 1 gene, it helps regulate the balance between excitatory mechanisms — those that increase communication between nerve cells — and inhibitory mechanisms — those that slow firing between nerve cells.
“An imbalance between excitatory and inhibitory activity in the brain may predispose people to addiction, such as alcoholism, drug dependence or nicotine dependence,” said Laura Jean Bierut, M.D., associate professor of psychiatry and principal investigator of both studies. “The Neurexin gene we’ve identified is really a key factor in the balance between inhibition and excitatory activity in neurons.”
Bierut said she suspects many genes are involved in nicotine dependence and said understanding how they work may make it possible to develop new treatments to help people quit smoking.
The research team analyzed data from almost 2,000 participants in two ongoing studies. One, called the Collaborative Genetic Study of Nicotine Dependence, is a U.S.-based sample that includes both addicted smokers and “social” smokers from St. Louis, Minneapolis and Detroit. The other is an Australian study of smokers of European ancestry called the Nicotine Addiction Genetics study.
The scientists combined two approaches for analyzing genetic information. One approach scanned the entire human genome for suspicious areas of DNA, while the second approach closely examined specific target genes.
“The combination of these two approaches represents the most powerful and extensive study on nicotine dependence to date and is an important step in a large-scale, genetic examination of nicotine dependence,” said Elias A. Zerhouni, M.D., director of the National Institutes of Health, which funded the studies. “As more genomic variations are discovered that are associated with substance abuse, we can better understand addictive disorders.”
The researchers identified an area of DNA variation that seems to alter the function of a nicotinic receptor protein. That small variation makes a big difference in risk for nicotine dependence.
Current drug treatments for nicotine dependence are only marginally successful, and Bierut said using information about genetic traits to tailor medications to individuals could make them significantly more effective. “The type of variant you have at this particular receptor — the alpha-5 nicotinic receptor — may actually predict whether or not you will do well on nicotine-replacement therapy,” she said.
Bierut said it’s important to find genetic factors related to nicotine dependence because so much of the population continues to smoke, in spite of the overwhelming evidence that it’s harmful. And she said she believes some of the genes her research team has identified will help scientists develop therapies for smokers who just can’t seem to quit with existing treatments.