Studies Find DNA Regions Linked To Nicotine Dependence

Americans are bombarded with antismoking messages, yet at least 65 million of us continue to light up. Genetic factors play an important role in this continuing addiction to cigarettes, suggest scientists at Washington University School of Medicine in St. Louis.

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 normally facilitate communication between nerve cells in the brain. One gene in particular, the alpha-5 nicotinic cholinergic receptor (CHRNA5) gene, was a very 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 (NRXN1) 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," says 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 suspects a large number of genes are involved in nicotine dependence, and she says understanding how they work may make it possible to develop new treatments for smoking cessation.

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," says Elias A. Zerhouni, M.D., the 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 continue to be only marginally successful, and Bierut believes 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 says.

Proving that, however, will require more studies, and the researchers have launched a new project to study DNA in a sample of both low-level smokers and heavier smokers. They are also working with colleagues at the University of Colorado to develop a mouse with the same variant in the CHRNA5 gene that seems to increase the risk of nicotine dependence. That would allow them to compare the effects of nicotine in mice with and without the genetic variation.

Tobacco use, primarily through cigarette smoking, is a leading cause of death and disability. Each year, approximately 440,000 Americans die of smoking-related illnesses, and worldwide, deaths attributed to tobacco total about 5 million. Although the prevalence of cigarette smoking has decreased over the last 30 years in the United States, the rate of smoking cessation among adults has been slowing since the mid-1990s. In addition, adolescents continue to start smoking, with 21 percent of high school students reporting they have smoked a cigarette sometime in the last month.

More than half of the people who smoke at least five packs in their lives — 100 cigarettes — go on to become nicotine dependent. But about 15 percent of people who smoke that amount won't develop any symptoms of nicotine dependence. "These people can give up smoking at any time," Bierut says. "They have no cravings. They smoke socially."

Earlier research suggested that smoking behaviors tend to cluster in families, and large studies of twins previously concluded that the clustering is partly related to genetic factors. An important aspect of these latest studies is that rather than comparing smokers to non-smokers, the researchers compared addicted smokers to non-addicted smokers.

"You're not at risk for nicotine dependence unless you've smoked," Bierut says. "You have to study smokers to identify the people who are at risk of becoming nicotine dependent versus those who smoke but can give it up at any time."

Bierut says 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 believes some of the genes her research team has identified will help scientists to develop therapies for smokers who just can't seem to quit with existing treatments.

[ScientificBlogging]

New smoking cessation therapy proves promising... assuming you still want your nicotine addiction

A novel technology for delivering nicotine to the lungs may soon give smokers a new way to kick the habit. When compared to the nicotine vapor delivery system used in the Nicotrol/Nicorette inhaler, the new technology proved more effective at delivering nicotine to the blood stream.

"We wanted to replicate the experience of smoking without incurring the dangers associated with cigarettes, and we wanted to do so more effectively than the nicotine replacement therapies currently on the market," said Jed Rose, Ph.D., director of the Duke Center for Nicotine and Smoking Cessation Research where the technology is being developed.

The Nicotrol inhaler is a smoking cessation therapy that delivers nicotine vapor to the mouth and upper airways, but little of it reaches the lungs. Duke's new technology combines the vapor phase of pyruvic acid, which occurs naturally in the body, and nicotine. [ScienceCodex]

All fascinating, but why so much research to keep people addicted to nicotine? As I have said many times, the stop smoking propaganda seems designed to make people's addiction more socially acceptable - and keep the profits rolling - rather than curing the nicotine addiction.

Study reveals a need to evaluate and regulate 'electronic cigarettes'

Electronic cigarettes should be evaluated, regulated, labeled and packaged in a manner consistent with cartridge content and product effect – even if that effect is a total failure to deliver nicotine as demonstrated in a study supported by the National Cancer Institute and led by a Virginia Commonwealth University researcher. The research was published in the Online First issue of the journal Tobacco Control. The article will appear in the February print issue of the journal.

Electronic cigarettes consist of a battery, heater and cartridge containing a solution of nicotine, propylene glycol and other chemicals and have been marketed to deliver nicotine without tobacco toxicants. Despite no published data concerning safety or efficacy, these products are sold in shopping malls and online. Further, "electronic cigarettes" currently are unregulated in the U.S., unlike other products intended to deliver nicotine to smokers such as lozenges, gum and patches.

"Consumers have a right to expect that products marketed to deliver a drug will work safely and as promised. Our findings demonstrate that the 'electronic cigarettes' that we tested do not deliver the drug they are supposed to deliver. It's not just that they delivered less nicotine than a cigarette. Rather, they delivered no measurable nicotine at all. In terms of nicotine delivery, these products were as effective as puffing from an unlit cigarette," said principal investigator Thomas Eissenberg, Ph.D., professor in the VCU Department of Psychology.

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Perhaps the good preofessor forgot to put a cartridge in his e-cigarette! Yes, e-cigs need regulating as they deliver a drug, and yes, this is a ploy by tobacco and pharmaceuticals to barge out of their profitable market an upstart product. They should bring out their own e-cigarettes but, for big tobacco, it would ruin their market and, for big pharma, it would expose the lie that NRT are some kind of medicine rather than just another profitable delivery system of a drug that is otherwise classed a poison. Go figure.

If your first cigarette gave you a buzz and you now smoke, blame a gene

Anyone who has ever tried smoking probably remembers that first cigarette vividly. For some, it brought a wave of nausea or a nasty coughing fit. For others, those first puffs also came with a rush of pleasure or "buzz." Now, a new study links those first experiences with smoking, and the likelihood that a person is currently a smoker, to a particular genetic variation. The finding may help explain the path that leads from that first cigarette to lifelong smoking.

The new finding also adds to growing suspicion surrounding the role of a particular nicotine-receptor gene in smoking-related behaviors and in lung cancer. The regular smokers in the study were far more likely than the never-smokers to have the less common rs16969968 form of the CHRNA5 gene, in which just one base-pair in the gene sequence was different from the more common form. This kind of genetic variation is called a single nucleotide polymorphism or SNP.

Smokers were also eight times as likely to report that their first cigarettes gave them a pleasurable buzz.

"It appears that for people who have a certain genetic makeup, the initial physical reaction to smoking can play a significant role in determining what happens next," says senior author and project leader, Ovide Pomerleau, a professor of psychiatry at the University of Michigan Medical School and founder of the U-M Nicotine Research Laboratory.

"If cigarette smoking is sustained, nicotine addiction can occur in a few days to a few months," he adds. "The finding of a genetic association with pleasurable early smoking experiences may help explain how people get addicted — and, of course, once addicted, many will keep smoking for the rest of their lives."