Gene Variant May Affect Nicotine Receptors in Lung, Brain or Both
Variations increase lung cancer risk


by Tom Valeo

July, 2008

Three groups working separately have scanned the human genome and discovered almost simultaneously that a gene on chromosome 15 increases susceptibility to lung cancer, though they disagree on how: Certain variants of the gene make the lungs more vulnerable to cancer, while other variants appear to make the brain more responsive to the effects of the nicotine.

The gene provides instructions for a receptor that binds with nicotine. These nicotine receptors are found both in lung tissue and in the brain.

One research group believes the gene contributes to lung cancer by promoting nicotine addiction, thereby causing people to smoke more. Another believes the gene makes the lungs more susceptible to cancer even in people who don’t smoke. And the third group suspects that the gene does both, causing people to smoke more while making some people particularly vulnerable to lung cancer.

The receptors in question, nicotinic acetylcholine receptors, normally bind in the brain with acetylcholine, a neurotransmitter that produces pleasurable sensations related to eating, sex and other life-sustaining activities. But as the name suggests, these receptors also bind with nicotine, and in 2004 Henry A. Lester of the California Institute of Technology and colleagues demonstrated that one of the 12 variations of the receptor accelerated the rate at which mice became dependent on nicotine. Since then other studies have revealed a correlation between variations of the nicotinic acetylcholine receptor and nicotine addiction.

Now, researchers in Iceland who studied the genome of nearly 11,000 smokers have found that those who had a particular variant on chromosome 15 tended to smoke more and had a harder time quitting. Each copy of the variant, they noted, increased smoking by about one cigarette per day. Smokers without this variant, which provides instructions for the nicotinic acetylcholine receptor, tended to smoke less, suggesting that this gene variant makes people more dependent on nicotine once they start smoking.

This demonstrates, the authors state in their April 2008 Nature paper, that this variation on chromosome 15 “confers risk of lung and cardiovascular diseases through an effect on behavior.”

However, Rayjean Hung of the International Agency for Research on Cancer in Lyon, France, and colleagues reported in the same issue of Nature that the variant for the nicotinic acetylcholine receptor they found on chromosome 15 does not promote nicotine addiction. They suspect that the gene alters nicotinic acetylcholine receptors in the epithelial cells of the lung.

Previous research supports that hypothesis. Nicotine delivers a “double whammy” to lung cells by both damaging genes and inhibiting the cell’s ability to self-destruct in response to the genetic damage, according to John Minna, director of the Hamon Center for Therapeutic Oncology Research at the University of Texas Southwestern Medical Center in Dallas.

Minna, who was not involved in the most recent studies, said these receptors cause cells in the lung to proliferate more readily when exposed to nicotine. Also, nicotine is converted by the body into highly carcinogenic compounds that are taken up by the nicotinic acetylcholine receptors and delivered to the cells.

However, Minna also believes that nicotine addiction could be intensified by changes in the nicotinic acetylcholine receptor. “One possibility is that genetic changes in chromosome 15 give you more addiction, and therefore more nicotine exposure,” he says.

A paper in Nature Genetics published at the same time as the two in Nature found a clear association between lung cancer and not one but two gene variants on chromosome 15. By surveying the 3 billion base pairs of the human genome of about 1,150 people of European descent, the researchers found that possessing one variant increased a smoker’s risk of lung cancer by about 28 percent, while possessing two increased it by about 80 percent.

Although the researchers believe these variants affect nicotinic acetylcholine receptors in lung cells, they also concede the possibility that they affect the receptors in the brain as well, thereby promoting nicotine addiction in people who have the variants.

The possibility that two gene variations could have such a widespread impact surprised lead author Christopher Amos, a professor in the Department of Epidemiology at the University of Texas M.D. Anderson Cancer Center in Houston. 

“I would have expected smoking behavior to be modulated by many genes,” Amos says. “One possible conclusion is that smoking behavior is simpler than we thought.” 

Still, Amos remains skeptical of the conclusion formed by the Icelandic researchers that all lung cancer effects are modulated through addictive smoking behavior, since certain gene variants on chromosome 15 clearly affect the development and progression of lung cancer.

“There’s a long history of biological studies to support a role for nicotinic acetylcholine receptors in lung cancer development,” he says.

But nicotine addiction clearly involves nicotinic acetylcholine receptors in the brain. Several studies have shown that long-term smokers may have up to twice as many of the receptors for nicotine in their brains, and those receptors begin responding to nicotine with the first cigarette, according to Joseph DiFranza, a professor of family medicine and community health at the University of Massachusetts Medical School.

“Nicotine changes the brain with the first dose,” he says. “New thinking suggests that nicotine addiction is, to some extent, an accident of physiology. Some people probably have a physiology that nicotine works very well on.”