April 2 (Bloomberg) -- Genetic changes may determine which smokers get hooked, smoke more than others and are most likely to develop lung cancer, scientists said today.

The variations in genes that control the body's response to nicotine, an addictive chemical in tobacco, raise the risk of lung cancer and blood-vessel disease, according to three studies published today by the journals Nature and Nature Genetics.

Researchers from DeCode Genetics Inc. and laboratories around the world found the risk-linked changes in a stretch of DNA containing genetic instructions for making proteins, called receptors, that respond to nicotine. Determining how the cancer- associated variant differs from lower-risk versions will throw much-needed light on prevention, said Norman Edelman, chief medical officer of the American Lung Association.

``Anything new that you know about the growth of the cancer might give you a strategy to prevent it or treat it,'' said Edelman, who also treats lung cancer patients at Stony Brook University Medical Center in New York, in a telephone interview. ``If you knew that lung cancers critically need nicotine to grow, you could develop blockers of nicotine receptors.''

About 162,000 people in the U.S. will die of lung cancer this year, according to the American Cancer Society.

DNA Sequence

DNA, the molecule that makes up genes, comprises four chemicals, known by the letters of A, C, G and T. The three large studies examined the genetic makeup of more than 37,000 people of European descent with and without lung cancer for substitutions in the expected sequence of these ``letters.'' These substitutions, called single-nucleotide polymorphisms, or ``snips,'' can serve as markers of more substantial changes, such as missing pieces of DNA.

The researchers looked for differences among participants with and without lung cancer. The most consistent variations showed up in the genes making receptor proteins that allow cells to respond to nicotine and acetylcholine, a nervous-system messenger. Earlier studies have implicated these genes in addiction and lung cancer.

Each cell normally contains two copies of all a person's genes, although the versions on each strand of the molecule may differ. People with one copy of the cancer-linked version had about 30 to 40 percent more chance of lung tumors than normal, and those with two copies had 70 to 80 percent higher risk.

Link to Lung Cancer

Among people who have smoked fewer than 100 cigarettes in their entire lives, the risk of cancer is so small that testing for the risk-linked version probably isn't worthwhile, said Paul Brennan, a genetic epidemiologist at the International Agency for Research on Cancer in Lyon, France, who led one of the studies. People who continue to smoke into middle age and have two copies of the variant might have a lung-cancer risk as high as 23 percent, he said.

More studies are needed to determine whether the gene version directly sparks the growth of lung tumors, the No. 1 cause of cancer death in the world, or simply raises the chances a person will become addicted to smoking, the researchers said.

Brennan's study involved 11,000 participants, and researchers from more than 18 countries linked the high-risk DNA version directly to lung cancer. People with the variant had a higher risk of cancer even if they had never smoked. Also, having the variant didn't raise the risk of other smoking-related cancers in the mouth and throat, he said.

``Our initial inclination was that this was an association caused by nicotine addiction,'' Brennan said in a telephone call with reporters. Their analysis led to ``the alternate conclusion: that it drives forward the cancer process at the cellular level.''

Other Two Studies

Another study, led by epidemiologist Christopher Amos at the University of Texas M.D. Anderson Cancer Center in Houston, found the variant raised lung-cancer risk and mildly affected smoking behavior. A third study, by DeCode, found that people with the genetic variant were more likely to smoke, to smoke longer, and to smoke more. At the same time, the variant was linked to peripheral artery disease.

The association with arterial disease makes it very unlikely that the gene variant directly spurs the growth of lung cancer, said Kari Stefansson, chief executive officer of DeCode, which is based in Reykjavik, Iceland.

``We'd be proposing that the same variant would affect, addiction to nicotine, the pathogenesis of lung cancer and peripheral arterial disease,'' he said. ``You're asking lightning to strike in the same place three times.''

The genetic link to lung cancer through susceptibility to addiction ``blurs the line between nature and nurture in the pathogenesis of disease,'' he said in a telephone interview. ``Here we find a variant that increases the probability that we expose ourselves to an event, smoking, that raises the risk of cancer.''

The M.D. Anderson group also studied people who had never smoked, and didn't find that the variant's presence raised the risk of lung cancer. Amos suggested that his group and Brennan's might combine their data to come up with a clearer answer.

To contact the reporter on this story: John Lauerman in Boston at jlauerman@bloomberg.net.

Last Updated: April 2, 2008 18:02 EDT