Some smokers face a particularly high risk of bladder cancer because of variations in two genes that work together to escalate their already high risk, scientists at the National Institute of Environmental Health Sciences report.

The distinctive study may be the first to define a three-way gene-gene-environmental relationship to disease risk.

Both genes were previously known to have roles in metabolizing a chemical, arylamine, present in tobacco smoke and some occupations, such as those involving petroleum. But surprisingly, while a variation of one of the genes (NAT1) alone increased risk about twofold for smokers, variations of the second gene (NAT2) conveys no demonstrated risk unless the NAT1 variation is also present. When both variations are present, the risk for smokers is highest.

For example, someone who smokes 25 years and carries the at-risk copies of both genes has a tenfold higher risk of bladder cancer than someone who does not smoke.

The study, conducted among bladder cancer patients at the nearby Duke University Medical Center, Durham, N.C., and the University of North Carolina Hospitals, Chapel Hill, is reported in the journal Cancer Research, Vol. 58, issue 15. NIEHS is in Research Triangle Park, N.C.

"While everyone who smokes experiences higher risks of bladder cancer, this study suggests there may be small, genetically defined subgroups that suffer much higher risks than the general population," Dr. Taylor said. Though this is a preliminary study, the authors point out that people known to be in the higher risk subgroups could avoid smoking to decrease their risk of bladder cancer.

The authors are Jack A. Taylor, M.D., Ph.D., David M. Umbach, Ph.D., Douglas A. Bell, Ph.D. Elizabeth Stephens, and Trisha Castranio, all of NIEHS, and Cary Robertson, M.D. and David Paulson, M.D. of the department of surgery at Duke, and James Mohler, M.D. of the department of surgery at UNC.