Gene variants linked to risk for nicotine dependence and lung cancer

NEW YORK (Reuters Health) - A cluster of gene variants on chromosome 15 associated with lung cancer risk also appear to affect risk for nicotine dependence, epidemiologists at the University of Texas M. D. Anderson Cancer Center report.

Three independent genome-wide association studies previously identified single nucleotide polymorphisms strongly associated with risk of lung cancer, Dr. Margaret R. Spitz and colleagues explain in the November 5 Journal of the National Cancer Institute.

"The region of interest," they write, "encompasses the nicotinic acetylcholine receptor subunit genes CHRNA3 and CHRNA5 (as well as CHRNB4), which have a defined role in nicotine dependence and have been hypothesized to have a direct role in downstream signaling pathways that promote carcinogenesis."

To ascertain whether or not the variants were linked to carcinogenesis per se or through effects of smoking behavior, or both, the Houston-based research team looked at specific smoking phenotypes according to genotypes.

They observed that adverse variants were significantly associated with the highest number of cigarettes smoked per day, highest scores on a test of nicotine dependence, shorter time to a first cigarette of the day, and earlier age at smoking initiation.

However, they also found that the carcinogenesis risk associated with the adverse variants was highest among those with lower levels of tobacco exposure, and lowest in the heaviest smoking category, "negating the hypothesis that variations in the CHRNA3/A5/B4 region solely modulate lung cancer risk through their effect on smoking intensity."

Moreover, there were no significant associations between the gene variants and risk of other smoking-related cancers (bladder and kidney), and the adverse variants did not affect risk in subjects who had never smoked.

They were, however, associated with earlier age at lung cancer onset and in probands with multiple first-degree relatives with lung cancer.

Dr. Spitz and her associates conclude that "the variants are implicated both in smoking behavior and more directly in lung cancer risk."

Editorialists at the National Cancer Institute in Bethesda, Maryland, remark that "despite impressive work on 15q24/25.1 and lung cancer, we are not close to understanding the precise mechanisms underlying the genotypic association."

For that to happen, Dr. Sholom Wacholder and colleagues maintain, "Inter-disciplinary teams will require high-quality information on environmental causes of disease; careful use of perhaps unfamiliar statistical methods; and more gritty, perhaps hypothesis-based investigation of molecular and behavioral mechanisms."

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