Glutathione S‐transferase T1‐null genotype interacts synergistically with heavy smoking on lung cancer risk

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Abstract
We studied the influence of genotype for glutathione S‐transferase T1 (GSTT1) on susceptibility to lung cancer among 184 Swedish lung cancer patients (88 never‐smokers and 96 ever‐smokers) and 162 matched population controls (79 never‐smokers and 83 ever‐smokers), with special emphasis on gene–environment interactions. Cases had significantly lower frequency of the GSTT1‐null genotype than that of controls among never‐smokers (4.6 vs. 16.5%, P = 0.02), whereas the frequencies were very close to each other among smokers (7.4 vs. 7.2%). Cases with high packyears of smoking, however, had a significantly higher frequency of the GSTT1‐null genotype compared to that of cases with low packyears (18.3 vs. 5.6%, P = 0.005). Adjusted for age and gender, the GSTT1‐null genotype appeared to be protective against lung cancer among never‐smokers (odds ratio [OR] = 0.2, 95% confidence interval [CI] = 0.07–0.7), although it was associated with an increased risk for lung cancer among smokers (OR = 2.1, 95% CI = 0.8–5.9), mainly attributed to the group of heavy smokers (>23 packyears; OR = 3.5, 95% CI = 0.7–17.3). Heavy smoking conferred a threefold increased risk for lung cancer (OR = 2.6, 95% CI = 1.3–5.0) among GSTT1‐positive individuals, but a ninefold increased risk when combined with the GSTT1‐null genotype (OR = 9.3, 95% CI = 1.9–46.3, relative to GSTT1‐positive light smokers). This joint effect was further demonstrated by a positive interaction between the GSTT1‐null genotype and packyears of smoking. The risk of lung cancer increased steeply with increasing packyears among GSTT1‐null smokers, whereas no such effect was seen among GSTT1‐positive smokers. We conclude that the GSTT1‐null genotype may strengthen the effect of heavy smoking on lung cancer risk. Environ. Mol. Mutagen. 38:83–86, 2001.