Maternal Smoking, Genetic Variation of Glutathione S-Transferases, and Risk for Orofacial Clefts

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Background:Maternal smoking is a known risk factor for orofacial clefts. We investigated whether risk is greater among offspring who lack the genetic capacity to produce glutathione S-transferase enzymes relevant to detoxification of chemicals in cigarette smoke.Methods:Using a population-based case–control design, we genotyped 423 California infants with an isolated cleft and 294 nonmalformed controls for null variants of the glutathione S-transferases GSTT1 and GSTM1.Results:If a mother smoked during pregnancy and her fetus was homozygous null for GSTT1, the risk of isolated cleft lip with or without cleft palate was tripled (odds ratio = 2.9; 95% confidence interval = 1.2–7.2). For fetuses who were homozygous null for GSTM1 and whose mothers smoked ≥20 cigarettes per day, we found nearly a 7-fold increased risk (6.8; 0.82–57). Combined absence of GSTM1 and GSTT1 enzymes among the offspring of smoking mothers was associated with a nearly 6-fold increased risk for cleft lip (6.3; 1.3–42). A similar increased risk for cleft palate was associated with absence of GSTM1, but not for absence of GSTT1.Conclusions:Maternal smoking during pregnancy increases risks for clefts among fetuses lacking enzymes involved in the detoxification of tobacco-derived chemicals.

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