Maternal smoking and oral clefts: The role of detoxification pathway genes

Department of Public Health and Primary Health Care, University of Bergen, Norway.
Epidemiology (Cambridge, Mass.) (Impact Factor: 6.2). 08/2008; 19(4):606-15. DOI: 10.1097/EDE.0b013e3181690731
Source: PubMed


There is evidence for an effect of cigarette smoking on risk of oral clefts. There are also hypothetical pathways for a biologic effect involving toxic chemicals in cigarette smoke.
We performed a combined case-control and family-triad study of babies born with oral clefts in Norway in the period 1996 to 2001, with 88% participation among cases (n = 573) and 76% participation among controls (n = 763). Mothers completed a questionnaire 4 months after birth of the baby. DNA was collected from parents and children, and assayed for genes related to detoxification of compounds of cigarette smoke (NAT1, NAT2, CYP1A1, GSTP1, GSTT1, and GSTM1).
For isolated cleft lip (with or without cleft palate) there was a dose-response effect of smoking in the first trimester. The odds ratio rose from 1.6 (95% confidence interval = 1.0-2.5) for passive smoking to 1.9 (0.9-4.0) for mothers who smoked more than 10 cigarettes per day. There was little evidence of an association with cleft palate. Genetic analyses used both case-control and family-triad data. In case-triads we found an association between a NAT2 haplotype and isolated cleft lip (relative risk of 1.6 with 1 copy of the allele and 2.5 with 2 copies), but with little evidence of interaction with smoking. Other genes did not show associations, and previously described interactions with smoking were not confirmed.
First-trimester smoking was clearly associated with risk of cleft lip. This effect was not modified by variants of genes related to detoxification of compounds of cigarette smoke.

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    • "Smokeless tobacco increases the risk for pharyngeal and esophageal cancers (Silverman, 2001). There is emerging evidence relating maternal smoking with the development of cleft lip in the child (Mirbod and Ahing, 2000; Little et al., 2004; Lie et al., 2008). Also some studies relate maternal smoking to development of primary caries in children (Aligne et al., 2003; Shenkin et al., 2004). "
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    • "Several studies suggest that maternal smoking moderately increases OFC risk, with some variation across studies in the magnitude of the effects and the affected cleft type (Bille et al. 2007; Chung et al. 2000; Honein et al. 2007; Khoury, Gomez-Farias, and Mulinare 1989; Lie et al. 2008; Lieff et al. 1999; Little et al. 2004a; MacLehose et al. 2009; Shaw et al. 2009; Werler et al. 1990). Two meta-analyses of earlier studies estimated 1.3 times increased odds for OFC (Little, Cardy, and Munger 2004b; Wyszynski, Duffy, and Beaty 1997). "
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