The Health Outcome
Nonsyndromic oral-facial clefts (OFC), including cleft lip and/or alveolus with or without cleft palate and isolated cleft palate, affect approximately 1 of every 700 –1,000 newborns of various geographic and ethnic background. Epidemiologic and familial data suggest that the etiology of OFCs involves both genetic and environmental factors. Several studies have implicated smoking as a weak risk factor for OFC, with an overall odds ratios (OR) around 2. Researchers have suggested that gene-dependent metabolism of the products of smoking, either by the fetus or the mother, might be important in determining smoking-associated risk for OFC. Candidate genes include both phase 1 (activating) genes and phase 2 genes (detoxifying) genes. Several of these genes exist in allelic forms that differ in biologic activity. For example, the isoenzyme cytochrome P450 1A1 (CYP1A1) is associated with higher activating activity for aromatic hydrocarbons than its Common-type counterpart. Conversely, the null allele of the gene coding for type theta-1 glutathione-s-transferase (GSTT1) lacks the activity of its Common-type counterpart to metabolize the products of the metabolism of aromatic hydrocarbons.
The Finding
Van Rooij and associates (1) report that the combination of smoking and presence of the null allele of GSTT1 in the mother increases three fold the risk for OFC in the child, compared with the combination of not smoking and the presence of the Common-type GSTT1. When both the child and the mother had the null allele of GSTT1, the joint effect of smoking and presence of the genotype was higher (OR 4.9). Smoking or GSTT1 alone were not associated with an increased risk for OFC, with the possible exception for maternal GSTT1 alone and the subset of OFC presenting with cleft palate alone (OR 2.8).
A similar analysis of smoking and CYP1A1 failed to show evidence for marginal effects or interactions involving this gene variant. The authors estimate that approximately 7% of OFC that is present in the Dutch population is attributable to the combination of smoking and GSTT1 genotype. The authors further comment that although they used convenient controls, and although the smoking habits of these controls most likely did not represent those of the underlying Dutch population, the findings most likely were neither due to bias nor confounding.
These following associations were made in a case-control study of OFC conducted in the Netherlands . Children with OFC (n=113) and their mothers were recruited from nine cleft specialty centers in the Netherlands . The diagnosis of OFC was made at these centers. Control children (n= 104) and their mothers were a convenient sample, selected in part by the case mothers (53 %of controls) and in part by nurseries in and around Nijmegen . Both case and control infants were Caucaasion and between 9 months and 3 years of age. (A detailed abstraction of this article is available online as part of the HuGENet™ e-journal club (2).)
Public Health Implications
The findings, if true, suggest that practically all the excess risk for OFC associated with smoking is confined to mothers with the GSTT1 null phenotype. The same data, however, indicate that if these mothers did not smoke, their risk was reduced to that of the nonsmoking GSTT1 Common-type reference group. Thus, programs that lead to prevention or cessation of smoking during the periconceptional period throughout pregnancy should be effective regardless of genotype. These data still require independent confirmation.
References
- van Rooij IA , Wegerif MJ, Roelofs HM, Peters WH, Kuijpers-Jagtman AM, Zielhuis GA , Merkus HM, Steegers-Theunissen RP. Smoking, genetic polymorphisms in biotransformation enzymes, and nonsyndromic oral clefting: a gene-environment interaction. Epidemiology 2001;12(5):502-7
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