Oral Clefts, Maternal Smoking, and TGFA: A Meta-Analysis of Gene-Environment Interaction

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Abstract
Objective: A meta-analysis was performed to examine the association among maternal cigarette smoking, infant genotype at the Taq1 site in the transforming growth factor α (TGFA) locus, and risk of nonsyndromic oral clefts, both cleft palate (CP) and cleft lip with or without cleft palate (CL/P). Design: Five published case-control studies were included in the meta-analyis. Pooled Mantel-Haenszel odds ratios (OR) and 95% confidence intervals (CIs) were computed. Gene-environment interaction was also assessed by using the pooled data in a case-only analysis and polytomous logistic regression. Results: Among nonsmoking mothers, there was no evidence of any increased risk for CP if the infant carried the TGFA Taq1 C2 allele. If the mother reported smoking, however, there was an overall increased risk for CP if the infant carried the C2 allele (ORsmokers = 1.95; 95% CI = 1.22 to 3.10). TGFA genotype did not increase risk to CL/P, regardless of maternal smoking status. Polytomous logistic regression revealed a significant overall smoking effect for CL/P (OR = 1.64, 95% CI = 1.33 to 2.02) and CP (OR = 1.42, 95% CI = 1.06 to 1.90). Conclusions: While maternal smoking was a consistent risk factor for both CL/P and CP across all studies, the suggestive evidence for gene-environment interaction between the infant's genotype at the Taq1 marker in TGFA and maternal smoking was limited to CP. Furthermore, evidence for such gene-environment interaction was strongest in a case-control study drawn from a birth defect registry where infants with non-cleft defects served as controls.