Oral clefts, transforming growth factor alpha gene variants, and maternal smoking: A population-based case-control study in Denmark, 1991-1994

Studies in the United States have indicated that maternal first trimester s moking and infant transforming growth factor alpha (TGFA) locus mutations a re associated with non-syndromic cleft lip and/or palate (CLP) and that a s ynergistic effect of these two risk factors occurs. Based on a Danish case- control study of CLP, the authors studied the effects of smoking and TGFA a lleles in an ethnically homogeneous setting. Interview information was obta ined for mothers of 302 CLP cases (96% of eligible) and for 567 mothers of nonmalformed children (94% of eligible). Multivariate logistic regression a nalyses revealed that smoking was associated with a moderately increased ri sk of cleft lip +/- cleft palate (CL(P)) (odds ratio = 1.40, 95% confidence interval 0.99-2.00), No association between smoking and isolated cleft pal ate (CP) was observed. TGFA genotype was not associated with either CL(P) o r CPI and no synergistic effect with smoking was observed. The "rare" TGFA allele occurred in 25% of both cases and controls compared with an average of 14% in other white control groups. Furthermore, the frequency of CLP in Scandinavia is among the highest in the world. Hence, it is possible that t he previously reported association between TGFA and CLP to some degree can be attributable to confounding by ethnicity.