OROFACIAL CLEFTS, PARENTAL CIGARETTE-SMOKING, AND TRANSFORMING GROWTH-FACTOR-ALPHA GENE VARIANTS

Results of studies to determine whether women who smoke during early p regnancy are at increased risk of delivering infants with orofacial cl efts have been mixed, and recently a gene-environment interaction betw een maternal smoking, transforming growth factor-alpha (TGFa), and cle fting has been reported. Using a large population-based case-control s tudy, we investigated whether parental periconceptional cigarette smok ing was associated with an increased risk for having offspring with or ofacial clefts. We also investigated the influence of genetic variatio n of the TGFa locus on the relation between smoking and clefting. Pare ntal smoking information was obtained from telephone interviews with m others of 731 (84.7% of eligible) orofacial cleft case infants and wit h mothers of 734 (78.2%) nonmalformed control infants. DNA was obtaine d from newborn screening blood spots and genotyped for the allelic var iants of TGFa. We found that risks associated with maternal smoking we re most elevated for isolated cleft lip with our without cleft palate, (odds ratio 2.1 [95% confidence interval 1.3-3.6]) and for isolated c left palate (odds ratio 2.2 [1.1-4.5]) when mothers smoked greater tha n or equal to 20 cigarettes/d. Analyses controlling for the potential influence of other variables did not reveal substantially different re sults. Clefting risks were even greater for infants with the TGFa alle le previously associated with clefting whose mothers smoked greater th an or equal to 20 cigarettes/d. These risks for white infants ranged f rom 3-fold to Ii-fold across phenotypic groups. Paternal smoking was n ot associated with clefting among the offspring of nonsmoking mothers, and passive smoke exposures were associated with at most slightly inc reased risks. This study offers evidence that the risk for orofacial c lefting in infants may be influenced by maternal smoke exposures alone as well as in combination (gene-environment interaction) with the pre sence of the uncommon TGFa allele.