Transforming growth factor alpha locus and nonsyndromic cleft lip with or without cleft palate: a reappraisal.

An association between nonsyndromic cleft lip with or without cleft palate (CL +/- P) and genetic variation at the transforming growth factor alpha (TGFA) locus was originally reported in 1989. Subsequent population-based studies of this association have provided conflicting results. The present analyses were undertaken to determine if the cumulative weight of the available data convincingly supports or refutes this association. The published data were analyzed for differences in allele frequencies between Caucasian CL +/- P patients (i.e., cases) and controls, and for heterogeneity between Caucasian samples. When all data except the original report were considered, there was a statistically significant association between TGFA and CL +/- P (M.H.O.R. = 1.43; 95% C.I. 1.12-1.80). However, there was evidence of significant heterogeneity in the TGFA allele frequencies between cases, but not controls, from different studies. The data suggest that the observed heterogeneity is unlikely to be attributable to differences in the ethnic composition of the cases among the various studies but may reflect differences in the proportion of cases with bilateral lip defects and/or with positive family histories of CL +/- P. Definitive conclusions regarding the source(s) of the observed heterogeneity could not, however, be drawn on the basis of the available data. Hence, at present, the evidence regarding an association between genetic variation at the TGFA locus and CL +/- P remains inconclusive.