ASSOCIATION BETWEEN HOMEOBOX-CONTAINING GENE MSX1 AND THE OCCURRENCE OF LIMB DEFICIENCY

Animal studies have suggested an important role for the homeobox-conta ining gene MSX1 in Limb, oralfacial, and cardiac malformations. In thi s study of 516 Caucasians with isolated birth defects registered in th e Maryland Birth Defects Reporting and Information System (BDRIS), we report an association between a dinucleotide repeat polymorphism in MS X1 and isolated limb deficiency. Frequencies of rare alleles at the MS X1 locus are significantly higher among 34 infants with Limb deficienc y compared to 482 infants with other isolated birth defects (oral clef ts, dislocation of hip, clubfoot, hypospadias, polydactyly, or syndact yly) (chi(2) = 11.0, df = 3, P = 0.012). Infants carrying the rare all eles had a 4.81-fold higher risk of a limb deficiency when the mother reported smoking during pregnancy, compared to infants who are homozyg ous for the common allele and whose mother did not smoke. The signific ance of this apparent gene-environment interaction is attributed to in fants with malformation of the lower limb. The statistical association and potential gene-environment interaction observed in this study (wh ich was originally designed to investigate oral clefts) are compatible with results from animal studies involving the MSX1 gene, and suggest s that further investigation into biological mechanisms is warranted.