Altered transmission of HOX and apoptotic SNPs identify a potential common pathway for clubfoot

Clubfoot is a common birth defect that affects 135,000 newborns each year worldwide. It is characterized by equinus deformity of one or both feet and hypoplastic calf muscles. Despite numerous study approaches, the causes remains poorly understood although a multifactorial etiology is generally accepted. We considered the HOXAand HOXDgene clusters and insulinlike growth factor binding protein 3 IGFBP3 as candidate genes because of their important roles in limb and muscle morphogenesis. Twenty SNPs from the HOXAand HOXDgene clusters and 12 SNPs in IGFBP3were genotyped in a sample composed of nonHispanic white and Hispanic multiplex and simplex families discovery samples and a second sample of nonHispanic white simplex trios validation sample. Four SNPs rs6668, rs2428431, rs3801776, and rs3779456 in the HOXAcluster demonstrated altered transmission in the discovery sample, but only rs3801776, located in the HOXAbasal promoter region, showed altered transmission in both the discovery and validation samples P  0.004 and 0.028. Interestingly, HOXA9is expressed in muscle during development. An SNP in IGFBP3, rs13223993, also showed altered transmission P  0.003 in the discovery sample. Gene–gene interactions were identified between variants in HOXA, HOXD, and IGFBP3and with previously associated SNPs in mitochondrialmediated apoptotic genes. The most significant interactions were found between CASP3SNPS and variants in HOXA, HOXD, and IGFBP3. These results suggest a biologic model for clubfoot in which perturbation of HOXand apoptotic genes together affect muscle and limb development, which may cause the downstream failure of limb rotation into a plantar grade position. © 2009 WileyLiss, Inc.