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

ABSTRACT: 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 cause(s) remains poorly understood although a multifactorial etiology is generally accepted. We considered the HOXA and HOXD gene clusters and insulin-like growth factor binding protein 3 (IGFBP3) as candidate genes because of their important roles in limb and muscle morphogenesis. Twenty SNPs from the HOXA and HOXD gene clusters and 12 SNPs in IGFBP3 were genotyped in a sample composed of non-Hispanic white and Hispanic multiplex and simplex families (discovery samples) and a second sample of non-Hispanic white simplex trios (validation sample). Four SNPs (rs6668, rs2428431, rs3801776, and rs3779456) in the HOXA cluster demonstrated altered transmission in the discovery sample, but only rs3801776, located in the HOXA basal promoter region, showed altered transmission in both the discovery and validation samples (P = 0.004 and 0.028). Interestingly, HOXA9 is 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 IGFBP3 and with previously associated SNPs in mitochondrial-mediated apoptotic genes. The most significant interactions were found between CASP3 SNPS and variants in HOXA, HOXD, and IGFBP3. These results suggest a biologic model for clubfoot in which perturbation of HOX and apoptotic genes together affect muscle and limb development, which may cause the downstream failure of limb rotation into a plantar grade position.

SUBMITTER: Ester AR

PROVIDER: S-EPMC2795347 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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

Ester Audrey R AR Weymouth Katelyn S KS Burt Amber A Wise Carol A CA Scott Allison A Gurnett Christina A CA Dobbs Matthew B MB Blanton Susan H SH Hecht Jacqueline T JT

American journal of medical genetics. Part A 20091201 12

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 cause(s) remains poorly understood although a multifactorial etiology is generally accepted. We considered the HOXA and HOXD gene clusters and insulin-like growth factor binding protein 3 (IGFBP3) as candidate genes because of their important roles in limb and muscle morphogenesis. Tw ...[more]

PMID: 19938081

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Project description:BackgroundIsolated clubfoot is a common orthopedic birth defect that affects approximately 135,000 newborns worldwide. It is characterized by ankle equinus, hindfoot varus, and forefoot adductus. Although numerous studies suggest a multifactorial etiology, the specific genetic and environmental components have yet to be delineated. Maternal smoking during pregnancy is the only common environmental factor consistently shown to increase the risk for clubfoot. Moreover, a positive family history of clubfoot, in conjunction with maternal smoking, increases the risk 20-fold. These findings suggest that genetic variation in smoking metabolism (xenobiotic) genes may increase susceptibility to clubfoot. Based on this reasoning, we interrogated eight candidate genes from the xenobiotic metabolism.MethodsTwenty-two single-nucleotide polymorphisms and two null alleles in these genes (CYP1A1, CYP1A2, CYP1B1, CYP2A6, EPHX1, NAT2, GSTM1, and GSTT1) were genotyped in a dataset composed of non-Hispanic white and Hispanic multiplex and simplex families.ResultsOnly rs1048943/CYP1A1 had significantly altered transmission in the aggregate and multiplex non-Hispanic white datasets (p = 0.003 and p = 0.009, respectively). Perturbation of CYP1A1 can cause an increase in harmful, adduct-forming metabolic intermediates. A significant interaction between EPHX1 and NAT2 was also found (p = 0.007). Importantly, for CYP1A2, significant maternal (p = 0.03; relative risk [RR] = 1.24; 95% confidence interval [CI], 1.04-1.44) and fetal (p = 0.01; RR = 1.33; 95% CI, 1.13-1.54) genotypic effects were identified, suggesting that both maternal and fetal genotypes can negatively impact limb development. No association was found between maternal smoking status and variation in xenobiotic metabolism genes.ConclusionTogether, these results suggest that xenobiotic metabolism genes are unlikely to play a major role in clubfoot; however, perturbation of this pathway may still play a contributory role.

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

Publications

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

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