title: Evaluation of genes involved in limb development, angiogenesis, and coagulation as risk factors for congenital limb deficiencies.
abstract: We conducted a population-based case-control study of single nucleotide polymorphisms (SNPs) in selected genes to find common variants that play a role in the etiology of limb deficiencies (LDs). Included in the study were 389 infants with LDs of unknown cause and 980 unaffected controls selected from all births in New York State (NYS) for the years 1998-2005. We used cases identified from the NYS Department of Health (DOH) Congenital Malformations Registry. Genotypes were obtained for 132 SNPs in genes involved in limb development (SHH, WNT7A, FGF4, FGF8, FGF10, TBX3, TBX5, SALL4, GREM1, GDF5, CTNNB1, EN1, CYP26A1, CYP26B1), angiogenesis (VEGFA, HIF1A, NOS3), and coagulation (F2, F5, MTHFR). Genotype call rates were >97% and SNPs were tested for departure from Hardy-Weinberg expectations by race/ethnic subgroups. For each SNP, odds ratios (OR)s and confidence intervals (CI)s were estimated and corrected for multiple comparisons for all LDs combined and for LD subtypes. Among non-Hispanic white infants, associations between FGF10 SNPs rs10805683 and rs13170645 and all LDs combined were statistically significant following correction for multiple testing (OR = 1.99; 95% CI = 1.43-2.77; uncorrected P = 0.000043 for rs10805683 heterozygous genotype, and OR = 2.37; 95% CI = 1.48-3.78; uncorrected P = 0.00032 for rs13170645 homozygous minor genotype). We also observed suggestive evidence for associations with SNPs in other genes including CYP26B1 and WNT7A. Animal studies have shown that FGF10 induces formation of the apical ectodermal ridge and is necessary for limb development. Our data suggest that common variants in FGF10 increase the risk for a wide range of non-syndromic limb deficiencies.
authors.affiliation: Congenital Malformations Registry, New York State Department of Health, Troy, USA. mlb10@health.state.ny.us
authors.forename: Marilyn L
authors.initials: ML
authors.lastname: Browne
authors.forename: Tonia C
authors.initials: TC
authors.lastname: Carter
authors.forename: Denise M
authors.initials: DM
authors.lastname: Kay
authors.forename: Devon
authors.initials: D
authors.lastname: Kuehn
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Brody
authors.forename: Paul A
authors.initials: PA
authors.lastname: Romitti
authors.forename: Aiyi
authors.initials: A
authors.lastname: Liu
authors.forename: Michele
authors.initials: M
authors.lastname: Caggana
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Druschel
authors.forename: James L
authors.initials: JL
authors.lastname: Mills
mesh_terms: D000328:Adult; D001777:Blood Coagulation / Q000235:genetics; D016022:Case-Control Studies; D005121:Extremities / Q000098:blood supply / Q000254:growth & development; D005260:Female; D051526:Fibroblast Growth Factor 10 / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D017880:Limb Deformities, Congenital / Q000208:ethnology / Q000235:genetics*; D008297:Male; D009024:Morphogenesis / Q000235:genetics; D018919:Neovascularization, Physiologic / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics; D055815:Young Adult
chemical_list: C496463:FGF10 protein, human; D051526:Fibroblast Growth Factor 10; D011506:Proteins