Evaluation of genes involved in limb development, angiogenesis, and coagulation as risk factors for congenital limb deficiencies

Marilyn L Browne; Tonia C Carter; Denise M Kay; Devon Kuehn; Lawrence C Brody; Paul A Romitti; Aiyi Liu; Michele Caggana; Charlotte M Druschel; James L Mills

doi:10.1002/ajmg.a.35565

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Evaluation of genes involved in limb development, angiogenesis, and coagulation as risk factors for congenital limb deficiencies

Journal article

Peer reviewed

Evaluation of genes involved in limb development, angiogenesis, and coagulation as risk factors for congenital limb deficiencies

Marilyn L Browne, Tonia C Carter, Denise M Kay, Devon Kuehn, Lawrence C Brody, Paul A Romitti, Aiyi Liu, Michele Caggana, Charlotte M Druschel and James L Mills

American journal of medical genetics. Part A, Vol.158A(10), pp.2463-2472

10/2012

DOI: 10.1002/ajmg.a.35565

PMCID: PMC3448837

PMID: 22965740

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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.

Limb Deformities, Congenital - genetics

Morphogenesis - genetics

Neovascularization, Physiologic - genetics

Humans

Genotype

Male

Case-Control Studies

Proteins - genetics

Young Adult

Extremities - blood supply

Limb Deformities, Congenital - ethnology

Adult

Blood Coagulation - genetics

Female

Polymorphism, Single Nucleotide

Fibroblast Growth Factor 10 - genetics

Extremities - growth & development

Infant, Newborn

Details

Title: Subtitle: Evaluation of genes involved in limb development, angiogenesis, and coagulation as risk factors for congenital limb deficiencies
Creators: Marilyn L Browne - Congenital Malformations Registry, New York State Department of Health, Troy, USA. mlb10@health.state.ny.us
Tonia C Carter
Denise M Kay
Devon Kuehn
Lawrence C Brody
Paul A Romitti
Aiyi Liu
Michele Caggana
Charlotte M Druschel
James L Mills
Resource Type: Journal article
Publication Details: American journal of medical genetics. Part A, Vol.158A(10), pp.2463-2472
DOI: 10.1002/ajmg.a.35565
PMID: 22965740
PMCID: PMC3448837
NLM abbreviation: Am J Med Genet A
ISSN: 1552-4825
eISSN: 1552-4833
Publisher: United States
Grant note: HHSN267200703431C / PHS HHS N01-DK-7-3431 / NIDDK NIH HHS N01DK73431 / NIDDK NIH HHS
Language: English
Date published: 10/2012
Academic Unit: Epidemiology; Biostatistics
Record Identifier: 9983996099702771

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