Evaluation of Genes Involved in Limb Development, Angiogenesis, and Coagulation as Risk Factors for Congenital Limb Deficiencies
Evaluation of Genes Involved in Limb Development, Angiogenesis, and Coagulation as Risk Factors for Congenital Limb Deficiencies
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DOI：
10.1002/ajmg.a.35565
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发表时间：
2012-10-01
影响因子：
2
通讯作者：
Mills, James L.
中科院分区：
文献类型：
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作者：
Browne, Marilyn L.;Carter, Tonia C.;Mills, James L.
我们对选定基因中的单核苷酸多态(SNPs)进行了一项基于人群的病例对照研究，以寻找在肢体缺陷(LDS)病因中发挥作用的常见变异。这项研究包括389名原因不明的LDS婴儿和980名未受影响的对照组婴儿，这些婴儿是从纽约州1998-2005年出生的所有婴儿中挑选出来的。我们使用了从纽约卫生部(DOH)先天性畸形登记处鉴定的病例。在与肢体发育相关的基因(SHH、WNT7A、FGF4、FGF8、FGF10、TBX3、TBX5、SALL4、GREM1、GDF5、CTNNB1、EN1、CYP26A1、CYP26B1)、血管生成(VEGFA、HIF1a、NOS3)和凝血(F2、F5、MTHFR)基因上共检测到132个SNPs。基因型呼叫率为>；97%，并按种族/民族亚组测试SNPs是否偏离Hardy-Weinberg预期。对每个SNP的优势比(OR)S和可信区间(CI)S进行估计和校正，以用于所有LD组合和LD亚型的多次比较。在非西班牙裔白人婴儿中，rs10805683、rs13170645 SNPs和全部LDS的关联在多重检验校正后有统计学意义(OR=1.99；95%CI=1.43~2.77；rs10805683杂合子未校正P=0.000043，OR=2.37；95%CI=1.48~3.78；rs13170645纯合子次要基因型未校正P=0.00032)。我们还观察到了与其他基因的SNP相关的提示性证据，包括CYP26B1和WNT7A。动物研究表明，FGF10诱导顶端外胚层脊的形成，是肢体发育所必需的。我们的数据表明，FGF10的常见变异增加了广泛的非综合征性肢体缺陷的风险。(C)2012年威利期刊公司。
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. (C) 2012 Wiley Periodicals, Inc.