Transforming growth factor-beta receptor type 1 (TGFBR1) is not associated with non-syndromic cleft lip with or without cleft palate in patients of Central European descent
Transforming growth factor-beta receptor type 1 (TGFBR1) is not associated with non-syndromic cleft lip with or without cleft palate in patients of Central European descent
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DOI：
10.1016/j.ijporl.2009.06.004
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发表时间：
2009-10-01
影响因子：
1.5
通讯作者：
Mangold, Elisabeth
中科院分区：
文献类型：
--
作者：
Reutter, Heiko;Birnbaum, Stefanie;Mangold, Elisabeth
目的：转化生长因子-β (TGF-β) 1 型受体（也称为激活素受体样激酶 5，ALK5）在胚胎发生过程中在腭组织中表达。对 Alk5 基因缺失的转基因小鼠进行的实验研究表明，上唇以及硬腭和软腭中线融合需要 TGF-β 1 受体。在人类中，在中国、菲律宾、印度和土耳其家庭的多种族样本中观察到 TGF-β 1 型受体基因 (TGFBR1) 与伴有或不伴有腭裂的非综合征性唇裂 (NSCL/P) 的发生有关。为了重新评估这些发现的相关性，我们在 218 个中欧血统的 NSCL/P 家族中开展了一项基于家族的关联研究。方法：从 218 个完全 NSCL/P 亲子三联征的外周血中获取基因组 DNA。样本包括 14 名单纯唇裂 (CLO) 患者和 204 名唇腭裂 (CLP) 患者。对所有 218 个三联体进行了基因分型和传递不平衡测试 (TDT)，总共有 17 个标记单核苷酸多态性 (SNP)。我们还对扩展单倍型进行了测试，并使用温伯格的对数线性模型来筛选亲本效应。此外，还获得了对 Weinberg 模型的相对风险 (RR) 的估计。结果：TDT 分析显示，无论是在个体标记水平还是在单倍型水平，都没有显着的传输失真。当我们将分析限制在 CLP 患者亚组 (n = 204) 时，也得到了类似的阴性结果。在校正多重测试的 p 值后，儿童和母亲基因型的相对风险计算 (RR) 获得阴性结果。同样，应用 Weinberg 的对数线性模型在我们的样本中没有发现任何亲本效应的证据。结论：尽管有充足的证据支持 TGF-β 1 型受体作为小鼠模型中颅面发育的极其重要且广泛的形态发生调节剂的作用，但我们的结果并不支持 TGFBR I 作为中欧血统患者 NSCL/P 的主要危险因素。 (C) 2009 Elsevier Ireland Ltd. 保留所有权利。
Objective: Transforming growth factor-beta (TGF-beta) type 1 receptor (also known as activin receptor-like kinase 5, ALK5) is expressed in palatal tissue during embryogenesis. Experimental studies in transgenic mice with a genetic deletion of Alk5 showed that TGF-beta type 1 receptor is required for upper lip and midline fusion of the hard and soft palate. In humans, association of TGF-beta type 1 receptor gene (TGFBR1) and the development of non-syndromic cleft lip with or without cleft palate (NSCL/P) had been observed in a multiethnic sample of Chinese, Philippine, Indian and Turkish families. In order to re-evaluate the relevance of these findings, we carried out a family-based association study among 218 NSCL/P families of Central European descent.Methods: Genomic DNA was obtained from peripheral blood of 218 complete parent-offspring triads with NSCL/P. The sample comprised 14 patients with cleft lip only (CLO) and 204 patients with cleft lip and palate (CLP). Genotyping and transmission disequilibrium test (TDT) were performed on all 218 triads with a total of 17 tagging single-nucleotide polymorphisms (SNPs). We also performed testing for extended haplotypes and a log-linear model by Weinberg was used to screen parent-of-origin effects. Furthermore the use of estimates for the relative risks (RR) of Weinberg's model was obtained.Results: TDT analysis revealed no significant transmission distortion, neither at the level of individual markers nor at the level of haplotypes. Similarly negative results were obtained when we restricted our analysis to the subgroup of patients with CLP (n = 204). Relative risk calculations (RR) of the children's and mothers' genotypes obtained negative results, after correction of p-values for multiple testing. Likewise application of Weinberg's log-linear model did not find any evidence for parent-of-origin effects in our sample.Conclusion: Despite the ample evidence supporting the role of TGF-beta type 1 receptor as a critically important and widespread morphogenetic regulator of craniofacial development in murine models, our results do not support TGFBR I as major risk factor for NSCL/P in patients of Central European descent. (C) 2009 Elsevier Ireland Ltd. All rights reserved.