Craniofacial Microsomia and Genetic Variation in Hemostasis and Vasculogenesis

颅面微小与止血和血管发生的遗传变异

• 批准号: 8657647
• 负责人: Jacqueline R Starr
• 金额: $ 26.26万
• 依托单位: ADA FORSYTH INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8657647
• 关键词: Craniofacial; Microsomia; Genetic; Variation; Hemostasis

DESCRIPTION (provided by applicant): Craniofacial microsomia (CFM) involves the asymmetric underdevelopment of facial skeletal bones and soft tissue and occurs in over 1 in 3500 births. Typically affecting the jaw and ear, CFM impairs basic functions such as hearing, speech, respiration, and/or chewing, in addition to its aesthetic effects. It can be life- threatening due to airway compromise. Animal models of teratogenesis have demonstrated a relationship between the features of CFM and vascular disruption (bleeding, clotting, or disruption of blood vessel formation). The only large epidemiologic study of CFM showed associations with maternal exposures that influence the risk of bleeding or clotting, such as pseudoephedrine use and cigarette smoking during pregnancy. CFM-like features have also been observed together with disrupted vasculogenesis in animals lacking genes related to the activities of retinoic acid (a transcription factor) and endothelin (a vasoconstrictor). Common variation in such genes could alter their activity and thereby influence the risk of CFM. Our specific aims are to address the vascular disruption hypothesis of CFM etiology by assessing its association with variation in candidate genes involved in vasculogenesis and hemostasis. We will implement a novel case-parent triad hybrid approach that incorporates data from control parents. We will extract and amplify DMA from existing buccal specimens banked as part of a multicenter case-control study of CFM (172 case-parent and 382 control-parent sets). We will perform single nucleotide polymorphism (SNP) discovery in genes related to retinoic acid activity by resequencing two sample populations. We will select "tagSNPs" that comprehensively characterize the variation in each of these and other candidate genes (totaling 19) involved in the activities of retinoic acid, endothelin, and thrombin, a key coagulation factor. We will genotype cases, their parents, and the parents of controls by using a high-throughput genotyping platform. We will estimate the association between CFM and offspring and maternal genotypes by fitting log-linear models and perform gene-wide tests of significance. Combining data from case-parent triads and parental controls allows one to capitalize on the advantages offered by the two different study designs and test assumptions of the log-linear model. Epidemiologic, clinical, and teratology studies have strongly supported the vascular disruption hypothesis for CFM. However, further research is necessary to elucidate the pathogenic processes involved in the vascular etiologies of this condition. The proposed research addresses this gap in knowledge through a state-of-the-art tagSNP approach. This will be the first molecular epidemiologic study of CFM. The results of our proposed research could lead to the development of interventions that reduce CFM incidence. The findings should also improve understanding of craniofacial development.

描述（由申请人提供）：颅面短小症 (CFM) 涉及面部骨骼和软组织的不对称发育不良，每 3500 名新生儿中就有超过 1 人发生这种情况。 CFM 通常会影响下巴和耳朵，除了影响美观之外，还会损害听力、言语、呼吸和/或咀嚼等基本功能。由于气道受损，可能会危及生命。致畸动物模型已证明 CFM 特征与血管破坏（出血、凝血或血管形成破坏）之间存在关系。唯一的 CFM 大型流行病学研究表明，CFM 与影响出血或凝血风险的母体暴露有关，例如怀孕期间使用伪麻黄碱和吸烟。在缺乏视黄酸（一种转录因子）和内皮素（一种血管收缩剂）活性相关基因的动物中，也观察到了类似 CFM 的特征以及血管生成中断。这些基因的常见变异可能会改变其活性，从而影响 CFM 的风险。我们的具体目标是通过评估 CFM 病因学的血管破坏假说与涉及血管生成和止血的候选基因变异的关系来解决该假说。我们将实施一种新颖的病例-父母三联体混合方法，其中包含来自对照父母的数据。我们将从作为 CFM 多中心病例对照研究（172 个病例亲本组和 382 个对照亲本集）的一部分存储的现有颊样本中提取和扩增 DMA。我们将通过对两个样本群体进行重新测序，在与视黄酸活性相关的基因中进行单核苷酸多态性 (SNP) 发现。我们将选择“tagSNP”，全面表征这些基因和其他候选基因（总共 19 个）的变异，这些基因涉及视黄酸、内皮素和凝血酶（一种关键的凝血因子）的活性。我们将使用高通量基因分型平台对病例、其父母和对照父母进行基因分型。我们将通过拟合对数线性模型来估计 CFM 与后代和母体基因型之间的关联，并进行全基因范围的显着性检验。将病例-父母三联体和父母对照的数据结合起来，可以利用两种不同研究设计和对数线性模型的测试假设所提供的优势。流行病学、临床和畸形学研究强烈支持 CFM 的血管破坏假说。然而，需要进一步的研究来阐明这种疾病的血管病因所涉及的致病过程。拟议的研究通过最先进的 tagSNP 方法解决了这一知识空白。这将是第一个 CFM 分子流行病学研究。我们提出的研究结果可能会导致开发出减少 CFM 发生率的干预措施。这些发现还应该提高对颅面发育的理解。