Craniofacial Microsomia and Genetic Variation in Hemostasis and Vasculogenesis

描述（由申请人提供）：颅面小畸形（CFM）涉及面部骨骼和软组织发育不对称，每3500个新生儿中就有1个发生。CFM通常影响下颌和耳朵，损害基本功能，如听力，语言，呼吸，和/或咀嚼，除了它的美学效果。由于气道受损，它可能危及生命。畸形的动物模型已经证明了CFM的特征与血管破坏（出血、凝血或血管形成破坏）之间的关系。唯一一项关于CFM的大型流行病学研究表明，CFM与母亲接触影响出血或凝血风险的因素有关，如怀孕期间使用伪麻黄碱和吸烟。在缺乏维甲酸（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cfm样特征以及血管生成中断。这些基因的共同变异可能改变它们的活性，从而影响CFM的风险。我们的具体目的是通过评估其与参与血管发生和止血的候选基因变异的关系来解决CFM病因学的血管破坏假说。我们将实现一种新的case-parent triad混合方法，该方法包含来自控制父方的数据。作为CFM多中心病例对照研究的一部分，我们将从现有的口腔标本中提取和扩增DMA（172组病例亲本和382组对照亲本）。我们将通过对两个样本群体进行重测序来进行维甲酸活性相关基因的单核苷酸多态性（SNP）发现。我们将选择“标签snp”，全面表征这些和其他候选基因（共19个）的变异，这些基因参与维甲酸、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及其父母和对照组父母进行基因分型。我们将通过拟合对数线性模型来估计CFM与后代和母亲基因型之间的关系，并进行基因范围的显著性检验。结合病例-父母三位一体和父母控制的数据，可以利用两种不同研究设计提供的优势，并检验对数线性模型的假设。流行病学、临床和致畸学研究有力地支持了CFM的血管破裂假说。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标记snp方法解决了这一知识差距。这将是首次对CFM进行分子流行病学研究。我们提出的研究结果可能会导致减少CFM发病率的干预措施的发展。研究结果也应该提高对颅面发育的认识。

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.