Craniofacial Microsomia and Genetic Variation in Hemostasis and Vasculogenesis

描述（由申请人提供）：颅面矮小症（CFM）涉及面部骨骼和软组织的不对称发育不足，发生率超过1/3500。CFM通常影响颌和耳，除了其美学效果外，还会损害基本功能，如听力、言语、呼吸和/或咀嚼。会危及生命因为呼吸道受损。致畸作用的动物模型已经证明了CFM的特征与血管破坏（出血、凝血或血管形成的破坏）之间的关系。CFM的唯一一项大型流行病学研究显示，与影响出血或凝血风险的母亲接触有关，例如怀孕期间使用伪麻黄碱和吸烟。在缺乏与视黄酸（一种转录因子）和内皮素（一种血管收缩剂）活性相关的基因的动物中，也观察到CFM样特征以及血管发生中断。这些基因的常见变异可能会改变它们的活性，从而影响CFM的风险。我们的具体目标是解决CFM病因学的血管中断假说，通过评估其与参与血管发生和止血的候选基因变异的相关性。我们将实施一种新的情况下，父母三位一体的混合方法，结合控制父母的数据。我们将从现有的口腔样本中提取和扩增DMA，这些样本是CFM多中心病例对照研究的一部分（172个病例-父母组和382个对照-父母组）。我们将进行单核苷酸多态性（SNP）的发现与维甲酸活性的基因重新测序两个样本人群。我们将选择“tagSNPs”，全面表征这些和其他候选基因（共19个）中的每一个的变化，参与视黄酸，内皮素和凝血酶，一个关键的凝血因子的活动。我们将使用高通量基因分型平台对病例、其父母和对照的父母进行基因分型。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，并进行全基因显着性检验。结合病例-父母三联体和父母对照组的数据，可以利用两种不同研究设计和对数线性模型检验假设所提供的优势。流行病学、临床和畸形学研究强烈支持CFM的血管中断假说。然而，进一步的研究是必要的，以阐明参与血管病因这种情况下的致病过程。拟议的研究通过最先进的tagSNP方法解决了这一知识差距。这将是CFM的第一个分子流行病学研究。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。这些发现也应该提高对颅面发育的理解。

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.