Maternal Vasoactive Exposures and Risk of Clubfoot

描述(由调查者提供)：马蹄内翻足或马蹄内翻足大约发生在每1000个活产婴儿中。虽然它是最常见的结构畸形之一，但对其病因知之甚少。有强有力的证据表明，遗传因素在马蹄内翻足的发育过程中发挥了作用。在一个单独的研究人群中，我们的研究团队已经确定了马蹄内翻足在同源盒信号、程序性细胞死亡、胰岛素生长因子和N-乙酰转移酶途径中的候选基因。此外，在几项研究中，母亲吸烟与马蹄内翻足有关，这种联系可能会被N-乙酰转移酶基因很好地改变，因为这种酶参与了香烟烟雾副产物的生物转化。在父母研究中，DNA收集自婴儿和母亲的Oragene唾液试剂盒。然而，父母的研究没有明确的目标或资金来检查DNA中的遗传风险因素。这项应用旨在研究候选基因的遗传变异，这些基因以前在家庭研究中被证明与马蹄内翻足有关。候选基因将在另一项关于马蹄内翻足的研究中确定，该研究目前已经确定了马蹄内翻足与HoxA、HoxD、IGFBP3和凋亡途径基因的变异之间的关联。此外，将评估NAT2中的三个功能多态，以寻找与母亲吸烟和马蹄内翻足风险的交互作用。将对400多名马蹄内翻足患者及其母亲和900多对对照母婴提供唾液样本。母亲在分娩后一年内接受采访，并收集有关吸烟的详细信息。我们预计&gt；80%的统计能力可以检测到基因多态的微小差异，基因与吸烟相互作用的优势比为2.5倍。本附录将提供资源，以测试这一强大的数据集的遗传和环境原因的马蹄内翻足，并将产生重要的信息，将转化为更好的管理马蹄内翻足。公共卫生相关性：马蹄内翻足是最常见的先天性畸形之一，但其原因尚不清楚。这项补充拨款的目的是确定与马蹄内翻足风险有关的遗传因素以及基因与吸烟的相互作用。我们的目标是了解马蹄内翻足的病因和发病机制，从而指导预防。

DESCRIPTION (provided by investigator): Talipes equinovarus or clubfoot occurs in approximately one of every 1000 live births. Although it is one of the most common structural malformations, little is known about its etiology. There is strong evidence to suggest that genetic factors play a role in the development of clubfoot. In a separate study population, our investigative team has identified candidate genes for clubfoot in the homeobox signaling, program cell death, insulin growth factor, and n-acetyl transferase pathways. Further, maternal cigarette smoking has been linked to clubfoot in several studies, and this association may be well be modified by n-acetyl transferase genotypes because this enzyme is involved in the biotransformation of the byproducts of cigarette smoke. In the parent study, DNA is collected from baby and mother with Oragene saliva kits. However, the parent study included no specific aims or funding to examine DNA for genetic risk factors. This application aims to study genetic variation in candidate genes, which were previously shown to be associated with clubfoot in family studies. The candidate genes will be identified in a separate study of clubfoot which has currently identified associations between clubfoot and variation in HoxA, HoxD, IGFBP3 and apoptotic pathway genes. In addition, three functional polymorphisms in NAT2 will be evaluated to look for an interaction with maternal smoking and the risk of clubfoot. Saliva samples will be available on over 400 clubfoot cases and their mothers and over 900 control mother-baby pairs. Mothers are interviewed within one year after delivery and detailed information is collected on cigarette smoking. We anticipate >80 per cent statistical power to detect slight differences for polymorphisms and 2.5-fold odds ratios for gene-smoking interaction. This supplement will provide the resources to test this powerful dataset for genetic and environmental causes of clubfoot and will yield important information that will translate into better management of clubfoot. PUBLIC HEALTH RELEVANCE: Clubfoot is one of the most common congenital malformations but its causes are not known. The aims of this supplemental grant are to identify genetic factors, as well as gene-smoking interactions, in relation to risk of clubfoot. Our goal is to understand the etiology and pathogenesis of clubfoot, leading to prevention.