Maternal Vasoactive Exposures and Risk of Clubfoot

母体血管活性物质暴露和马蹄内翻足的风险

• 批准号: 7582685
• 负责人: MARTHA M. WERLER
• 金额: $ 7.65万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-20 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7582685
• 关键词: Address; Apoptosis; Apoptotic; Candidate Disease Gene; Congenital Abnormality; Congenital clubfoot; DNA; Data Set; Development; Enzymes; Etiology; Family Study; Funding; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Goals; Grant; Growth Factor; Homeobox; IGFBP3 gene; Infant; Insulin; Interview; Laboratories; Link; Live Birth; Metabolic Biotransformation; Mothers; NAT2 gene; Odds Ratio; Parents; Pathogenesis; Pathway interactions; Play; Population Study; Pregnancy; Prevention; Research Personnel; Resources; Risk; Role; Saliva; Sampling; Signal Transduction; Smoke; Testing; Transferase; Translating; Variant; cigarette smoking; cigarette smoking; experience; gene discovery; genetic risk factor; genetic variant; malformation; maternal cigarette smoking; public health relevance

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.

描述（由研究者提供）：马蹄内翻足或马蹄内翻足发生率约为每1000例活产1例。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展中发挥作用。在一个单独的研究人群中，我们的研究小组已经确定了马蹄内翻足的候选基因在同源框信号传导，程序细胞死亡，胰岛素生长因子和N-乙酰转移酶途径。此外，在一些研究中，母亲吸烟与马蹄内翻足有关，这种关联可能被n-乙酰转移酶基因型所改变，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，使用Oragene唾液试剂盒从婴儿和母亲中收集DNA。然而，这项母体研究没有具体的目标或资金来检查DNA的遗传风险因素。该应用旨在研究候选基因的遗传变异，这些基因先前在家族研究中被证明与马蹄内翻足相关。候选基因将在一项单独的马蹄内翻足研究中鉴定，该研究目前已鉴定了马蹄内翻足与HoxA、HoxD、IGFBP 3和凋亡途径基因变异之间的关联。此外，将评估NAT 2的三种功能多态性，以寻找与母亲吸烟和马蹄内翻足风险的相互作用。将对400多名马蹄内翻足病例及其母亲和900多对对照母婴提供唾液样本。在分娩后一年内对母亲进行面谈，收集关于吸烟的详细资料。我们预计有超过80%的统计能力检测到多态性的微小差异和基因吸烟相互作用的2.5倍优势比。这个补充将提供资源来测试这个强大的数据集，以了解马蹄内翻足的遗传和环境原因，并将产生重要的信息，这些信息将转化为更好的马蹄内翻足管理。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-吸烟相互作用。我们的目标是了解马蹄内翻足的病因和发病机制，从而预防。