Maternal Vasoactive Exposures and Risk of Clubfoot

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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.