Candidate gene studies for human spina bifida : a dissertation /
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| Format: | Thesis Book |
| Language: | English |
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[College Station, Tex.] :
[Texas A&M University System Health Science Center],
[2008]
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| Abstract: | ABSTRACT: In this study, we investigated the association between 6 candidate genes/genetic pathways suspected of having a role in dertermining the risk of human NTDs. Planar cell polarity (PCP) genetic pathway controls normal neural tube development. We used a case-control design to analyze the possible association between single nucleotide polymorphisms (SNPs) in PCP genes and the risk of NTDs. Of the 14 genes and 211 SNPs examined, we determined that PRICKLE2 might be modestly associated with increased risk of NTDs. Previous studies have revealed the importance of PAX3 genes as regulators of normal development. We resequenced the human PAX3 gene and found 19 SNPs. FIfteen novel SNPs observed in controls have been submitted to the National Center for Biotechnology Information (NCBI) database with allele frequencies. Using a case-controlled study, we identified a single PAX3 haplotype that appeared to be associated with an increase risk of NTDs. Maternal folic acid supplementation is known to reduce NTDs risk, but the mechanism underlying this association is largely unknown. The current hypothesis is that the increasing maternal folate concentration compensates for the individual genetic susceptibilities of folate metabolism pathway in the maternal environment and/or the embryos. We tested the association between variations in three folate metabolic genes: Betaine-homocysteine methyltransferase 1 and 2 (BHMT and BHMT2) and nicotinamide N-methyl transferase and the risk of NTDs in two separate case-control studies. The results suggest that variants of the BHMT/BHMT2 genes and NNMT genes in infants do not substantially contribute to the risk of spina bifida or orofacial clefts in our study population. Oxidative stress is widely considered to have adverse developmental effects. An antioxidant gene, thiredoxin 2 (Txn2), has been associated with mouse NTDs. We hypothesize variation in this gene might relate to risk of human NTDs. We identified a novel ins/del polymorphism in the promoter region of this gene. We tested the transcriptional activities of this polymorphism and found that the GA, G and GGGA genotypes are associated with lower activities. Further analyses in a case-control study revealed that the GA insertion was associated with increased spina bifida risk for Hispanic white infants, although the measure was rather imprecise. |
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| Item Description: | Vita. "Major Subject: Medical Sciences". "Submitted to the Office of Research and Graduate Studies of The Texas A&M University System Health Science Center in partial fulfillment for the requirements for the degree of Doctor of Philosophy December 2008." Approved as to style and content by: Richard H. Finnell, Laura E. Mitchell, Dekai Zhang, Gary M. Shaw, Robert J. Schwartz, Stephen H. Safe. |
| Physical Description: | xi, 119 leaves : illustrations ; 28 cm. |
| Bibliography: | Includes bibliographical references (leaves 100-118). |