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Genetic variation and complex disease: the examination of an X-linked disorder and a multifactorial disease

Cottrell, Catherine E
http://rave.ohiolink.edu/etdc/view?acc_num=osu1196182829

Abstract Details

2007, Doctor of Philosophy, Ohio State University, Integrated Biomedical Science.
Improved treatment strategies in pediatric Hodgkin Lymphoma (HL) have resulted in a cure rate approaching 95%, yet the development of a second primary malignant neoplasm (SMN) is a risk for survivors. Oxidative stress has been linked to the development of cancer due to the damaging effects of reactive species on DNA, lipids, and proteins. The aim of this study was to assess the associations of antioxidant gene alleles and the risk of developing a SMN in HL patients. Polymorphisms were chosen from antioxidant-related genes including; SOD GPX, CAT, and NOS. Statistical analysis was completed using tests of association, haplotype, and multiple regression modeling. Out of the 36 SNPs that were included in the final analysis, 4 SNPs in the GPX1, GPX3, GPX4, and SOD2 genes, were potentially suggestive (p<0.05) of an association between genotype and the development of a SMN. Replication studies are necessary, though it is notable that polymorphisms within the GPX family may be associated with the development SMN in our cohort. X-chromosome inactivation (XCI) is an epigenetic process used to regulate gene dosage in mammalian females by silencing one X-chromosome. While the pattern of XCI is typically random in normal females, abnormalities of the X-chromosome may result in skewing due to disadvantaged cell growth. We describe a female patient with an X;1 translocation [46,X, t(X;1)(q28;q21)dn] and unusual pattern of XCI who was clinically diagnosed with Otopalatodigital syndrome (OPD) type 1. There was complete skewing of XCI in the patient, along with the atypical findings of an active normal X-chromosome and an inactive derivative X. OPD1 is characterized by skeletal abnormalities, craniofacial defects, and hearing loss. Mutations within the FLNA gene (Xq28) are known to cause OPD, though none were detected in our patient. Characterization of the translocation revealed that the patient’s Xq28 breakpoint interrupts the DKC1 gene, located 400kB distal to FLNA. Analysis of the breakpoint region revealed functional disomy of Xq28 genes distal to DKC1. Possible explanations for the patient’s phenotype include a position effect due to the translocation breakpoint, an undetected FLNA-related mutation, or altered gene dosage due to consequences of atypical XCI.
Julie Gastier-Foster (Advisor)
201 p.
Biology, Genetics
Antioxidant; Hodgkin Lymphoma; Second Primary Malignant Neoplasm; Otopalatodigital Syndrome; X-Chromosome Inactivation; X:1 Translocation

Recommended Citations

Citations

  • Cottrell, C. E. (2007). Genetic variation and complex disease: the examination of an X-linked disorder and a multifactorial disease [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1196182829

    APA Style (7th edition)

  • Cottrell, Catherine. Genetic variation and complex disease: the examination of an X-linked disorder and a multifactorial disease. 2007. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1196182829.

    MLA Style (8th edition)

  • Cottrell, Catherine. "Genetic variation and complex disease: the examination of an X-linked disorder and a multifactorial disease." Doctoral dissertation, Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=osu1196182829

    Chicago Manual of Style (17th edition)

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This open access ETD is published by The Ohio State University and OhioLINK.