Date of Award

Spring 5-21-2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biological Science

First Advisor

Jaideep Chaudhary, Ph.D.

Second Advisor

Nathan Bowen, Ph.D.

Third Advisor

Carlos Moreno, Ph.D.

Abstract

2’ -5’ –oligoadenylate synthetase 1 (OAS1) is an antiviral enzyme that in the presence of double-stranded RNA structures, such as viral genomes or single-stranded RNA transcripts with significant double-stranded character, converts ATP to a series of 2’ -5’ –oligoadenylates (2-5A). 2-5A promotes dimerization of latent ribonuclease (RNaseL) to form catalytically active RNaseL, a candidate hereditary prostate cancer (PCa) gene. RNaseL is anti-proliferative and promotes senescence and apoptosis in PCa cells. Genotyping analysis was completed on over 600 genomic DNA samples from African-American and Caucasian, normal and PCa subjects. Genotyping was performed to screen the following SNPs in the last exon of OAS1 (rs10774671, rs1131476, rs1051042 and rs2660) to determine splicing and linkage disequilibrium (LD) or LD decay in relation to PCa.

The rs10774671 GG and AA genotypes generate isoform 1 (p46) and isoform 3 (p48), respectively and were distributed equally in the healthy population. However, in cases, the AA genotype (p46) was significantly associated with PCa risk (OR: 1.80, P-value: < 0.0001). The genotypic frequencies of rs1131476, rs1051042 and rs2660 demonstrated significant LD but showed no association to PCa risk. We also identified protective (AACA, OR =0.06612, P < 0.001) and risk (GACA, OR= 2.31, p

Additionally, we utilized two genome-wide association studies analyzing OAS1 and variants found on chromosome 12 to determine their relationship with PCa susceptibility for meta-analysis: This was done to elucidate the role of OAS1 SNPs and chromosome 12 variants in a larger population cohort with PCa susceptibility for a greater understanding of gene to gene interactions. The genome wide association studies used were, the Geneva Multiethnic Genome-wide Scan of Prostate Cancer (MEC), containing 2,841 African-American samples (1,343 cases and 1,498 controls) and 1,660 Japanese/Latino samples (834 cases and 826 controls), as well as Cancer Genetic Markers of Susceptibility (CGEMS) Prostate Cancer-Primary Scan (Stage 1) - PLCO which contains 2,841 samples of European ancestry (1,172 cases and 1,157 controls). We used PLINK, a whole genome association analysis toolset, to extract data on SNPs in association with PCa.

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