Prostate cancer (PC) remains a significant public health concern for men throughout the world. Identification of the environmental and genetic factors that predispose to PC for prevention or early intervention is a significant public health concern. PC is more prevalent in males of African descent living in the western hemisphere. Also, recent studies have shown high rates of PC in Afro-Caribbean populations. Men in the 40-79 year age range from the Caribbean island of Tobago have a 3 fold higher risk of developing prostate cancer than do Caucasians. We performed two candidate gene-based association studies to explore the genetic determinants for high risk of PC in Tobago population.
In the first study, we performed an extensive study to identify sequence variation in the DC-SIGN gene, a candidate gene for PC, in the Tobago population, and carried out a case/control association study of DC-SIGN polymorphisms and PC susceptibility in the high-risk population of Tobago. We found a unique haplotype in the 5 proximal promoter of DC-SIGN that is associated with PC in Tobago. We further extended the association study to single gene polymorphisms likely to be in linkage disequilibrium with DC-SIGN. We also found that a single nucleotide polymorphism, rs4804806, which is located in the intragenic region between the DC-SIGN and DCSIGN-R genes (4228bp upstream of DC-SIGN), is significantly associated with elevated risk of PC in Tobago population. The function of rs4804806, and whether the risk associated with it is due to linkage disequilibrium between it and other causal variation remains to be explored.
In the second study, we examined whether genetic variation in the androgen receptor (AR) and PSA genes was associated with risk of prostate cancer or with serum PSA levels in the Tobago population. Previous studies have proposed that the rs266882 G/A polymorphism, located in the androgen response element upstream of the PSA gene and the (CAG)n repeat polymorphism in DNA binding domain of the AR are associated with risk of PC and serum PSA levels, and those two genetic variants show evidence of genetic interaction. In order to examine whether those two genetic variants affect PC risk or PSA level in Tobago population, an association study was carried out in 167 PC cases and 320 controls. Association analysis with PC was conducted among all cases and controls for each locus individually, and also for both loci together, to test for interaction between them in determining risk of PC or PSA levels. Regression analysis was carried out for each locus and combined with serum PSA level in 320 controls only. Results from this study do not provide any association evidence with PC risk or PSA level for PSA rs266882 G/A genotypes or AR (CAG)n repeat length genotypes.
The results from these two studies lend support to exploring genetic causes and prevention of prostate cancer.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-03242010-105735 |
| Date | 28 June 2010 |
| Creators | Li, You |
| Contributors | Eleanor Feingold, Clareann Bunker, Jeremy Martinson, Robert E. Ferrell |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-03242010-105735/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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