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Haplotype-Based Prostate Cancer Association Study in Afro-Caribbeans of Tobago

Li, You (2010) Haplotype-Based Prostate Cancer Association Study in Afro-Caribbeans of Tobago. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

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.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Li, Youyol11@pitt.eduYOL11
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairFerrell, Robert Erferrell@pitt.eduRFERRELL
Committee MemberBunker, ClareannBUNKERC@pitt.eduBUNKERC
Committee MemberFeingold, Eleanorfeingold@pitt.eduFEINGOLD
Committee MemberMartinson, Jeremyjmartins@pitt.eduJMARTINS
Date: 28 June 2010
Date Type: Completion
Defense Date: 24 March 2010
Approval Date: 28 June 2010
Submission Date: 24 March 2010
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Human Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: association study; haplotype; prostate cancer; tobago
Other ID: http://etd.library.pitt.edu/ETD/available/etd-03242010-105735/, etd-03242010-105735
Date Deposited: 10 Nov 2011 19:32
Last Modified: 15 Nov 2016 13:37
URI: http://d-scholarship.pitt.edu/id/eprint/6581

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