Date of Award

12-15-2014

Document Type

Open Access Dissertation

Department

Epidemiology and Biostatistics

First Advisor

Susan E. Steck

Abstract

Prostate cancer is the leading invasive malignancy and the second most common cause of cancer death among American men. Despite compelling evidence that oxidative stress, ineffective DNA damage repair, and habitually low antioxidants intake may act in tandem to influence prostate carcinogenesis, few studies have examined gene-diet interactions involving these risk factors. Even fewer studies have examined such interactions in relation to prostate cancer aggressiveness. This study investigated whether single nucleotide polymorphisms (SNPs) in DNA repair- and oxidative stress-related genes modulated associations between antioxidant intake and prostate cancer aggressiveness. We utilized data from the North Carolina-Louisiana Prostate Cancer Project (PCaP) among African-American (n = 948) and European-American (n = 1,016) men. Antioxidant intake was assessed using a food frequency questionnaire, and genotypes of 30 germline SNPs were examined. Effect modification by certain polymorphic variants were observed with some variations by race, including variants in XRCC1 (rs2854508, T > A), XPA (rs3176644, G > T), NOS3 (rs1799983, G > T), OGG1 (rs1805373, G > A) and NQO1 (rs689453, C > T). For example, significant interaction was observed between XRCC1 (rs2854508) genotype and α-tocopherol intake among African Americans and European Americans, such that among those with the TT genotype, higher α-tocopherol intake was inversely related to prostate cancer aggressiveness, while higher α-tocopherol intake was positively related to high aggressive prostate cancer among those who harbor the AA or AT genotype. A similar pattern of effect modification by XRCC1 (rs2854508) was observed for the association between γ-tocopherol and prostate cancer aggressiveness, but only among African Americans. Lower odds of high aggressive prostate cancer was observed among European Americans who possess the CT or TT genotype of NQO1 (rs689453) and had higher lycopene intake, but not European Americans with the CC genotype, and there was no evidence of effect modification among African Americans. Reduced odds and increased odds of high aggressive prostate cancer were observed with higher intakes of certain antioxidants (i.e., α-tocopherol, γ-tocopherol and lycopene) dependent on genotype, indicating potentially differential dietary recommendations based on genetic susceptibility. Because germline genotype is unalterable, these findings underscore the importance of considering genetic risk variability as part of dietary intervention strategies to identify the subgroup of men who are likely to benefit from such interventions.

Rights

© 2014, Samuel Antwi

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