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EXAMINING THE RELATIONSHIP BETWEEN COMMON GENETIC VARIATION, TYPE 2 DIABETES AND PROSTATE CANCER RISK IN THE MULTIETHNIC COHORT by Kevin M. Waters A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (EPIDEMIOLOGY) August 2010 Copyright 2010 Kevin M. Waters
|Title||Examining the relationship between common genetic variation, type 2 diabetes and prostate cancer risk in the multiethnic cohort|
|Author||Waters, Kevin M.|
|Author firstname.lastname@example.org; email@example.com|
|Degree||Doctor of Philosophy|
|School||Keck School of Medicine|
|Advisor (committee chair)||Haiman, Christopher A.|
|Advisor (committee member)||
Henderson, Brian E.
Stram, Daniel O.
Coetzee, Gerhard A.
Watanabe, Richard M.
|Abstract||This thesis is comprised of five studies that examine the relationship between common genetic variation, type 2 diabetes and prostate cancer risk.; Generalizability of Associations from Prostate Cancer GWAS in Multiple Populations:; Genome-wide association studies have identified multiple common alleles associated with prostate cancer risk in populations of European ancestry. Testing these variants in other populations is needed to assess the generalizability of the associations, and may guide fine-mapping efforts. We examined 13 of these risk variants in a multiethnic sample of 2,768 incident prostate cancer cases and 2,359 controls from the Multiethnic Cohort (MEC; African Americans, European Americans, Latinos, Japanese Americans and Native Hawaiians). We estimated ethnic-specific and pooled odds ratios and tested for ethnic heterogeneity of effects using logistic regression. In ethnic-pooled analyses, 12 of the 13 variants were positively associated with risk, with statistically significant associations (p<0.05) noted with 6 variants (odds ratio, 95% confidence interval): JAZF1, rs10486567, 1.23(1.12-1.35); Xp11.2, rs5945572, 1.31(1.13-1.51); HNF1B, rs4430796, 1.15(1.06-1.25); MSMB, rs10993994, 1.13(1.04-1.23); 11q13.2, rs7931342, 1.13(1.03-1.23); 3p12.1, rs2660753, 1.11(1.01-1.21); SLC22A3, rs9364554, 1.10(1.00-1.21); CTBP2, rs12769019, 1.11(0.99-1.25); HNF1B, rs11649743, 1.10(0.99-1.22); EHBP1, rs721048, 1.08(0.94-1.25); KLK2/3, rs2735839, 1.06(0.97-1.16); 17q24.3, rs1859962, 1.04(0.96-1.13); and LMTK2, rs6465657, 0.99(0.89-1.09). Significant ethnic heterogeneity of effects was noted for 4 variants (EHBP1, phet = 3.9x10-3; 11q13, phet = 0.023; HNF1B (rs4430796), phet = 0.026; and KLK2/3, phet = 2.0x10-3). Although power was limited in some ethnic/racial groups due to variation in sample size and allele frequencies, these findings suggest that a large fraction of prostate cancer variants identified in populations of European ancestry are global markers of risk. For many of these regions, fine-mapping in non-European samples may help localize causal alleles and better determine their contribution to prostate cancer risk in the population.; Common Prostate Cancer Risk Variant in the 5’ Region of MSMB is a Strong Predictor of Circulating MSP Levels in Multiple Populations: The Multiethnic Cohort Study:; Beta-microseminoprotein (MSP) is one of the three most abundantly secreted proteins of the prostate, and has been suggested as a biomarker for prostate cancer risk. A common variant, rs10993994, in the 5’ region of the gene which encodes MSP (MSMB), has recently been identified as a risk factor for prostate cancer. We examined the association between rs10993994 genotype and MSP levels in a sample of 500 prostate cancer-free men from four racial/ethnic populations in the Multiethnic Cohort (European Americans, African Americans, Latinos, and Japanese Americans). Generalized linear models were used to estimate the association between rs10993994 genotype and MSP levels. We observed robust associations between rs10994994 genotype and MSP levels in each racial/ethnic population (all P<10-8) with carriers of the C allele having lower geometric mean MSP levels (ng/mL) (CC/CT/TT genotypes: European Americans, 28.8/20.9/10.0; African Americans, 29.0/21.9/10.9; Latinos, 29.2/17.1/8.3; and Japanese Americans 25.8/16.4/6.7). We estimated the variant accounts for 30-50% of the variation in MSP levels in each population. We also observed significant differences in MSP levels between populations (P=3.5x10-6), with MSP levels observed to be highest in African Americans and lowest in Japanese Americans. Rs10993994 genotype is strongly associated with plasma MSP levels in multiple racial/ethnic populations. This supports the hypothesis that rs10993994 may be the biologically functional allele.; Association of Diabetes with Prostate Cancer Risk in the Multiethnic Cohort:; Among men of European ancestry, diabetics have a lower risk of prostate cancer than non-diabetics. The biological basis of this association is unknown. The authors have examined whether the association is robust across populations in a population-based prospective study. The analysis included 5,941 prostate cancer cases identified over a 12-year period (1993-2005) among 86,303 European American, African American, Latino, Japanese American, and Native Hawaiian men from the Multiethnic Cohort. The association between diabetes and Prostate-Specific Antigen (PSA) levels (n=2,874), and PSA screening frequencies (n=46,970) was also examined. Diabetics had significantly lower risk of prostate cancer than non-diabetes (Relative Risk (RR) =0.81, 95% Confidence Interval (CI): 0.74, 0.87, P<0.001), with relative risks ranging from 0.65 (95% CI: 0.50, 0.84, P=0.001) among European Americans to 0.89 (95% CI: 0.77, 1.03, P=0.13) among African Americans. Mean PSA levels were significantly lower in diabetics than in non-diabetes (mean PSA levels, 1.07 and 1.28, respectively, P=0.003) as were PSA screening frequencies (44.7% vs. 48.6%, P<0.001), however, this difference could explain only a small portion (~20%) of the inverse association between these diseases. Diabetes is a protective factor for prostate cancer across populations, suggesting shared risk factors that influence a common mechanism.; Consistent Association of Type 2 Diabetes Risk Variants Found in Europeans in Diverse Racial-and Ethnic Group:; It has been recently hypothesized that many of the signals detected in genome-wide association studies (GWAS) to T2D and other diseases, despite being observed to common variants, might in fact result from causal mutations that are rare. One prediction of this hypothesis is that the allelic associations should be population-specific, as the causal mutations arose after the migrations that established different populations around the world. We selected 19 common variants found to be reproducibly associated to T2D risk in European populations, and studied them in a large multiethnic case-control study (6,142 cases and 7,403 controls) among men and women from 5 racial/ethnic groups (European Americans, African Americans, Latinos, Japanese Americans, and Native Hawaiians). In analysis pooled across ethnic groups, the allelic associations were in the same direction as the original report for all 19 variants, and 14 of the 19 were significantly associated with risk. In summing the number of risk alleles for each individual, the per allele associations were highly statistically significant (P<10-4) and similar in all populations (odds ratios 1.09-1.12) except in Japanese Americans the estimated effect per allele was larger than in the other populations (1.20; Phet=3.8x10-4). We did not observe ethnic differences in the distribution of risk that would explain the increased prevalence of type 2 diabetes in these groups as compared to European Americans. The consistency of allelic associations in diverse racial/ethnic groups is not predicted under the hypothesis of Goldstein regarding “synthetic associations” of rare mutations in T2D.; Examining Known Diabetes Risk Variants for Association with Prostate Cancer in a Multiethnic Population:; Epidemiologic studies have found evidence of an inverse association between diabetes status and prostate cancer risk. Recently genome-wide association studies of these two diseases have identified a single risk allele at the HNF1B locus that is associated with both diseases along with two risk loci (JAZF1 and THADA) that have been associated with both diseases through distinct unlinked variants. We, as part of the Population Architecture using Genomics and Epidemiology (PAGE) Study, explored the hypothesis that common genetic variation may explain, in part, the inverse association between type 2 diabetes and prostate cancer, by examining known diabetes risk variants for their association with prostate cancer. Our study consists of men from a prostate cancer case-control set of 2,746 cases and 3,317 controls from five racial-ethnic groups (African American, European American, Latino, Japanese American, and Native Hawaiian) of the Multiethnic Cohort. The allelic discrimination assay was used to genotype 17 diabetes risk variants identified by genome-wide association studies. Unconditional logistic regression was used to examine these alleles for association with prostate cancer risk. In ethnic-pooled analysis, we did not find evidence of an association with prostate cancer for the diabetes risk alleles in either of the two loci previously associated with prostate cancer (JAZF1, rs864745, OR 0.98, 95% CI 0.90-1.06; THADA, rs7578597, OR 1.11, 95% CI 0.98-1.25). An allele (rs7961581) in the TSPAN8 locus, which has been shown to be positively associated with diabetes risk had a protective association with prostate cancer at a nominally statistically significant level (OR 0.90, 95% CI 0.83-0.99, P=0.021).; Except for the risk allele at HNF1B (allele G of rs4430796), which we previously reported to be associated inversely with prostate cancer, we found no evidence of an association with prostate cancer for the diabetes risk loci at JAZF1 and THADA despite other independent alleles at these loci being associated with prostate cancer. In summary, we found an association between the TSPAN8 allele and prostate cancer risk that needs to be replicated in larger populations. Resequencing and fine-mapping studies to identify causal alleles in large association studies will be important in exploring the role of common risk variants in the inverse association between diabetes and prostate cancer.|
|Keyword||prostate cancer; type 2 diabetes; common genetic variation; genetic susceptibility; multiethnic cohort; MSMB|
|Geographic subject (city or populated place)||Los Angeles|
|Geographic subject (state)||California; Hawaii|
|Part of collection||University of Southern California dissertations and theses|
|Publisher (of the original version)||University of Southern California|
|Place of publication (of the original version)||Los Angeles, California|
|Publisher (of the digital version)||University of Southern California. Libraries|
|Provenance||Electronically uploaded by the author|
|Legacy record ID||usctheses-m3312|
|Contributing entity||University of Southern California|
|Rights||Waters, Kevin M.|
|Repository name||Libraries, University of Southern California|
|Repository address||Los Angeles, California|
|Contributing entity||University of Southern California|
|Full text||EXAMINING THE RELATIONSHIP BETWEEN COMMON GENETIC VARIATION, TYPE 2 DIABETES AND PROSTATE CANCER RISK IN THE MULTIETHNIC COHORT by Kevin M. Waters A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (EPIDEMIOLOGY) August 2010 Copyright 2010 Kevin M. Waters|