Ebony Shah

Fine-Mapping of IL16 Gene and Prostate Cancer Risk in African Americans

Background: Prostate cancer is the most common type of cancer among men in the United States, and its incidence and mortality rates are disproportionate among ethnic groups. Although genome-wide association studies of European descents have identified candidate loci associated with prostate cancer risk, including a variant in IL16, replication studies in African Americans (AA) have been inconsistent. Here we explore single-nucleotide polymorphism (SNP) variation in IL16 in AAs and test for association with prostate cancer. Methods: Association tests were conducted for 2,257 genotyped and imputed SNPs spanning IL16 in 605 AA prostate cancer cases and controls from Washington, D.C. Eleven of them were also genotyped in a replication population of 1,093 AAs from Chicago. We tested for allelic association adjusting for age, global and local West African ancestry. Results: Analyses of genotyped and imputed SNPs revealed that a cluster of IL16 SNPs were significantly associated with prostate cancer risk. The strongest association was found at rs7175701 (P = 9.8 × 10−8). In the Chicago population, another SNP (rs11556218) was associated with prostate cancer risk (P = 0.01). In the pooled analysis, we identified three independent loci within IL16 that were associated with prostate cancer risk. SNP expression quantitative trait loci analyses revealed that rs7175701 is predicted to influence the expression of IL16 and other cancer-related genes. Conclusion: Our study provides evidence that IL16 polymorphisms play a role in prostate cancer susceptibility among AAs. Impact: Our findings are significant given that there has been limited focus on the role of IL16 genetic polymorphisms on prostate cancer risk in AAs. Cancer Epidemiol Biomarkers Prev; 21(11); 2059–68. ©2012 AACR.

Association of genetic ancestry with breast cancer in ethnically diverse women from Chicago.

Introduction Non-Hispanic (nH) Black and Hispanic women are disproportionately affected by early onset disease, later stage, and with more aggressive, higher grade and ER/PR negative breast cancers. The purpose of this analysis was to examine whether genetic ancestry could account for these variation in breast cancer characteristics, once data were stratified by self-reported race/ethnicity and adjusted for potential confounding by social and behavioral factors. Methods We used a panel of 100 ancestry informative markers (AIMs) to estimate individual genetic ancestry in 656 women from the “Breast Cancer Care in Chicago” study, a multi-ethnic cohort of breast cancer patients to examine the association between individual genetic ancestry and breast cancer characteristics. In addition we examined the association of individual AIMs and breast cancer to identify genes/regions that may potentially play a role in breast cancer disease disparities. Results As expected, nH Black and Hispanic patients were more likely than nH White patients to be diagnosed at later stages, with higher grade, and with ER/PR negative tumors. Higher European genetic ancestry was protective against later stage at diagnosis (OR 0.7 95%CI: 0.54–0.92) among Hispanic patients, and higher grade (OR 0.73, 95%CI: 0.56–0.95) among nH Black patients. After adjustment for multiple social and behavioral risk factors, the association with later stage remained, while the association with grade was not significant. We also found that the AIM SNP rs10954631 on chromosome 7 was associated with later stage (p = 0.02) and higher grade (p = 0.012) in nH Whites and later stage (p = 0.03) in nH Blacks. Conclusion Non-European genetic ancestry was associated with later stage at diagnosis in ethnic minorities. The relation between genetic ancestry and stage at diagnosis may be due to genetic factors and/or unmeasured environmental factors that are overrepresented within certain racial/ethnic groups.

Association of aldosterone synthase polymorphism (CYP11B2 -344T>C) and genetic ancestry with atrial fibrillation and serum aldosterone in African Americans with heart failure.

The objective of this study was to examine the extent to which aldosterone synthase genotype (CYP11B2) and genetic ancestry correlate with atrial fibrillation (AF) and serum aldosterone in African Americans with heart failure. Clinical data, echocardiographic measurements, and a genetic sample for determination of CYP11B2 -344T>C (rs1799998) genotype and genetic ancestry were collected from 194 self-reported African Americans with chronic, ambulatory heart failure. Genetic ancestry was determined using 105 autosomal ancestry informative markers. In a sub-set of patients (n = 126), serum was also collected for determination of circulating aldosterone. The CYP11B2 −344C allele frequency was 18% among the study population, and 19% of patients had AF. Multiple logistic regression revealed that the CYP11B2 −344CC genotype was a significant independent predictor of AF (OR 12.7, 95% CI 1.60–98.4, p = 0.0150, empirical p = 0.011) while holding multiple clinical factors, left atrial size, and percent European ancestry constant. Serum aldosterone was significantly higher among patients with AF (p = 0.036), whereas increased West African ancestry was inversely correlated with serum aldosterone (r = −0.19, p = 0.037). The CYP11B2 −344CC genotype was also overrepresented among patients with extreme aldosterone elevation (≥90th percentile, p = 0.0145). In this cohort of African Americans with chronic ambulatory heart failure, the CYP11B2 −344T>C genotype was a significant independent predictor of AF while holding clinical, echocardiographic predictors, and genetic ancestry constant. In addition, increased West African ancestry was associated with decreased serum aldosterone levels, potentially providing an explanation for the lower risk for AF observed among African Americans.

Genetic ancestry and prostate cancer susceptibility SNPs in Puerto Rican and African American men

The Puerto Rican (PR) population is a racially admixed population that has a high prostate cancer (PCa) mortality rate. We hypothesized in this pilot study that West African Ancestry (WAA) was associated with PCa in this heterogeneous (PR) population.

Prostatic compensation of the vitamin D axis in African American men

BACKGROUND. African American (AA) men are disproportionately affected by both prostate cancer (PCa) and vitamin D deficiency compared with European American (EA) men. Vitamin D deficiency is linked to increased PCa aggressiveness and mortality. Therefore, it has been hypothesized that vitamin D deficiency may contribute to the PCa disparity between AA and EA men. METHODS. We studied a cross sectional group of 60 PCa patients (AA, n = 31; EA, n = 29) who underwent radical prostatectomy. Vitamin D metabolites 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) were measured in the serum and tissue by uHPLC-MS-MS. Tissue was laser capture microdissected, and gene expression was quantified by microarray. DNA isolated from whole blood was genotyped for West African ancestry markers and vitamin D-related SNPs. RESULTS. Serum concentrations of 25(OH)D were lower in AAs, but concentrations of 1,25(OH)2D in the prostate tissue were higher compared with EAs. Expression of the vitamin D receptor was higher in prostate tissue from AAs. Expression of the extracellular receptor of vitamin D binding protein, LRP2, was positively associated with West African ancestry and inversely associated with tissue 25(OH)D concentrations in AAs. CONCLUSIONS. The relationships between vitamin D binding protein LRP2 and vitamin D metabolites suggest that the prohormone is actively transported into the prostate, followed by intraprostatic conversion to the active hormone, rather than passive diffusion. These findings support the presence of a compensatory response in prostate tissue to vitamin D deficiency in AAs and reveal a previously unknown complexity involving tissue distribution of vitamin D metabolites. FUNDING. Department of Defense Prostate Cancer Research Program Idea Award for Disparities Research PC121923 (LN and RK) and the NIH 1R01MD007105 (RK).

Zinc Intake and Risk of Prostate Cancer: Case-Control Study and Meta-Analysis.

Zinc is an essential dietary element that has been implicated in the pathogenesis of prostate cancer, a cancer that disproportionately affects men of African descent. Studies assessing the association of zinc intake and prostate cancer have yielded inconsistent results. Furthermore, very little is known about the relationship between zinc intake and prostate cancer among African Americans. We examined the association between self-reported zinc intake and prostate cancer in a hospital-based case-control study of African Americans. We then compared our results with previous studies by performing a meta-analysis to summarize the evidence regarding the association between zinc and prostate cancer. Newly diagnosed African American men with histologically confirmed prostate cancer (n = 127) and controls (n = 81) were recruited from an urban academic urology clinic in Washington, DC. Controls had higher zinc intake, with a mean of 14 mg/day versus 11 mg/day for cases. We observed a non-significant, non-linear increase in prostate cancer when comparing tertiles of zinc intake (OR <6.5 vs 6.5–12.5mg/day 1.8, 95% CI: 0.6,5.6; OR <6.5 vs >12.5mg/day 1.3, 95% CI: 0.2,6.5). The pooled estimate from 17 studies (including 3 cohorts, 2 nested case-control, 11 case-control studies, and 1 randomized clinical trial, with a total of 111,199 participants and 11,689 cases of prostate cancer) was 1.07hi vs lo 95% CI: 0.98–1.16. Using a dose-response meta-analysis, we observed a non-linear trend in the relationship between zinc intake and prostate cancer (p for nonlinearity = 0.0022). This is the first study to examine the relationship between zinc intake in black men and risk of prostate cancer and systematically evaluate available epidemiologic evidence about the magnitude of the relationship between zinc intake and prostate cancer. Despite of the lower intake of zinc by prostate cancer patients, our meta-analysis indicated that there is no evidence for an association between zinc intake and prostate cancer.

Abstract B16: Association of calcium and vitamin D intake and vitamin D receptor genotypes with prostate cancer in multiethnic samples

Background: Prostate cancer (PCa) is the most common cancer among men in the U.S., and African American (AA) men have higher incidence and mortality rate compared to European American (EA) men. Social and behavioral factors affect stage and tumor grade at diagnosis, treatment choice, and mortality. However, the cause for PCa disparities is still unclear. Several roles have been proposed for calcium, vitamin D, and the vitamin D receptor (VDR) in PCa pathogenesis and progression, but epidemiologic studies, mainly conducted in European descent populations, often show inconsistent evidence of associations. Here, we investigated the association of calcium and vitamin D intake and VDR genotypes with prostate cancer incidence and aggressiveness in multiethnic samples. Methods: The total of 1,403 individuals was included in this study (751 AAs, 481 EAs, 126 Hispanic Americans, and 45 others). Study participants were recruited from six hospitals in Chicago, IL and Washington, D.C. Calcium and vitamin D intake was evaluated using the Block calcium and vitamin D screener. Seven single-nucleotide polymorphisms (SNPs) in and around the VDR gene and 105 ancestry informative markers were genotyped. STRUCTURE was used to estimate genetic ancestry. We performed logistic regression analyses adjusting for relevant variables using SPSS. Results: In the pooled data set, calcium and vitamin D intake was not associated with PCa risk (P>0.05), but high total calcium intake (≥800 mg/day) was significantly associated with aggressive PCa (Gleason Score ≥4+3, P=0.002, OR=2.05, 95% C.I.: 1.29-3.26). In the race/ethnicity stratified analyses, we confirmed the statistically significant associations of calcium intake with aggressive PCa in AAs. High total vitamin D intake (≥600IU/day), on the other hand, revealed a protective effect against aggressive PCa (OR=0.47, 95% C.I.: 0.24-0.92, P=0.026). In EAs, total calcium intake was significantly associated with PCa aggressiveness, only when we compared PCa cases with Gleason Score ≥4+3 to cases with Gleason Score Conclusion: In this study, we showed that high calcium intake increases the risk of prostate cancer aggressiveness, while high vitamin D intake has protective effects. Although a larger sample size is necessary to confirm the observation, we demonstrated that VDR genotypes may modify the effect of calcium intake. The findings from this study may help develop better PCa management plans. Citation Format: Ken Batai, Adam B. Murphy, Ebony Shah, Maria Ruden, Jennifer Newsome, Michael A. Dixon, Ahaghotu Chiledum, Rick A. Kittles. Association of calcium and vitamin D intake and vitamin D receptor genotypes with prostate cancer in multiethnic samples. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr B16.

Abstract C32: Native American genetic ancestry is protective against prostate cancer in African Americans and European Americans

Prostate cancer (PCa) incidence and mortality varies by racial/ethnic groups in the U.S. African American (AA) men have a 60% higher incidence and twice the mortality rate of European America (EA) men, while Hispanic Americans and Native Americans have lower incidence rates than EA men. Several genetic admixture studies have examined the role of west African ancestry on prostate cancer risk in AA men, however the influence of Native American ancestry on PCa risk has not been explored. Here we evaluated the relationship between individual genetic ancestry proportions and the likelihood of PCa diagnosis and aggressiveness. Methods: We recruited 40-79 year old men who were undergoing prostate biopsy or routine PSA screening at outpatient urology clinics in Chicago, IL. Blood was drawn at the time of enrollment for genotyping of 105 ancestry informative markers. West African, European, and Native American genetic ancestry was estimated using the Bayesian Markov Chain-Monte Carlo method implemented in the program STRUCTURE. Unconditional binary logistic regression models were used to estimate odds ratios for the likelihood of PCa diagnosis and for the likelihood of having high-risk PCa relative to controls, adjusting for age and family history of PCa. Results: In AAs, NAA ranged from 0.4% to 28.8%. Mean NAA was 4.6% in AA cases, while controls had mean NAA of 6.6%. NAA ranged from 0.5% to 17.4% in EAs. Mean NAA was 5.1% in cases and 6.8% in controls. NAA was negatively associated with PCa diagnosis. AA men in the highest quartile of NAA had significantly reduced odds of PCa diagnosis compared to men in the lowest quartile of NAA (OR 0.47, 95% C.I.: 0.29-0.77). Similarly, EA men in the highest quartile of NAA had significantly reduced odds of PCa diagnosis compared men in the lowest NAA quartile (OR 0.36, 95% C.I.: 0.21-0.61). Additional adjustment of body mass index, education, smoking, alcohol use, and marital status did not change the results. NAA was also negatively associated with diagnosis of high risk PCa in EAs (P=0.04) and also trending in the same direction in AAs however not significant. Conclusions: Our study reveals that NAA is protective against PCa diagnosis and high-risk PCa. Hispanic Americans and Native Americans have lower PCa incidence rates than AAs and EAs, and the identification of inherited genetic or environmental factors that are associated with high NAA may improve PCa risk prediction and/or help to develop prevention strategies. Citation Format: Adam Murphy, Ken Batai, Ebony Shah, Rick A. Kittles. Native American genetic ancestry is protective against prostate cancer in African Americans and European Americans. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr C32.

Abstract B39: Effect modifiers of vitamin D receptor common polymorphisms on prostate cancer risk

Background: Studies have long proposed the influence of vitamin D and the vitamin D receptor (VDR) on prostate cancer (PCa) initiation and progression, however few studies support the association of VDR variants with PCa. The VDR is a transcription factor which binds to vitamin D and influences the expression of many genes implicated in Pca. Given the complexity of vitamin D availability, we hypothesized that the associations of VDR single-nucleotide polymorphisms (SNPs) with PCa can be modified by various behavioral and biological factors. In this study, we examined VDR SNPs and PCa risk and aggressiveness in African Americans (AAs) and European Americans (EAs) and determined if the associations were modified by behavioral and biological factors that influence serum vitamin D levels, including vitamin D and calcium intake, tobacco use, body mass index (BMI), skin pigmentation, and ultraviolet radiation exposure. Methods: The total of 810 AAs and 487 EAs from Chicago, IL and Washington, D.C. were included. Seven SNPs in and around the VDR gene and 105 ancestry informative markers were genotyped. We performed logistic regression analyses adjusting for relevant variables. Results: In EAs, TaqI (rs73136) and BsmI (rs1544410) minor alleles (respectively C and A allele) revealed a protective effect against PCa, while BsmI AA genotype showed increased odds of having high grade PCa (Gleason Score ≥4+3) in AAs with OR=2.67 (95% C.I.: 1.01-7.11). We also observed evidence of interactions between VDR SNPs and behavioral and biological factors that modify serum vitamin D levels. The TaqI C allele increased odds of PCa in AAs with behavioral and biological factors that reduce serum vitamin D levels, such as low vitamin D intake, current or past tobacco use, and darker skin pigmentation. Among AA men with vitamin D intake Conclusion: Although a larger sample size is necessary to confirm our observations, our results suggest that the VDR gene is involved in PCa pathogenesis and progression, but the effects of VDR gene on PCa are modified by behavioral and biological factors that modify serum vitamin D levels. Citation Format: Ken Batai, Adam B. Murphy, Ebony Shah, Rick A. Kittles. Effect modifiers of vitamin D receptor common polymorphisms on prostate cancer risk. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr B39.

Abstract C34: Association of genetic ancestry with colorectal tumor characteristics in Puerto Rican Hispanics

Background: Colorectal cancer (CRC) is the 1st cause of cancer deaths in Puerto Rican Hispanics (PRH). Even though PRH have a lower incidence of CRC, when compared to other ethnic groups, their mortality rates are higher. As the 2nd largest Hispanic population on the United States, the increased CRC mortality rates for this ethnic group have a large socio-economic burden. The CRC epidemiologic data supports the importance of studying this cancer as a health disparity in PRH. The genetic background of the Puerto Rican population, which is mix of European, African and Amerindian races, could account, at least in part, for the differences observed in the CRC mortality rates for this population. The objective of this project was to assess the role of genetic ancestry in CRC risk and clinicopathological features of CRC tumors in the PRH population. Methods: We used a panel of 105 ancestry informative markers (AIMs) to estimate genetic ancestry in 224 PRH CRC cases and 202 PRH controls. Additionally, we examined the association of genetic ancestry estimates with CRC risk and clinicopathological characteristics of CRC tumors in our study population using the Bayesian Markov Chain Monte Carlo method implemented in the software STRUCTURE. Logistic regression analysis was used to determine the association of genetic ancestry with disease risk. Pearson9s Chi-Square and Fisher9s Exact Test was used to determine the association of categorical values of genetic ancestry with tumor clinicopathological characteristics. Results: Our results showed that the genetic ancestry mean estimates for the PRH population were 60% for European, 21% for African and 19% for Amerindian. No association of genetic ancestry with CRC risk in the PRH population was found in our study (OR= 0.86 [0.43-1.69], p=0.655). However, genetic ancestry was found to have a significant role on the CRC tumor characteristics of the studied population. High African ancestry (>21.0%) was associated with distal tumor location, when compared to low African ancestry (≤ 21.0%) (p=0.012). Furthermore, low Amerindian ancestry (≤ 19.2%) was associated with poorly differentiated tumors (p= 0.022). Conclusion: The preliminary results presented in this study show that genetic ancestry is associated with tumor location and differentiation, both associated with CRC prognosis. Additional studies are needed to fully elucidate the role of genetic ancestry in CRC susceptibility and prognosis. Citation Format: Julyann Perez-Mayoral, Marievelisse Soto, Maria Gonzalez-Pons, Belisa Suarez, Myrta I. Olivera, Ebony Shah, Rick Kittles, Marcia R. Cruz-Correa. Association of genetic ancestry with colorectal tumor characteristics in Puerto Rican Hispanics. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr C34.