Race and BMI modify associations of calcium and vitamin D intake with prostate cancer.

BACKGROUND: African Americans have disproportionately higher burden of prostate cancer compared to European Americans. However, the cause of prostate cancer disparities is still unclear. Several roles have been proposed for calcium and vitamin D in prostate cancer pathogenesis and progression, but epidemiologic studies have been conducted mainly in European descent populations. Here we investigated the association of calcium and vitamin D intake with prostate cancer in multiethnic samples. METHODS: A total of 1,657 prostate cancer patients who underwent screening and healthy controls (888 African Americans, 620 European Americans, 111 Hispanic Americans, and 38 others) from Chicago, IL and Washington, D.C. were included in this study. Calcium and vitamin D intake were evaluated using food frequency questionnaire. We performed unconditional logistic regression analyses adjusting for relevant variables. RESULTS: In the pooled data set, high calcium intake was significantly associated with higher odds for aggressive prostate cancer (ORQuartile 1 vs. Quartile 4 = 1.98, 95% C.I.: 1.01-3.91), while high vitamin D intake was associated with lower odds of aggressive prostate cancer (ORQuartile 1 vs. Quartile 4 = 0.38, 95% C.I.: 0.18-0.79). In African Americans, the association between high calcium intake and aggressive prostate cancer was statistically significant (ORQuartile 1 vs. Quartile 4 = 4.28, 95% C.I.: 1.70-10.80). We also observed a strong inverse association between total vitamin D intake and prostate cancer in African Americans (ORQuartile 1 vs. Quartile 4 = 0.06, 95% C.I.: 0.02-0.54). In European Americas, we did not observe any significant associations between either calcium or vitamin D intake and prostate cancer. In analyses stratifying participants based on Body Mass Index (BMI), we observed a strong positive association between calcium and aggressive prostate cancer and a strong inverse association between vitamin D intake and aggressive prostate cancer among men with low BMI (<27.8 kg/m2), but not among men with high BMI (≥27.8 kg/m2). Interactions of race and BMI with vitamin D intake were significant (P Interaction < 0.05). CONCLUSION: Calcium intake was positively associated with aggressive prostate cancer, while vitamin D intake exhibited an inverse relationship. However, these associations varied by race/ethnicity and BMI. The findings from this study may help develop better prostate cancer prevention and management strategies.

Common vitamin D pathway gene variants reveal contrasting effects on serum vitamin D levels in African Americans and European Americans.

Vitamin D deficiency is more common among African Americans (AAs) than among European Americans (EAs), and epidemiologic evidence links vitamin D status to many health outcomes. Two genome-wide association studies (GWAS) in European populations identified vitamin D pathway gene single-nucleotide polymorphisms (SNPs) associated with serum vitamin D [25(OH)D] levels, but a few of these SNPs have been replicated in AAs. Here, we investigated the associations of 39 SNPs in vitamin D pathway genes, including 19 GWAS-identified SNPs, with serum 25(OH)D concentrations in 652 AAs and 405 EAs. Linear and logistic regression analyses were performed adjusting for relevant environmental and biological factors. The pattern of SNP associations was distinct between AAs and EAs. In AAs, six GWAS-identified SNPs in GC, CYP2R1, and DHCR7/NADSYN1 were replicated, while nine GWAS SNPs in GC and CYP2R1 were replicated in EAs. A CYP2R1 SNP, rs12794714, exhibited the strongest signal of association in AAs. In EAs, however, a different CYP2R1 SNP, rs1993116, was the most strongly associated. Our models, which take into account genetic and environmental variables, accounted for 20 and 28 % of the variance in serum vitamin D levels in AAs and EAs, respectively.

Smoking and prostate cancer in a multi-ethnic cohort.

BACKGROUND: Prostate cancer (PCa) and smoking-related morbidity disproportionately burdens African American (AA) men. Smoking is associated with high-grade PCa and incidence, but few studies have focused on AA men. This study aims to determine the effect of tobacco-use on odds of PCa and of high-grade PCa in a population of predominantly AA men. METHODS: This is a cross-sectional study evaluating smoking and PCa status in men with incident PCa and screened healthy controls. Altogether, 1,085 men (527 cases and 558 controls), age ≥ 40 years were enrolled through outpatient urology clinics in two US cities from 2001 to 2012. Validated questionnaires were used to gather clinical and socioeconomic data. RESULTS: The cases and controls were predominantly AA (79.9% and 71.3%, respectively, P = 0.01). AA men smoked more frequently (53.4% vs. 47.9%, P < 0.001) and quit less frequently than European American (EA) men (31.5% vs. 40.4%, P = 0.01). AA heavy smokers had increased odds of PCa diagnosis (OR 2.57, 95% CI 1.09, 6.10) and high-grade cancer (OR 1.89, 95% CI 1.03, 3.48) relative to never smokers and light smokers. Among AAs, heavy smokers had lower odds of NCCN low PCa recurrence risk stratification. AA former smokers had a trend for increased odds of high-grade cancer compared to never smokers. The associations between smokings, cancer diagnosis and cancer grade did not reach statistical significance in EA men. CONCLUSION: We found ethnic differences in smoking behavior. Heavy smoking is associated with increased odds of PCa and of higher Gleason grade in AA men.

Association of CD14 variant with prostate cancer in African American men.

BACKGROUND: African American men have the highest rates of prostate cancer worldwide, and immunogenetic studies suggest that people of African descent have increased susceptibility to diseases of inflammation. Since genetic susceptibility is an etiological factor in prostate cancer, we hypothesize that sequence variants in the promoter region of the CD14 gene that regulate inflammation may modify individual susceptibility to this disease. METHODS: The CD14 promoter was screened for single-nucleotide polymorphisms (SNPs) using dHPLC. One variant, -260 C>T (rs2569190), was genotyped via restriction digest in all study participants (264 cases and 188 controls). The association of disease status and the polymorphism was analyzed by unconditional logistic regression. Odds ratios with 95% confidence intervals were calculated, stratifying by ethnicity and adjusting for age. Two-sided P-values of < or =0.05 were considered as statistically significant. RESULTS: Eleven variants (four novel) were identified in the promoter region of CD14. A marginal association between the C genotypes (C/C + C/T) and prostate cancer was found (P = 0.07). When stratified by age, among men > or =55 years of age, the C genotypes were significantly associated with prostate cancer (P < 0.05). When stratified by self-reported ethnicity, African American males who had the C genotypes were at a higher risk for prostate cancer (P < 0.05). CONCLUSIONS: This is the first study to show an association between the C genotypes of the CD14 (-260) variant and prostate cancer which supports the hypothesis that genetic variation in the inflammatory process can contribute to prostate cancer susceptibility in African American men.

Replication of prostate cancer risk loci on 8q24, 11q13, 17q12, 19q33, and Xp11 in African Americans.

BACKGROUND: Prostate cancer (Pca) is a common malignancy that disproportionately affects African American men (AA). Recently there have been several genome-wide association studies (GWAS) implicating new prostate cancer risk loci along chromosomes 2, 3, 6, 7, 8, 10, 11, 12, 17, 19, and X in populations of European ancestry. Given the higher incidence and mortality for AAs, and differences in allele frequencies and haplotype structures between African and European descent populations, it is important to assess the impact of these candidate risk loci in AAs. METHODS: Here we evaluated 20 single nucleotide polymorphisms (SNPs) associated with prostate cancer risk in recent GWAS studies, in AA prostate cancer cases and controls. RESULTS: We replicated five of the SNPs in our AA population, rs10896449 on 11q13.2 (P = 0.009), rs2735839 on 19q33.33 region, (P = 0.04), rs443076 on chromosome 17q12 (P = 0.008), rs5945572 on Xp11.22 (P = 0.05), as well as the rare variant specific to west African ancestry, bd11934905 in region 2 of 8q24 (P = 1 x 10(-4)). CONCLUSIONS: While we were able to replicate a few of the previous GWAS SNPs, we were not able to confirm the vast majority of these associations in our AA population. This finding further supports the need to perform GWAS and additional fine mapping in AAs to locate additional susceptibility loci.

Survival of African-American and Caucasian men after sipuleucel-T immunotherapy: outcomes from the PROCEED registry.

PURPOSE: African Americans experience greater prostate cancer risk and mortality than do Caucasians. An analysis of pooled phase III data suggested differences in overall survival (OS) between African American and Caucasian men receiving sipuleucel-T. We explored this in PROCEED (NCT01306890), an FDA-requested registry in over 1900 patients with metastatic castration-resistant prostate cancer (mCRPC) treated with sipuleucel-T. PATIENTS AND METHODS: OS for patients who received ≥1 sipuleucel-T infusion was compared between African American and Caucasian men using an all patient set and a baseline prostate-specific antigen (PSA)-matched set (two Caucasians to every one African American with baseline PSAs within 10% of each other). Univariable and multivariable analyses were conducted. Survival data were examined using Kaplan-Meier and Cox proportional hazard methodologies. RESULTS: Median follow-up was 46.6 months. Overall survival differed between African American and Caucasian men with hazard ratios (HR) of 0.81 (95% confidence interval [CI]: 0.68-0.97, P = 0.03) in the all patient set and 0.70 (95% CI: 0.57-0.86, P < 0.001) in the PSA-matched set. Median OS was longer in African Americans than in Caucasian men for both analysis sets, e.g., 35.3 and 25.8 months, respectively, in the PSA-matched set. Similar results were observed in the all patient set. Differences were larger when treatment began at lower baseline PSA; curves were more similar among patients with higher baseline PSA. In patients with baseline PSA below the median, the HR was 0.52 (95% CI: 0.37-0.72, P < 0.001), with median OS of 54.3 versus 33.4 months. Known prognostic factors and African American race (multivariable analyses; HR: 0.60, 95% CI: 0.48-0.74, P < 0.001) were independently associated with OS. Use of post-sipuleucel-T anticancer interventions was balanced between races. CONCLUSION: In this exploratory analysis of a registry including nearly 12% African American men with mCRPC, OS was significantly different between African Americans and Caucasians, indicating further research is warranted.

Psychosocial factors influence parental decision for circumcision in pediatric males of African American descent.

BACKGROUND: The most recent policy statement by the American Academy of Pediatrics suggests there are insufficient data to recommend routine newborn circumcision. Nevertheless, circumcision rates have not declined in the United States. Some studies suggest that African Americans are less likely to be circumcised. In blacks that choose to circumcise their males, we sought to examine the factors that drive parents to favor circumcision. METHODS: The Parental Attitudes on Circumcision questionnaire was utilized to obtain demographic information and attitudinal responses to circumcision during urology clinic sessions at Howard University Hospital, a major teaching hospital located in an urban setting. Parents and caregivers of male children aged 3 months to 7 years participated. Valid responses from 146 participants were collected. RESULTS: Ninety-six percent of our respondents believe that circumcision is healthy. Forty-one percent indicated health reasons as the most important influencing factor for choosing to circumcise their child, while 25% selected maternal preference. Eighty-one percent of all respondents indicated that 1 or more health care providers asked about their decision to circumcise their child. The mother was 12 times more likely than the father to make the final decision for circumcision, especially when her personal preference played a role. Eighty-eight percent of respondents felt that circumcision is painful, but 87% considered the procedure safe, and another 72% believe that it is a necessary procedure. CONCLUSION: African American parents strongly believe that circumcision is essential for a healthy state and are willing to opt for the procedure despite the belief that it may be painful for the child. The mother primarily made the final decision to circumcise her child, largely based on the perceived health and hygiene benefits. In blacks, the mother yields considerable influence in the decision to circumcise the child, with maternal preference as the main reason for seeking circumcision in as much as a quarter of cases.

Association of HPC2/ELAC2 and RNASEL non-synonymous variants with prostate cancer risk in African American familial and sporadic cases.

INTRODUCTION: The RNASEL and HPC2/ELAC2 genes have been implicated in hereditary prostate cancer. Further assessment of the role of these genes in sporadic prostate cancer in African American men (AAM) is warranted. METHODS: Genotyping of HPC2/ELAC2 variants (S217L, A541T), along with RNASEL variants (R462Q and E541D) was completed in 155 African American sporadic and 88 familial prostate cancer cases, and 296 healthy male controls. Logistic regression analysis was performed and odds ratios (OR) were calculated, while correcting for both age and population stratification using admixture informative markers. RESULTS: The HPC2/ELAC2 217L allele was significantly associated with risk of prostate cancer when taking all cases into account (OR = 1.6; 1.0-2.6; P = 0.03). The RNASEL 541D allele was associated with a decrease in risk of prostate cancer in sporadic cases (OR = 0.4; 0.2-0.8; P = 0.01). We did not detect an association between prostate cancer risk and the RNASEL R462Q variant. Results from haplotype analyses of the two RNASEL variants revealed highly significant differences in haplotype allele frequencies between cases and controls suggesting a synergistic effect at the RNASEL locus. One haplotype in particular (462R-541D) is far more frequent in our control population and shows a strong protective effect against prostate cancer (OR = 0.47, P = 8.1 x 10(-9)). CONCLUSIONS: These results suggest that HPC2/ELAC2 and RNASEL may play a role, however minor, in prostate cancer risk among AAM.

IGF-1 and IGFBP-3 gene variants influence on serum levels and prostate cancer risk in African-Americans.

Insulin-like growth factor (IGF)-1 and Insulin-like growth factor binding protein-3 (IGFBP-3) are strong inhibitors of apoptosis and play a role in mediating the effects of growth hormone. Both IGF-1 and IGFBP-3 serum levels have been linked to cancer risk. Here, we explore the relationship between three common IGF polymorphisms [C/T single-nucleotide polymorphism (SNP) (rs7965399) and a dinucleotide repeat (CA)n within the 5' regulatory region of the IGF-1 gene and the -202 A/C SNP in the IGFBP-3 gene], serum levels and prostate cancer (Pca) risk in 767 African-Americans enrolled in a clinic-based case-control study. IGF-1 and IGFBP-3 levels were measured using immunochemiluminometric assay and the three polymorphisms were typed for 401 Pca cases and 366 age- and ethnicity-matched controls. Multiple linear regression and multivariable unconditional logistic regression were used to test for associations between genotypes and circulating IGF levels and Pca risk, respectively. The presence of at least one copy of the IGFBP-3 -202 C allele was strongly associated with lower IGFBP-3 serum levels (3532 versus 3106 ng/ml; P = 0.008). We also observed a 2-fold increase in Pca risk for individuals homozygous for the IGFBP-3 -202 C allele [odds ratio = 2.4; 95% confidence interval = 1.2-4.8). Furthermore, IGF-1 (CA)19 genotypes were significantly associated with lower IGFBP-3 serum levels (P = 0.003). Our results reveal that variation in the 5'-untranslated region of the IGF-1 and IGFBP-3 genes may be influencing IGF serum levels and Pca risk in African-Americans and suggest a need to explore this variation across diverse populations. Our study adds clarity and further support to the previous findings, implicating serum IGFBP-3 levels and the IGFBP-3 -202 A/C SNP in prostate carcinogenesis.

Genome-wide linkage of 77 families from the African American Hereditary Prostate Cancer study (AAHPC).

BACKGROUND: The African American Hereditary Prostate Cancer (AAHPC) Study was designed to recruit families with early-onset disease fulfilling criteria of >or=4 affected. METHODS: We present a approximately 10 cM genome-wide linkage (GWL) analysis on 77 families including 254 affected and 274 unaffected genotyped. RESULTS: Linkage analysis revealed three chromosomal regions with GENEHUNTER multipoint HLOD scores >or=1.3 for all 77 families at 11q22, 17p11, and Xq21. One family yielded genome-wide significant evidence of linkage (LOD = 3.5) to the 17p11 region with seven other families >or=2.3 in this region. Twenty-nine families with no-male-to-male (MM) transmission gave a peak HLOD of 1.62 (alpha = 0.33) at the Xq21 locus. Two novel peaks >or=0.91 for the 16 families with '>6 affected' occurred at 2p21 and 22q12. CONCLUSIONS: These chromosomal regions in the genome warrant further follow-up based on the hypothesis of multiple susceptibility genes with modest effects, or several major genes segregating in small subsets of families.