Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation.

Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.

Prostate Cancer Susceptibility in Men of African Ancestry at 8q24.

The 8q24 region harbors multiple risk variants for distinct cancers, including >8 for prostate cancer. In this study, we conducted fine mapping of the 8q24 risk region (127.8-128.8Mb) in search of novel associations with common and rare variation in 4853 prostate cancer case patients and 4678 control subjects of African ancestry. All statistical tests were two-sided. We identified three independent associations at P values of less than 5.00×10(-8), all of which were replicated in studies from Ghana and Uganda (combined sample = 5869 case patients, 5615 control subjects; rs114798100: risk allele frequency [RAF] = 0.04, per-allele odds ratio [OR] = 2.31, 95% confidence interval [CI] = 2.04 to 2.61, P = 2.38×10(-40); rs72725879: RAF = 0.33, OR = 1.37, 95% CI = 1.30 to 1.45, P = 3.04×10(-27); and rs111906932: RAF = 0.03, OR = 1.79, 95% CI = 1.53 to 2.08, P = 1.39×10(-13)). Risk variants rs114798100 and rs111906923 are only found in men of African ancestry, with rs111906923 representing a novel association signal. The three variants are located within or near a number of prostate cancer-associated long noncoding RNAs (lncRNAs), including PRNCR1, PCAT1, and PCAT2. These findings highlight ancestry-specific risk variation and implicate prostate-specific lncRNAs at the 8q24 prostate cancer susceptibility region.

Genome-wide association studies in women of African ancestry identified 3q26.21 as a novel susceptibility locus for oestrogen receptor negative breast cancer.

Multiple breast cancer loci have been identified in previous genome-wide association studies, but they were mainly conducted in populations of European ancestry. Women of African ancestry are more likely to have young-onset and oestrogen receptor (ER) negative breast cancer for reasons that are unknown and understudied. To identify genetic risk factors for breast cancer in women of African descent, we conducted a meta-analysis of two genome-wide association studies of breast cancer; one study consists of 1,657 cases and 2,029 controls genotyped with Illumina's HumanOmni2.5 BeadChip and the other study included 3,016 cases and 2,745 controls genotyped using Illumina Human1M-Duo BeadChip. The top 18,376 single nucleotide polymorphisms (SNP) from the meta-analysis were replicated in the third study that consists of 1,984 African Americans cases and 2,939 controls. We found that SNP rs13074711, 26.5 Kb upstream of TNFSF10 at 3q26.21, was significantly associated with risk of oestrogen receptor (ER)-negative breast cancer (odds ratio [OR]=1.29, 95% CI: 1.18-1.40; P = 1.8 × 10 − 8). Functional annotations suggest that the TNFSF10 gene may be involved in breast cancer aetiology, but further functional experiments are needed. In addition, we confirmed SNP rs10069690 was the best indicator for ER-negative breast cancer at 5p15.33 (OR = 1.30; P = 2.4 × 10 − 10) and identified rs12998806 as the best indicator for ER-positive breast cancer at 2q35 (OR = 1.34; P = 2.2 × 10 − 8) for women of African ancestry. These findings demonstrated additional susceptibility alleles for breast cancer can be revealed in diverse populations and have important public health implications in building race/ethnicity-specific risk prediction model for breast cancer.

Methodological Considerations in Estimation of Phenotype Heritability Using Genome-Wide SNP Data, Illustrated by an Analysis of the Heritability of Height in a Large Sample of African Ancestry Adults.

Height has an extremely polygenic pattern of inheritance. Genome-wide association studies (GWAS) have revealed hundreds of common variants that are associated with human height at genome-wide levels of significance. However, only a small fraction of phenotypic variation can be explained by the aggregate of these common variants. In a large study of African-American men and women (n = 14,419), we genotyped and analyzed 966,578 autosomal SNPs across the entire genome using a linear mixed model variance components approach implemented in the program GCTA (Yang et al Nat Genet 2010), and estimated an additive heritability of 44.7% (se: 3.7%) for this phenotype in a sample of evidently unrelated individuals. While this estimated value is similar to that given by Yang et al in their analyses, we remain concerned about two related issues: (1) whether in the complete absence of hidden relatedness, variance components methods have adequate power to estimate heritability when a very large number of SNPs are used in the analysis; and (2) whether estimation of heritability may be biased, in real studies, by low levels of residual hidden relatedness. We addressed the first question in a semi-analytic fashion by directly simulating the distribution of the score statistic for a test of zero heritability with and without low levels of relatedness. The second question was addressed by a very careful comparison of the behavior of estimated heritability for both observed (self-reported) height and simulated phenotypes compared to imputation R2 as a function of the number of SNPs used in the analysis. These simulations help to address the important question about whether today's GWAS SNPs will remain useful for imputing causal variants that are discovered using very large sample sizes in future studies of height, or whether the causal variants themselves will need to be genotyped de novo in order to build a prediction model that ultimately captures a large fraction of the variability of height, and by implication other complex phenotypes. Our overall conclusions are that when study sizes are quite large (5,000 or so) the additive heritability estimate for height is not apparently biased upwards using the linear mixed model; however there is evidence in our simulation that a very large number of causal variants (many thousands) each with very small effect on phenotypic variance will need to be discovered to fill the gap between the heritability explained by known versus unknown causal variants. We conclude that today's GWAS data will remain useful in the future for causal variant prediction, but that finding the causal variants that need to be predicted may be extremely laborious.

Generalizability of established prostate cancer risk variants in men of African ancestry.

Genome-wide association studies have identified more than 80 risk variants for prostate cancer, mainly in European or Asian populations. The generalizability of these variants in other racial/ethnic populations needs to be understood before the loci can be used widely in risk modeling. In our study, we examined 82 previously reported risk variants in 4,853 prostate cancer cases and 4,678 controls of African ancestry. We performed association testing for each variant using logistic regression adjusted for age, study and global ancestry. Of the 82 known risk variants, 68 (83%) had effects that were directionally consistent in their association with prostate cancer risk and 30 (37%) were significantly associated with risk at p < 0.05, with the most statistically significant variants being rs116041037 (p = 3.7 × 10(-26) ) and rs6983561 (p = 1.1 × 10(-16) ) at 8q24, as well as rs7210100 (p = 5.4 × 10(-8) ) at 17q21. By exploring each locus in search of better markers, the number of variants that captured risk in men of African ancestry (p < 0.05) increased from 30 (37%) to 44 (54%). An aggregate score comprised of these 44 markers was strongly associated with prostate cancer risk [per-allele odds ratio (OR) = 1.12, p = 7.3 × 10(-98) ]. In summary, the consistent directions of effects for the vast majority of variants in men of African ancestry indicate common functional alleles that are shared across populations. Further exploration of these susceptibility loci is needed to identify the underlying biologically relevant variants to improve prostate cancer risk modeling in populations of African ancestry.

Distribution of Duffy Antigen Receptor for Chemokines (DARC) and Risk of Prostate Cancer in Barbados, West Indies.

Blood typing across different racial groups has revealed that Caucasians predominantly test positive for the Duffy antigen/receptor for chemokines (DARC), while 70-95% of African-origin populations lack expression of DARC on their erythrocytes. Since men of African descent are known to have higher rates of prostate cancer (PC) and some animal studies have indicated anti-angiogenic effects associated with Duffy-positive mice, DARC-negativity may help to explain some of the racial differences in prostate tumorigenesis. The Prostate Cancer in a Black Population (PCBP) Study, a large case-control investigation including 1,007 incident PC cases and 1,005 controls, performed DARC testing on a subset of 1,295 participants (641 cases, 654 controls). The relationship between DARC expressivity and PC risk was evaluated using logistic regression models and findings are presented as odds ratios and 95% confidence intervals. More than three-quarters (76.5%) of African-Barbadian men lacked DARC expression, whereas almost three-fifths (59.3%) of White participants tested positive for the Duffy a and b alleles. DARC-negativity was not found to be associated with PC risk in the present investigation [OR 1.04, 95% CI (0.78, 1.37)], regardless of tumor grade. Findings from the PCBP study indicate that the majority of African-Barbadian men do not express DARC on their erythrocytes, yet absence of expression does not appear to be associated with PC development in this population.

8q24 risk alleles and prostate cancer in African-Barbadian men.

BACKGROUND: African American men (AA) exhibit a disproportionate share of prostate cancer (PRCA) incidence, morbidity, and mortality. Several genetic association studies have implicated select 8q24 loci in PRCA risk in AA. The objective of this investigation is to evaluate the association between previously reported 8q24 risk alleles and PRCA in African-Barbadian (AB) men known to have high rates of PRCA. METHODS: Ten previously reported candidate tag SNPs were genotyped and/or imputed in the 8q24 region in 532 AB men with PRCA and 513 AB controls from the Prostate Cancer in a Black Population (PCBP) study. RESULTS: Rs2124036 was significant in AB men, (OR = 2.7, 95% CI (1.3-5.3), P = 0.005, Empirical (max (T), corrected for multiple testing) P = 0.03) for the homozygous C/C genotype. Only a single SNP from this region remained statistically significant in our analysis of our AB population. These results may indicate the presence of a founder effect or due to the chosen SNPs not tagging an ancestral haplotype bearing the 8q24 risk allele(s) in this population or could reflect inadequate power to detect an association. We conducted a meta-analysis including our AB population along with two additional African Caribbean populations from Tobago and Jamaica for SNPs rs16901979 and rs1447295. Meta-analysis results were most significant for rs16901979 A allele (Z score 2.73; P = 0.006) with a summary OR = 1.31 (95% CI: 1.09-1.58). CONCLUSIONS: Additional studies are needed to provide deeper genotype coverage to further interrogate the 8q24 region to understand its contribution to PRCA in this population.

Urologic characteristics and sexual behaviors associated with prostate cancer in an african-Caribbean population in barbados, west indies.

Prostate cancer (PC) is the principal malignancy affecting African descent men in the Caribbean and the USA. Disparities in incidence, prevalence, and mortality in these populations are poorly understood. We evaluated the urologic characteristics and sexual behaviors of men with histologically confirmed PC (cases) and age-matched controls in the nationwide Prostate Cancer in a Black Population (PCBP) study conducted in Barbados. Cases were around 1.5 to 3 times more likely to report symptoms of prostatic enlargement, hematuria/hematospermia, and previous prostatitis. Sexually transmitted infections (STIs) were similar among cases (24.5%) and controls (26.7%). First sexual intercourse before the age of 16 was associated with an increased likelihood of both low- (Gleason score < 7; OR 1.63; 95% CI: 1.03-1.66) and high-grade PC (Gleason score ≥ 7; OR 1.82; 1.11-2.99). PC risk decreased with later age of sexual debut (P-trend = 0.004). More lifetime sexual partners was associated with increased odds of high grade PC (P-trend = 0.02). The contribution of sexual behaviors to the development and the outcomes of PC is likely due to multiple mechanisms, and further study will be necessary to elucidate the underlying pathophysiologic mechanisms in this and similar populations.

Family history of prostate cancer in a black population.

Although family history of prostate cancer (PC) is an established risk factor for the disease, few studies have investigated this relationship among men with an African heritage. The Prostate Cancer in a Black Population (PCBP) study is a large, nationwide case-control study conducted in Barbados, West Indies from 2002 to 2011. In the PCBP study, a family history of PC in fathers or brothers was associated with a threefold increased risk of disease (OR = 3.04, 95 % CI (2.18, 4.22)) and a strong positive relationship was noted for the number of affected first degree relatives. Tumor grade did not generally influence the relationship between family history and PC. The magnitude of risks associated with having a father affected with the disease was slightly higher in the PCBP study compared to other populations. It remains unclear whether this finding is the result of an increased genetic susceptibility in African-Barbadian men.

Factors influencing prostate cancer healthcare practices in Barbados, West Indies.

Although some investigations have assessed the barriers to prostate cancer screening among African-American men, limited data are available regarding such practices in similar African-origin populations. Key informant interviews were employed to obtain a range of perspectives pertaining to the healthcare practices of African-Barbadian men and to identify factors that obstruct prostate cancer screening in Barbados, West Indies. Gender-related perceptions were identified as a major obstruction to prostate cancer screening. Additionally, concerns about privacy, taking time away from work and mistrust of the medical community were reported as themes impeding the healthcare-seeking behaviors of African-Barbadian men. System-level barriers included limitations in access to care and ineffective dissemination of health information. Findings from this study suggest that targeted efforts aimed at modifying socio-cultural perceptions may assist in improving prostate cancer screening and general healthcare-seeking practices of African-Barbadian men and others who share similar beliefs.

A genome-wide association study of breast cancer in women of African ancestry.

Genome-wide association studies (GWAS) in diverse populations are needed to reveal variants that are more common and/or limited to defined populations. We conducted a GWAS of breast cancer in women of African ancestry, with genotyping of >1,000,000 SNPs in 3,153 African American cases and 2,831 controls, and replication testing of the top 66 associations in an additional 3,607 breast cancer cases and 11,330 controls of African ancestry. Two of the 66 SNPs replicated (p < 0.05) in stage 2, which reached statistical significance levels of 10(-6) and 10(-5) in the stage 1 and 2 combined analysis (rs4322600 at chromosome 14q31: OR = 1.18, p = 4.3 × 10(-6); rs10510333 at chromosome 3p26: OR = 1.15, p = 1.5 × 10(-5)). These suggestive risk loci have not been identified in previous GWAS in other populations and will need to be examined in additional samples. Identification of novel risk variants for breast cancer in women of African ancestry will demand testing of a substantially larger set of markers from stage 1 in a larger replication sample.

CDKN2B polymorphism is associated with primary open-angle glaucoma (POAG) in the Afro-Caribbean population of Barbados, West Indies.

The purpose of this study was to confirm previously reported associations of common variants in or near CDC7/TGFBR3, ZP4, SRBD1, ELOVL5, CAV1/CAV2, TLR4, CDKN2B, CDKN2B-AS1, ATOH7, PLXDC2, TMTC2, SIX1, and CARD10, with primary open angle glaucoma (POAG) in the Afro-Caribbean population of Barbados, West Indies. A total of 437 unrelated subjects from the Barbados Family Study of Open Angle Glaucoma (BFSG), including 272 with POAG and 165 unaffected individuals were included in this study. Eighteen SNPs were genotyped by using the multiplex SNaPshot method. Allelic, genotypic and model-based (dominant, recessive, and additive) associations of the SNPs with POAG were analyzed using Chi-squared tests and logistic regression. SNP rs1063192 (near CDKN2B) was found to be significantly associated with POAG (allelic P = 0.0008, genotypic P = 0.0029), and the minor allele C of rs1063192 was protective against POAG (OR = 0.39; 95%CI = 0.22-0.69). Suggestive association was also noted for rs7916697 (near ATHO7, allelic P = 0.0096, genotypic P = 0.01) with the minor allele being protective (OR = 0.67; 95% CI = 0.50-0.91), although this finding did not withstand correction for multiple testing. However, a significant interactive effect on POAG risk was identified between rs1063192 and rs7916697 (P-interaction = 2.80 × 10(-5)). Individuals with the rs1063192 protective genotype CC or CT and also rs7916697 genotypes GG or GA show a significantly decreased risk of POAG (OR = 0.17, 95%CI: 0.07-0.41). Our study confirms the significant association between SNP rs1063192 (CDKN2B, previously shown to influence vertical cup-to-disc ratio and POAG at 9p21) and POAG in the Afro-Caribbean population of Barbados. The minor allele of rs1063192 interacts with that of rs7916697 (ATOH7)) to reduce POAG risk. Our results also suggest that rs1063912 is a common protective variant for POAG in populations of African as well as European descent.

Central adiposity and Prostate Cancer in a Black Population.

BACKGROUND: The relationship between central adiposity and prostate cancer remains unclear. METHODS: This report includes 963 newly diagnosed cases of histologically confirmed prostate cancer and 941 randomly selected age-matched controls ascertained from the population-based Prostate Cancer in a Black Population study conducted between July 2002 and January 2011 in Barbados, West Indies. Trained nurse interviewers obtained data on height, weight, waist and hip circumferences, family and medical history, and lifestyle factors. ORs and 95% confidence intervals (CI) were used to assess associations between anthropometric measures and prostate cancer. RESULTS: A two-fold increased risk of prostate cancer was found among men in the highest quartile of waist-hip ratio compared with those in the lowest quartile (OR = 2.11, 95% CI, 1.54-2.88). Similarly, men with the largest waist circumferences had an OR of 1.84 (95% CI, 1.19-2.85) compared with those with the smallest waist sizes. CONCLUSIONS: These results suggest that measures of central rather than global adiposity may be more predictive of prostate cancer, especially in westernized African populations, where patterns of visceral fat distribution are different than other groups. IMPACT: The findings highlight the need to further elucidate the mechanisms underlying the relationship between central adiposity and prostate cancer in populations of predominantly African descent.

Evaluation of 19 susceptibility loci of breast cancer in women of African ancestry.

Multiple breast cancer susceptibility loci have been identified in genome-wide association studies (GWAS) in populations of European and Asian ancestry using array chips optimized for populations of European ancestry. It is important to examine whether these loci are associated with breast cancer risk in women of African ancestry. We evaluated 25 single nucleotide polymorphisms (SNPs) at 19 loci in a pooled case-control study of breast cancer, which included 1509 cases and 1383 controls. Cases and controls were enrolled in Nigeria, Barbados and the USA; all women were of African ancestry. We found significant associations for three SNPs, which were in the same direction and of similar magnitude as those reported in previous fine-mapping studies in women of African ancestry. The allelic odds ratios were 1.24 [95% confidence interval (CI): 1.04-1.47; P = 0.018] for the rs2981578-G allele (10q26/FGFR2), 1.34 (95% CI: 1.10-1.63; P = 0.0035) for the rs9397435-G allele (6q25) and 1.12 (95% CI: 1.00-1.25; P = 0.04) for the rs3104793-C allele (16q12). Although a significant association was observed for an additional index SNP (rs3817198), it was in the opposite direction to prior GWAS studies. In conclusion, this study highlights the complexity of applying current GWAS findings across racial/ethnic groups, as none of GWAS-identified index SNPs could be replicated in women of African ancestry. Further fine-mapping studies in women of African ancestry will be needed to reveal additional and causal variants for breast cancer.

Genetic susceptibility to type 2 diabetes and breast cancer risk in women of European and African ancestry.

BACKGROUND: Epidemiologic studies have reported a positive association between type 2 diabetes (T2D) and breast cancer risk, independent of body weight. METHODS: We investigated 40 genetic variants known to be associated with T2D in relation to breast cancer risk among 2,651 breast cancer cases and 2,520 controls of African or European ancestry that were pooled from seven studies. RESULTS: We found that two T2D risk alleles in Caucasian women (rs5945326-G, rs12518099-C) and one in women of African ancestry (rs7578597-T) were positively associated with breast cancer risk at a nominal significance level of 0.05, whereas two T2D risk alleles were inversely associated with breast cancer risk in Caucasian women (rs1111875-C, rs10923931-T). The composite T2D susceptibility score (the number of risk allele) was not significantly associated with breast cancer risk. CONCLUSION: The association between established T2D genetic susceptibility variants and breast cancer risk in women of African or European ancestry is likely weak, if it does exist. IMPACT: The pleiotropic effects of known T2D risk alleles cannot explain the association between T2D and breast cancer risk.

Prostate cancer incidence and mortality in barbados, west indies.

We describe prostate cancer incidence and mortality in Barbados, West Indies. We ascertained all histologically confirmed cases of prostate cancer during the period July 2002 to December 2008 and reviewed each death registration citing prostate cancer over a 14-year period commencing January 1995. There were 1101 new cases for an incidence rate of 160.4 (95% Confidence Interval: 151.0-170.2) per 100,000 standardized to the US population. Comparable rates in African-American and White American men were 248.2 (95% CI: 246.0-250.5) and 158.0 (95% CI: 157.5-158.6) per 100,000, respectively. Prostate cancer mortality rates in Barbados ranged from 63.2 to 101.6 per 100,000, compared to 51.1 to 78.8 per 100,000 among African Americans. Prostate cancer risks are lower in Caribbean-origin populations than previously believed, while mortality rates appeared to be higher than reported in African-American men. Studies in Caribbean populations may assist understanding of disparities among African-origin populations with shared heredity.

Effects of argon laser trabeculoplasty in the Early Manifest Glaucoma Trial.

PURPOSE: To analyze reduction of intraocular pressure (IOP) by argon laser trabeculoplasty (ALT) in the Early Manifest Glaucoma Trial and factors influencing the effect of such treatment. DESIGN: Cohort study based on 127 patients from the treatment group of the Early Manifest Glaucoma Trial, a randomized clinical trial. METHODS: Patients randomized to the treatment arm of the Early Manifest Glaucoma Trial received a standard treatment protocol (topical betaxolol hydrochloride followed by 360-degree ALT) and then were followed up prospectively at 3-month intervals for up to 8 years. One eye per patient was included in the analyses. We investigated the relationship between IOP before ALT and subsequent IOP reduction and other factors that might have influenced the effect of ALT, including stage of the disease, trabecular pigmentation, presence of exfoliation syndrome, and treating surgeon. RESULTS: The mean ± standard deviation IOP before ALT and after betaxolol treatment was 18.1 ± 3.9 mm Hg, and the mean ± standard deviation short-term IOP reduction 3 months after ALT was 2.8 ± 3.9 mm Hg (12.6 ± 20.5%). The IOP before ALT strongly affected IOP reduction (P < .001); each 3-mm Hg higher IOP before ALT value was associated with an additional mean IOP reduction of approximately 2 mm Hg. The treating surgeons also had a significant impact on IOP reduction (P = 0.001), with mean values ranging from 5.8 to -1.3 mm Hg. CONCLUSIONS: In this cohort, which included many patients with low IOP levels, IOP before ALT markedly influenced the IOP reduction induced by ALT, seen as a much larger decrease in eyes with higher IOP before ALT. The treating surgeon also had a significant impact on ALT outcome.

Genome-wide association study of prostate cancer in men of African ancestry identifies a susceptibility locus at 17q21.

In search of common risk alleles for prostate cancer that could contribute to high rates of the disease in men of African ancestry, we conducted a genome-wide association study, with 1,047,986 SNP markers examined in 3,425 African-Americans with prostate cancer (cases) and 3,290 African-American male controls. We followed up the most significant 17 new associations from stage 1 in 1,844 cases and 3,269 controls of African ancestry. We identified a new risk variant on chromosome 17q21 (rs7210100, odds ratio per allele = 1.51, P = 3.4 × 10(-13)). The frequency of the risk allele is ∼5% in men of African descent, whereas it is rare in other populations (<1%). Further studies are needed to investigate the biological contribution of this allele to prostate cancer risk. These findings emphasize the importance of conducting genome-wide association studies in diverse populations.