Edward D. Yeboah

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.

Prevalence of Monoclonal Gammopathy of Undetermined Significance Among Men in Ghana

OBJECTIVE To determine the prevalence of monoclonal gammopathy of undetermined significance (MGUS), a precursor of multiple myeloma (MM), in Ghanaian men vs white men and to test for evidence to support an underlying race-related predisposition of the 2-fold higher prevalence of MGUS in African Americans vs whites. PARTICIPANTS AND METHODS Between September 1, 2004, and September 30, 2006, 917 men (50-74 years) underwent in-person interviews and physical examinations. Serum samples from all participants were analyzed by electrophoresis performed on agarose gel; any serum sample with a discrete or localized band was subjected to immunofixation. Age-adjusted and standardized (to the 2000 world population) prevalence estimates of MGUS and 95% confidence intervals (CIs) were computed in the Ghanaian men and compared with MGUS prevalence in 7996 white men from Minnesota. Associations between selected characteristics and MGUS prevalence were assessed by the Fisher exact test and logistic regression models. RESULTS Of the 917 study participants, 54 were found to have MGUS, yielding an age-adjusted prevalence of 5.84 (95% CI, 4.27-7.40) per 100 persons. No significant variation was found by age group, ethnicity, education status, or prior infectious diseases. The concentration of monoclonal immunoglobulin was undetectable in 41 (76%) of the 54 MGUS cases, less than 1 g/dL in 10 patients (19%), and 1 g/dL or more in only 3 patients (6%). Compared with white men, the age-adjusted prevalence of MGUS was 1.97-fold (95% CI, 1.94-2.00) higher in Ghanaian men. CONCLUSION The prevalence of MGUS in Ghanaian men was twice that in white men, supporting the hypothesis that race-related genetic susceptibility could explain the higher rates of MGUS in black populations. An improved understanding of MGUS and MM pathophysiology would facilitate the development of strategies to prevent progression of MGUS to MM.

Global Patterns of Prostate Cancer Incidence, Aggressiveness, and Mortality in Men of African Descent

Prostate cancer (CaP) is the leading cancer among men of African descent in the USA, Caribbean, and Sub-Saharan Africa (SSA). The estimated number of CaP deaths in SSA during 2008 was more than five times that among African Americans and is expected to double in Africa by 2030. We summarize publicly available CaP data and collected data from the men of African descent and Carcinoma of the Prostate (MADCaP) Consortium and the African Caribbean Cancer Consortium (AC3) to evaluate CaP incidence and mortality in men of African descent worldwide. CaP incidence and mortality are highest in men of African descent in the USA and the Caribbean. Tumor stage and grade were highest in SSA. We report a higher proportion of T1 stage prostate tumors in countries with greater percent gross domestic product spent on health care and physicians per 100,000 persons. We also observed that regions with a higher proportion of advanced tumors reported lower mortality rates. This finding suggests that CaP is underdiagnosed and/or underreported in SSA men. Nonetheless, CaP incidence and mortality represent a significant public health problem in men of African descent around the world.

Two susceptibility loci identified for prostate cancer aggressiveness

Most men diagnosed with prostate cancer will experience indolent disease; hence discovering genetic variants that distinguish aggressive from non-aggressive prostate cancer is of critical clinical importance for disease prevention and treatment. In a multistage, case-only genome-wide association study of 12,518 prostate cancer cases, we identify two loci associated with Gleason score, a pathological measure of disease aggressiveness: rs35148638 at 5q14.3 (RASA1, P=6.49×10-9) and rs78943174 at 3q26.31 (NAALADL2, P=4.18×10-8). In a stratified case-control analysis, the SNP at 5q14.3 appears specific for aggressive prostate cancer (P=8.85×10-5) with no association for non-aggressive prostate cancer compared to controls (P=0.57). The proximity of these loci to genes involved in vascular disease suggests potential biological mechanisms worthy of further investigation.

Acute renal failure in tropical Africa.

Between 1972 and 1975, 55 adult patients with acute renal failure were admitted to the renal unit of Korle Bu Hospital. Fourteen patients died, giving an overall death rate of 25%. Massive intravascular haemolysis after a short febrile illness was the commonest cause of acute renal failure. Clinically these patients presented with blackwater fever but in only one could Plasmodium falciparum malaria be confidently diagnosed. In half the patients various bacterial and viral infections (especially typhoid) could be incriminated as causing this blackwater fever syndrome. The incidence of glucose-6-phosphate dehydrogenase deficiency was 22.5%, but we could not confirm the impression of a greater predisposition to acute renal failure in patients with this enzyme defect.

Integration of multiethnic fine-mapping and genomic annotation to prioritize candidate functional SNPs at prostate cancer susceptibility regions

Interpretation of biological mechanisms underlying genetic risk associations for prostate cancer is complicated by the relatively large number of risk variants (n = 100) and the thousands of surrogate SNPs in linkage disequilibrium. Here, we combined three distinct approaches: multiethnic fine-mapping, putative functional annotation (based upon epigenetic data and genome-encoded features), and expression quantitative trait loci (eQTL) analyses, in an attempt to reduce this complexity. We examined 67 risk regions using genotyping and imputation-based fine-mapping in populations of European (cases/controls: 8600/6946), African (cases/controls: 5327/5136), Japanese (cases/controls: 2563/4391) and Latino (cases/controls: 1034/1046) ancestry. Markers at 55 regions passed a region-specific significance threshold (P-value cutoff range: 3.9 × 10(-4)-5.6 × 10(-3)) and in 30 regions we identified markers that were more significantly associated with risk than the previously reported variants in the multiethnic sample. Novel secondary signals (P < 5.0 × 10(-6)) were also detected in two regions (rs13062436/3q21 and rs17181170/3p12). Among 666 variants in the 55 regions with P-values within one order of magnitude of the most-associated marker, 193 variants (29%) in 48 regions overlapped with epigenetic or other putative functional marks. In 11 of the 55 regions, cis-eQTLs were detected with nearby genes. For 12 of the 55 regions (22%), the most significant region-specific, prostate-cancer associated variant represented the strongest candidate functional variant based on our annotations; the number of regions increased to 20 (36%) and 27 (49%) when examining the 2 and 3 most significantly associated variants in each region, respectively. These results have prioritized subsets of candidate variants for downstream functional evaluation.

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.

Prevalence of BPH and lower urinary tract symptoms in West Africans.

Background:BPH and lower urinary tract symptoms (LUTS) are very common among older men in Western countries. However, the prevalence of these two conditions in the developing countries is less clear.Methods:We assessed the age-standardized prevalence of BPH and/or LUTS among West Africans in a probability sample of 950 men aged 50–74 in Accra, Ghana, with no evidence of biopsy-confirmed prostate cancer after screening with PSA and digital rectal examination (DRE). Information on LUTS was based on self-reports of the International Prostate Symptom Score (IPSS). BPH was estimated using DRE, PSA levels and imputed prostate volume.Results:The prevalence of DRE-detected enlarged prostate was 62.3%, while that of PSA⩾1.5 ng ml–1 (an estimate of prostate volume ⩾ 30 cm3) was 35.3%. The prevalence of moderate-to-severe LUTS (IPSS⩾8) was 19.9%. The prevalence of IPSS⩾8 and an enlarged prostate on DRE was 13.3%. Although there is no universally agreed-upon definition of BPH/LUTS, making comparisons across populations difficult, BPH and/or LUTS appear to be quite common among older Ghanaian men.Conclusions:We found that after age standardization, the prevalence of DRE-detected enlarged prostate in Ghanaian men is higher than previously reported for American men, but the prevalence of LUTS was lower than previously reported for African Americans. Further studies are needed to confirm these findings and identify the risk factors for BPH in both Africans and African Americans.

Hemodialysis in the Treatment of Acute Renal Failure in Tropical Africa: A 20-Year Review at the Korle Bu Teaching Hospital, Accra

From 1972 to 1992, 170 patients with acute renal failure (87 M, 83 F; mean age 32.51 +/- SE 0.945) underwent hemodialysis at the renal unit of the Korle Bu Teaching Hospital, Accra. Vascular access was established initially by arteriovenous shunt (133 cases), femoral venous cannulation (10 cases), and subclavian vein cannulation (27 cases). The overall mortality for acute renal failure (ARF) was 31.8% (54/170). The mortality for obstetric cases was 43.7% (14/32); for surgical cases, 33.3% (6/18); medical cases, 28.3% (13/32); and gynecologic (posthysterectomy) cases, 28.3% (2/7). The most important causes of death in ARF were pulmonary edema (42%), sepsis (20%), and cardiac tamponade (10.4%). Hemodialysis is now established as a form of treatment for ARF and a overall survival rate of 68.2% justifies the development of our program. With improvement of economies of developing countries and health insurance schemes, this form of treatment should be available in all developing countries.

Acute Renal Failure in Ghanaian Children

This paper discusses the results of a study undertaken in Ghana assessing the 13 cases of acute renal failure in children seen over a period of 4 1/2 years in Korle-Bu Hospital. The major cause of acute renal failure (ARF) as seen from the data (presented in tables) was infection with hemolysis. In 5 children hemolysis was due to Plasmodium falciparum infection. In 1 child renal failure was associated with measles and in 6 with septicemia either proven (2) or suspected (4). 8 children were treated with peritoneal dialysis and 5 were managed conservatively. 10 children survived. It appears that many children in tropical Africa are dying with unrecognized and untreated ARF. Recovery is proven to be common with adequate peritoneal dialysis.