Yao Tettey

Cerebrospinal fluid and serum biomarkers of cerebral malaria mortality in Ghanaian children

BackgroundPlasmodium falciparum can cause a diffuse encephalopathy known as cerebral malaria (CM), a major contributor to malaria associated mortality. Despite treatment, mortality due to CM can be as high as 30% while 10% of survivors of the disease may experience short- and long-term neurological complications. The pathogenesis of CM and other forms of severe malaria is multi-factorial and appear to involve cytokine and chemokine homeostasis, inflammation and vascular injury/repair. Identification of prognostic markers that can predict CM severity will enable development of better intervention.MethodsPostmortem serum and cerebrospinal fluid (CSF) samples were obtained within 2–4 hours of death in Ghanaian children dying of CM, severe malarial anemia (SMA), and non-malarial (NM) causes. Serum and CSF levels of 36 different biomarkers (IL-1β, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 (p70), IL-13, IL-15, IL-17, Eotaxin, FGF basic protein, CRP, G-CSF, GM-CSF, IFN-γ, TNF-α, IP-10, MCP-1 (MCAF), MIP-1α, MIP-1β, RANTES, SDF-1α, CXCL11 (I-TAC), Fas-ligand [Fas-L], soluble Fas [sFas], sTNF-R1 (p55), sTNF-R2 (p75), MMP-9, TGF-β1, PDGF bb and VEGF) were measured and the results compared between the 3 groups.ResultsAfter Bonferroni adjustment for other biomarkers, IP-10 was the only serum biomarker independently associated with CM mortality when compared to SMA and NM deaths. Eight CSF biomarkers (IL-1ra, IL-8, IP-10, PDGFbb, MIP-1β, Fas-L, sTNF-R1, and sTNF-R2) were significantly elevated in CM mortality group when compared to SMA and NM deaths. Additionally, CSF IP-10/PDGFbb median ratio was statistically significantly higher in the CM group compared to SMA and NM groups.ConclusionThe parasite-induced local cerebral dysregulation in the production of IP-10, 1L-8, MIP-1β, PDGFbb, IL-1ra, Fas-L, sTNF-R1, and sTNF-R2 may be involved in CM neuropathology, and their immunoassay may have potential utility in predicting mortality in CM.

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.

High-level cerebellar expression of cytokines and adhesion molecules in fatal, paediatric, cerebral malaria

Abstract Although the roles played by systemic tumour necrosis factor (TNF) and interleukin 1β (IL-1β), and their upregulation of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and E-selectin, in the pathogenesis of human cerebral malaria (CM) are well established, the role of local cytokine release, in the brain, remains unclear. Immunohistochemistry was therefore used to compare the expression of ICAM-1, VCAM-1, E-selectin, IL-1β, TNF and transforming growth factor β (TGF-β) at light-microscope level, in cryostat sections of cerebral, cerebellar and brainstem tissues collected, post-mortem, from Ghanaian children. Among the 21 children investigated were 10 cases of CM, five of severe malarial anemia (SMA), one of purulent bacterial meningitis (PBM), two of non-central-nervous-system infection (NCNSI) and three children who had no infection (NI) when they died. Parasitised erythrocytes were detected in all of the sections from the cases of fatal malaria (CM and SMA), and sequestered leucocytes were present in most of the sections from the CM cases (but none of the sections from the SMA cases). Significantly elevated vascular expression of all three adhesion molecules investigated was detected in the brains of the 15 cases of fatal malaria and one of the cases of NCNSI (a child with Salmonella septicaemia), and in the malaria cases this showed highly significant co-localization with the areas of erythrocyte sequestration. In terms of the levels of expression of ICAM-1, VCAM-1 and E-selectin, there were, however, negligible differences between the CM and SMA cases. Although TGF-β showed intravascular and perivascular distribution in all the subjects, its expression was most intense in the PBM case and the CM group. Only in the sections from the PBM and CM cases did TNF and IL-1β show prominent brain parenchymal staining, in addition to the intravascular and perivascular staining seen in all subjects. The highest observed expression of each of the six antigens studied was in the cerebellar sections of the malaria cases. Endothelial activation in the brain therefore appears to be a feature of fatal malaria and Salmonella sepsis, and in cases of fatal malaria is closely associated with leucocyte sequestration. In the present study, IL-1β and TNF were only up-regulated in the brains of children with neurodegenerative lesions, whereas TGF-β was present in all cases.

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.

Hepatitis E virus infection is highly prevalent among pregnant women in Accra, Ghana

BackgroundHepatitis E virus (HEV) is highly endemic in several African countries with high mortality rate among pregnant women. The prevalence of antibodies to HEV in Ghana is not known. Therefore we evaluated the prevalence of anti-HEV IgG and anti-HEV IgM among pregnant women seen between the months of January and May, 2008 at the Obstetrics and Gynaecology Department, Korle-Bu Teaching Hospital, Accra, Ghana.ResultsOne hundred and fifty-seven women provided blood samples for unlinked anonymous testing for the presence of antibodies to HEV. The median age of participants was 28.89 ± 5.76 years (range 13–42 years). Of the 157 women tested, HEV seroprevelance was 28.66% (45/157). Among the seropositive women, 64.40% (29/45) tested positive for anti-HEV IgM while 35.60% (16/45) tested positive to HEV IgG antibodies. HEV seroprevalence was highest (46.15%) among women 21–25 years of age, followed by 42.82% in = 20 year group, then 36.84% in = 36 year group. Of the 157 women, 75.79% and 22.92% were in their third and second trimesters of pregnancy, respectively. Anti-HEV antibodies detected in women in their third trimester of pregnancy (30.25%) was significantly higher, P < 0.05, than in women in their second trimester of pregnancy (25.0%).ConclusionConsistent with similar studies worldwide, the results of our studies revealed a high prevalence of HEV infection in pregnant women.

Soluble factors from Plasmodium falciparum-infected erythrocytes induce apoptosis in human brain vascular endothelial and neuroglia cells

The severity of malaria is multi-factorial. It is associated with parasite-induced alteration in pro-inflammatory and anti-inflammatory cytokine and chemokine levels in host serum and cerebrospinal fluid. It is also associated with sequestration and cytoadherence of parasitized erythrocytes (pRBCs) in post-capillary venules and blood-brain barrier (BBB) dysfunction. The role of these factors in development of vascular injury and tissue damage in malaria patients is unclear. While some studies indicate a requirement for pRBC adhesion to vascular endothelial cells (ECs) in brain capillaries to induce apoptosis and BBB damage, others show no role of apoptosis resulting from adhesion of pRBC to EC. In the present study, the hypothesis that soluble factors from Plasmodium falciparum-infected erythrocytes induce apoptosis in human brain vascular endothelial (HBVEC) and neuroglia cells (cellular components of the BBB) was tested. Apoptotic effects of parasitized (pRBC) and non-parasitized erythrocyte (RBC) conditioned medium on HBVEC and neuroglia cells were determined in vitro by evaluating nuclear DNA fragmentation (TUNEL assay) in cultured cells. Soluble factors from P. falciparum-infected erythrocytes in conditioned medium induced extensive DNA fragmentation in both cell lines, albeit to a greater extent in HBVEC than neuroglia, indicating that extended exposure to high levels of these soluble factors in serum may be associated with vascular, neuronal and tissue injury in malaria patients.

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.