Browsing by Author "Fernandez, Pedro"

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    African KhoeSan ancestry linked to high-risk prostate cancer
    (BMC (part of Springer Nature), 2019-06-04) Petersen, Desiree C.; Jaratlerdsiri, Weerachai; Van Wyk, Abraham; Chan, Eva K. F.; Fernandez, Pedro; Lyons, Ruth J.; Mutambirw, Shingai B. A.; Van der Merwe, Andre; Venter, Philip A.; Bates, William; Bornman, M. S. R.; Hayes, Vanessa M.
    Backgrounds: Genetic diversity is greatest within Africa, in particular the KhoeSan click-speaking peoples of southern Africa. South African populations represent admixture fractions including differing degrees of African, African-KhoeSan and non-African genetic ancestries. Within the United States, African ancestry has been linked to prostate cancer presentation and mortality. Together with environmental contributions, genetics is a significant risk factor for high-risk prostate cancer, defined by a pathological Gleason score ≥ 8. Methods: Using genotype array data merged with ancestry informative reference data, we investigate the contribution of African ancestral fractions to high-risk prostate cancer. Our study includes 152 South African men of African (Black) or African-admixed (Coloured) ancestries, in which 40% showed high-risk prostate cancer. Results: Genetic fractions were determined for averaging an equal African to non-African genetic ancestral contribution in the Coloured; we found African ancestry to be linked to high-risk prostate cancer (P-value = 0.0477). Adjusting for age, the associated African ancestral fraction was driven by a significant KhoeSan over Bantu contribution, defined by Gleason score ≥ 8 (P-value = 0.02329) or prostate specific antigen levels ≥20 ng/ml (Pvalue = 0.03713). Additionally, we observed the mean overall KhoeSan contribution to be increased in Black patients with high-risk (11.8%) over low-risk (10.9%) disease. Linking for the first time KhoeSan ancestry to a common modern disease, namely high-risk prostate cancer, we tested in this small study the validity of using KhoeSan ancestry as a surrogate for identifying potential high-risk prostate cancer risk loci. As such, we identified four loci within chromosomal regions 2p11.2, 3p14, 8q23 and 22q13.2 (P-value = all age-adjusted < 0.01), two of which have previously been associated with high-risk prostate cancer. Conclusions: Our study suggests that ancient KhoeSan ancestry may be linked to common modern diseases, specifically those of late onset and therefore unlikely to have undergone exclusive selective pressure. As such we show within a uniquely admixed South African population a link between KhoeSan ancestry and high-risk prostate cancer, which may explain the 2-fold increase in presentation in Black South Africans compared with African Americans.
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    Androgen metabolism gene polymorphisms, associations with prostate cancer risk and pathological characteristics : a comparative analysis between South African and Senegalese men
    (2012) Fernandez, Pedro; Zeigler-Johnson, Charnita M.; Spangler, Elaine; Van der Merwe, Andre; Jalloh, Mohamed; Gueye, Serigne M.; Rebbeck, Timothy R.
    Prostate cancer is the most common cancer in men in developed countries and the leading cause of mortality in males in less developed countries. African ethnicity is one of the major risk factors for developing prostate cancer. Pathways involved in androgen metabolism have been implicated in the etiology of the disease. Analyses of clinical data and CYP3A4, CYP3A5, and SRD5A2 genotypes were performed in South African White (120 cases; 134 controls), Mixed Ancestry (207 cases; 167 controls), and Black (25 cases; 20 controls) men, as well as in Senegalese men (86 cases; 300 controls). Senegalese men were diagnosed earlier with prostate cancer and had higher median PSA levels compared to South African men. Metastasis occurred more frequently in Senegalese men. Gene polymorphism frequencies differed significantly between South African and Senegalese men. The CYP3A4 rs2740574 polymorphism was associated with prostate cancer risk and tumor aggressiveness in South African men, after correction for population stratification, and the SRD5A2 rs523349 CG genotype was inversely associated with high-stage disease in Senegalese men. These data suggest that variants previously associated with prostate cancer in other populations may also affect prostate cancer risk in African men.
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    A candidate and novel gene search to identify the PFHBII-causative gene
    (Stellenbosch : Stellenbosch University, 2004-12) Fernandez, Pedro; Corfield, Valerie A.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences.
    ENGLISH ABSTRACT: Heart failure due to cardiomyopathy or cardiac conduction disease is a major cause of mortality and morbidity in both developed and developing countries. Although defined as separate clinical entities, inherited forms of cardiomyopathies and cardiac conduction disorders have been identified that present with overlapping clinical features and/or have common molecular aetiologies. The objective of the present study was to identify the molecular cause of progressive familial heart block type II (PFHBII), an inherited cardiac conduction disorder that segregates in a South African Caucasian Afrikaner family (Brink and Torrington, 1977). The availability of family data tracing the segregation of PFHBII meant that linkage analysis could be employed to identify the chromosomal location of the disease-causative gene. Human Genome Project (HGP) databases have provided additional resources to facilitate the identification of positional candidate genes. Clinical examinations were performed on individuals of the PFHBII-affected family, and, where available, clinical records of subjects examined in a previous study by Brink and Torrington (1977) were re-assessed. Retrospective data suggested redefining the classification of PFHBII. Subsequently, linkage analysis was used to test described dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM) and cardiac conduction-causative loci on chromosomes 1, 2, 3, 6, 7, 9, 11, 14, 15 and 19 for their involvement in the development of PFHBII. Once a locus was mapped, bioinformatics tools were applied to identify and prioritise positional candidate genes for mutation screening. The retrospective and prospective clinical study redefined PFHBII as a cardiac conduction and DCM-associated disorder and simultaneously allowed more family members to be traced. Fortuitously, candidate loci linkage analysis mapped the PFHBII locus to chromosome 1q32, to a region that overlapped a previously described DCM-associated disorder (CMD1D), by the generation of a maximum pairwise lod score of 3.13 at D1S3753 (theta [Ξ]=0.0) and a maximum multipoint lod score of 3.7 between D1S3753 and D1S414. However, genetic fine mapping and haplotype analysis placed the PFHBII-causative locus distal to the CMD1D locus, within a 3.9 centimorgan (cM) interval on chromosome 1q32.2-q32.3, telomeric of D1S70 and centromeric of D1S505. Bioinformatics analyses prioritised seven candidate genes for mutation analysis, namely, a gene encoding a potassium channel (KCNH1), an extracellular matrix protein (LAMB3), a protein phosphatase (PPP2R5A), an adapter protein that interacts with a cytoskeletal protein (T3JAM), a putative acyltransferase (KIAA0205) and two genes encoding proteins possibly involved in energy homeostasis (RAMP and VWS59). The PFHBII-causative mutation was not identified, although single sequence variations were identified in four of the seven candidate genes that were screened. Although the molecular aetiology was not established, the present study defined the underlying involvement of DCM in the pathogenesis of PFHBII. The new clinical classification of PFHBII has been published (Fernandez et al., 2004) and should lead to tracing more affected individuals in South Africa or elsewhere. The identification of a novel disease-causative locus may point toward the future identification of a new DCM-associated aetiology, which, in turn, might provide insights towards understanding the associated molecular pathophysiologies of heart failure.
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    Complex patterns of genomic admixture within Southern Africa
    (PLOS, 2013-03) Petersen, Desiree C.; Libiger, Ondrej; Tindall, Elizabeth A.; Hardie, Rae-Anne; Hannick, Linda I.; Glashoff, Richard H.; Mukerji, Mitali; Indian Genome Variation Consortium; Fernandez, Pedro; Haacke, Wilfrid; Schork, Nicholas J.; Hayes, Vanessa M.
    Within-population genetic diversity is greatest within Africa, while between-population genetic diversity is directly proportional to geographic distance. The most divergent contemporary human populations include the click-speaking forager peoples of southern Africa, broadly defined as Khoesan. Both intra- (Bantu expansion) and inter-continental migration (European-driven colonization) have resulted in complex patterns of admixture between ancient geographically isolated Khoesan and more recently diverged populations. Using gender-specific analysis and almost 1 million autosomal markers, we determine the significance of estimated ancestral contributions that have shaped five contemporary southern African populations in a cohort of 103 individuals. Limited by lack of available data for homogenous Khoesan representation, we identify the Ju/’hoan (n = 19) as a distinct early diverging human lineage with little to no significant non- Khoesan contribution. In contrast to the Ju/’hoan, we identify ancient signatures of Khoesan and Bantu unions resulting in significant Khoesan- and Bantu-derived contributions to the Southern Bantu amaXhosa (n = 15) and Khoesan !Xun (n = 14), respectively. Our data further suggests that contemporary !Xun represent distinct Khoesan prehistories. Khoesan assimilation with European settlement at the most southern tip of Africa resulted in significant ancestral Khoesan contributions to the Coloured (n = 25) and Baster (n = 30) populations. The latter populations were further impacted by 170 years of East Indian slave trade and intra-continental migrations resulting in a complex pattern of genetic variation (admixture). The populations of southern Africa provide a unique opportunity to investigate the genomic variability from some of the oldest human lineages to the implications of complex admixture patterns including ancient and recently diverged human lineages.
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    Effective Project Management of a Pan-African Cancer Research Network : Men of African Descent and Carcinoma of the Prostate (MADCaP)
    (American Society of Clinical Oncology, 2018) Odiaka, Emeka; Lounsbury, David W.; Adusei, Ben; Diallo, Thierno Amadou; Kane, Papa Moussa Sene; Rockson, Isabella; Okyne, Vicky; Irusen, Hayley; Pentz, Audrey; Makinde, Ifeoluwa; Ajibola, Olalekan Hafees; Petersen, Lindsay; McBride, Jo; Petersen, Desiree C.; Mante, Sunny; Agalliu, Ilir; Adebiyi, Akindele Olupelumi; Popoola, Olufemi; Yeboah, Edward; Mensah, James E.; Hsing, Ann; Fernandez, Pedro; Aisuodionoe- Shadrach, Oseremen; Joffe, Maureen; Singh, Elvira; Gueye, Serigne Magueye; Quintana, Yuri; Fortier, Brian; Rebbeck, Timothy R.; Andrews, Caroline
    Purpose Health research in low- and middle-income countries can generate novel scientific knowledge and improve clinical care, fostering population health improvements to prevent premature death. Project management is a critical part of the success of this research, applying knowledge, skills, tools, and techniques to accomplish required goals. Here, we describe the development and implementation of tools to support a multifaceted study of prostate cancer in Africa, focusing on building strategic and operational capacity. Methods Applying a learning organizational framework, we developed and implemented a project management toolkit (PMT) that includes a management process flowchart, a cyclical centerspecific schedule of activities, periodic reporting and communication, and center-specific monitoring and evaluation metrics. Results The PMT was successfully deployed during year one of the project with effective component implementation occurring through periodic cycles of dissemination and feedback to local center project managers. A specific evaluation was conducted 1 year after study initiation to obtain enrollment data, evaluate individual quality control management plans, and undertake risk log assessments and follow-up. Pilot data obtained identified areas in which centers required mentoring, strengthening, and capacity development. Strategies were implemented to improve project goals and operational capacity through local problem solving, conducting quality control checks and following compliancy with study aims. Moving forward, centers will perform quarterly evaluations and initiate strengthening measures as required. Conclusion The PMT has fostered the development of both strategic and operational capacity across project centers. Investment in project management resources is essential to ensuring high-quality, impactful health research in low- and middle-income countries.
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    A multi-parameter approach for predicting prostate cancer
    (Cogent OA, 2017) Serafin, Antonio; Chinhengo, Angela; Fernandez, Pedro; Akudugu, John
    Urokinase plasminogen activator (uPA) and its inhibitor (PAI-1) have shown to be of merit as biomarkers for a variety of cancers. The objective of this project was to assay for uPA and PAI-1 in prostate needle biopsy tissue from 217 patients using the FEMTELLE enzyme linked immunosorbent (ELISA) assay, and to examine the robustness of PAI-1 as a candidate marker in benign prostatic hyperplasia (BPH) and prostate cancer (PCa), as previously identified in a different cohort of 111 patients. These results validate the assertion that PAI-1 levels of >4.5 ng mg−1 protein in prostate biopsies are indicative of prostate malignancy in elderly men, but further show that tissue from BPH patients in the 70–80 year age interval express significantly high levels of this marker. To address this anomaly, a malignancy index, derived from the concentrations of prostate-specific antigen (PSA), uPA, and PAI-1, and patient age is proposed. This simple index discriminates prostate tissue from BPH and PCa patients with concordance indices of 0.59 and 0.69 when tissues are taken as biopsy or transurethral resection of the prostate (TURP), respectively. Corresponding indices for PSA as a predictor of prostate disease were 0.67 and 0.73. Further evaluation of the proposed malignancy index using specimens, such as venous blood, could prove valuable in the search for non-invasive predictive assays.
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    Point-of-care screening for hepatitis B virus infection in pregnant women at an antenatal clinic : a South African experience
    (Public Library of Science, 2017) Chotun, Nafiisah; Preiser, Wolfgang; Van Rensburg, Christoffel Johannes; Fernandez, Pedro; Theron, Gerhard Barnard; Glebe, Dieter; Andersson, Monique Ingrid
    Background & aims: Elimination of HIV and syphilis mother-to-child transmission (MTCT) has received much attention but little consideration has been given to the possibility of elimination of HBV MTCT. In sub-Saharan Africa, HBV vertical transmission continues to be reported and it remains an important public health problem. This study aimed to assess the feasibility of screening pregnant women for HBV using a point-of-care (POC) test and implementing interventions to prevent HBV MTCT. Methods: In this observational prospective cohort study, HIV-uninfected pregnant women who consented to testing were screened for HBV using a rapid POC test for HBsAg. Positive results were laboratory-confirmed and tested for HBV DNA and serological markers. Women with viral loads ≥ 20 000 IU/ml received tenofovir (TDF) treatment and all infants received birth-dose HBV vaccine. Two blood samples collected six months apart from HBV-exposed infants within their first year of life were tested for HBV DNA. Results: Of 144 women who were approached, 134 consented to participating (93% acceptance rate of HBV POC test). Six women tested positive for HBsAg (4.5%; 95% CI 0.99%–8.01%), all confirmed by laboratory testing. Two mothers, M1 and M4, were treated with TDF during their third trimester of pregnancy. Six HBV-exposed infants received the HBV vaccine within 24 hours of birth, of whom two were lost to follow-up and four (including the two born to M1 and M4) had undetectable levels of HBV DNA when tested at the two time points. Conclusion: We found that HBV screening using POC testing fulfilled the criteria considered necessary for implementation. It has acceptable performance, is inexpensive, reliable, and was well accepted by the study participants. Screening pregnant women as part of the HBV MTCT prevention strategy is therefore feasible in a South African clinical setting.