Human Leukocyte Antigen Diversity: A Southern African Perspective

Despite the increasingly well-documented evidence of high genetic, ethnic, and linguistic diversity amongst African populations, there is limited data on human leukocyte antigen (HLA) diversity in these populations. HLA is part of the host defensemechanism mediated through antigen presentation to effector cells of the immune system. With the high disease burden in southern Africa, HLA diversity data is increasingly important in the design of population-specific vaccines and the improvement of transplantation therapeutic interventions. This review highlights the paucity of HLA diversity data amongst southern African populations and defines a need for information of this kind.This information will support disease association studies, provide guidance in vaccine design, and improve transplantation outcomes.The Medical Research Council of South Africa in terms of MRC’s Flagships Awards Project SAMRCRFA-UFSP-01-2013/STEM CELLS, the Institute for Cellular and Molecular Medicine of the University of Pretoria, and the National Research Foundation of South Africa.http://www.hindawi.com/journals/jiram2016Immunolog

Human Leukocyte Antigen-A, B, C, DRB1, and DQB1 Allele and Haplotype Frequencies in a subset of 237 donors in the South African Bone Marrow Registry

Human leukocyte antigen- (HLA-) A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 allele and haplotype frequencies were studied in a subset of 237 volunteer bone marrow donors registered at the South African Bone Marrow Registry (SABMR). Hapl-o-Mat software was used to compute allele and haplotype frequencies from individuals typed at various resolutions, with some alleles in multiple allele code (MAC) format. Four hundred and thirty-eight HLA-A, 235 HLA-B, 234 HLA-DRB1, 41 HLA-DQB1, and 29 HLA-C alleles are reported. The most frequent alleles were A02:02g (0.096), B07:02g (0.082), C07:02g (0.180), DQB106:02 (0.157), and DRB115:01 (0.072). The most common haplotype was A03:01g~B07:02g~C07:02g~DQB106:02~DRB115:01 (0.067), which has also been reported in other populations. Deviations from Hardy-Weinberg equilibrium were observed in A, B, and DRB1 loci, with C~DQB1 being the only locus pair in linkage disequilibrium. This study describes allele and haplotype frequencies from a subset of donors registered at SABMR, the only active bone marrow donor registry in Africa. Although the sample size was small, our results form a key resource for future population studies, disease association studies, and donor recruitment strategies

Prevalence of Extensively Drug Resistant Tuberculosis among Archived Multidrug Resistant Tuberculosis Isolates in Zimbabwe

We conducted a cross-sectional study of second line drug resistance patterns and genetic diversity of MDR-TB isolates archived at the BRTI-TB Laboratory, Harare, between January 2007 and December 2011. DSTs were performed for second line antituberculosis drugs. XDR-TB strains were defined as MDR-TB strains with resistance to either kanamycin and ofloxacin or capreomycin and ofloxacin. Strain types were identified by spoligotyping. No resistance to any second line drugs was shown in 73% of the isolates, with 23% resistant to one or two drugs but not meeting the definition of XDR-TB. A total of 26 shared types were identified, and 18 (69%) matched preexisting shared types in the current published spoligotype databases. Of the 11 out of 18 clustered SITs, 4 predominant (>6 isolates per shared type) were identified. The most and least abundant types were SIT 1468 (LAM 11-ZWE) with 12 (18%) isolates and SIT 53 (T1) with 6 (9%) isolates, respectively. XDR-TB strains are rare in Zimbabwe, but the high proportion of "pre-XDR-TB" strains and treatment failure cases is of concern. The genetic diversity of the MDR-TB strains showed no significant association between SITs and drug resistance

Human leukocyte antigen (HLA) diversity and clinical applications in South Africa

The major histocompatibility complex, known as the human leukocyte antigen (HLA) complex in humans, forms an integral component of adaptive T cell immunity by presenting self and non-self peptides to the T cell receptor, thereby allowing clonal expansion of responding peptide-specific CD4+ and CD8+ T cells. HLA likewise forms an integral part of the innate immune response through the binding of killercell immunoglobulin-like receptor (KIR) molecules, which regulate the response of natural killer (NK) cells. The HLA complex is found on the short arm of chromosome 6 and is the most polymorphic region in the human genome. Africans are genetically more diverse than other populations; however, information on HLA diversity among southern Africans, including South African populations, is limited. Paucity of African HLA data limits our understanding of disease associations, the ability to identify donor-recipient matches for transplantation and the development of disease-specific vaccines. This review discusses the importance of HLA in the clinical setting in South Africans and highlights how tools such as HLA imputation might augment standard HLA typing methods to increase our understanding of HLA diversity in our populations, which will better inform disease association studies, donor recruitment strategies into bone marrow registries and our understanding of human genetic diversity in South Africa.http://www.samj.org.zapm2020Immunolog

Surveillance of Transmitted Antiretroviral Drug Resistance among HIV-1 Infected Women Attending Antenatal Clinics in Chitungwiza, Zimbabwe

The rapid scale-up of highly active antiretroviral therapy (HAART) and use of single dose Nevirapine (SD NVP) for prevention of mother-to-child transmission (pMTCT) have raised fears about the emergence of resistance to the first line antiretroviral drug regimens. A cross-sectional study was conducted to determine the prevalence of primary drug resistance (PDR) in a cohort of young (<25 yrs) HAART-naïve HIV pregnant women attending antenatal clinics in Chitungwiza, Zimbabwe. Whole blood was collected in EDTA for CD4 counts, viral load, serological estimation of duration of infection using the BED Calypte assay and genotyping for drug resistance. Four hundred and seventy-one women, mean age 21 years; SD: 2.1 were enrolled into the study between 2006 and 2007. Their median CD4 count was 371cells/µL; IQR: 255–511 cells/µL. Two hundred and thirty-six samples were genotyped for drug resistance. Based on the BED assay, 27% were recently infected (RI) whilst 73% had long-term infection (LTI). Median CD4 count was higher (p<0.05) in RI than in women with LTI. Only 2 women had drug resistance mutations; protease I85V and reverse transcriptase Y181C. Prevalence of PDR in Chitungwiza, 4 years after commencement of the national ART program remained below WHO threshold limit (5%). Frequency of recent infection BED testing is consistent with high HIV acquisition during pregnancy. With the scale-up of long-term ART programs, maintenance of proper prescribing practices, continuous monitoring of patients and reinforcement of adherence may prevent the acquisition and transmission of PDR

Human leukocyte antigen (HLA) genetic diversity in South African populations

There is documented evidence of high genetic diversity amongst African populations, but there is limited data on human leukocyte antigen (HLA) diversity in these populations. HLA genes are highly polymorphic, and encode for proteins that are part of the host defence mechanism mediated through antigen presentation to immune system effector cells. The highly polymorphic nature of HLA genes facilitates the presentation of a wide range of antigenic peptides to the immune system leading to an immune response. With the high disease burden in Africa, it is important to fully understand HLA diversity in these populations, to establish HLA-disease associations, and potentially use this data for the informed design of population-specific vaccines against the many diseases, and to improve on donor-recipient matching. The aim of this thesis is to understand HLA diversity in South African populations to support transplantation programs, add knowledge on human diversity and build a potential future resource for disease association and population studies. There is generally limited HLA data from southern African populations (Chapter 2) to support disease association studies, provide guidance in vaccine design and donor recruitment for transplantation programs. Despite being the only active bone marrow donor registry in Africa supporting transplantation programs, HLA diversity in volunteer bone marrow donors registered at the South African Bone Marrow Registry (SABMR) is largely undocumented. This study documents HLA -A, -B, -C, -DRB1 and -DQB1 allele and haplotype frequencies from a subset of 237 SABMR registered donors with the objective of highlighting HLA diversity in South Africans (Chapter 3). Additionally, mixed resolution HLA data from the National Health Laboratory Services (NHLS) and the South African National Blood Transfusion Service (SANBS) are reported (Chapter 4). A comparison of South African HLA data (NHLS and SANBS) with other global populations including sub Saharan Africans confirm the genetic diversity of South Africans. To counter the paucity of HLA data, in silico HLA imputation tools may be used to determine HLA alleles from existing whole genome sequencing (WGS) data. HLA imputation is an economically feasible typing option for resource limited settings. To support the feasibility of HLA imputation, this study describes high resolution (up to 8 digit typing) HLA alleles determined by in silico HLA imputation tools from 24 WGS of South African individuals (chapter 5). Generally, HLA diversity of South African populations is described in detail through literature meta-analysis, documentation of previously typed individuals (SANBS, NHLS and SABMR) and HLA imputation from existing next generation sequencing (NGS) data. Although results reported here are from a small subset of 237 SABMR registered donors (chapter 3), 24 WGS (chapter 5) and mixed resolution typing NHLS and SANBS data (chapter 4), allele and haplotype frequencies generated could be a useful resource for future anthropological and population genetics studies. Furthermore, these findings may better inform donor recruitment strategies for the SABMR, and disease association studies. Future study recommendations include development of an HLA diversity resource for African populations, a comparison of large SABMR dataset with other global registries, and using more robust assembly based computational tools to fully understand the HLA diversity in South Africans.Thesis (PhD)--University of Pretoria, 2018.South African Medical Research Council (SAMRC) in terms of the MRC’s Flagships Awards Project (SAMRC-RFA-UFSP-01-2013/STEM CELLS), the SAMRC Extramural Unit for stem cell Research and Therapy, the Institute for Cellular and Molecular Medicine of the University of Pretoria, and the National Research Foundation of South Africa.ImmunologyPhD Medical ImmunologyUnrestricte

Human Leukocyte Antigen Diversity: A Southern African Perspective

Despite the increasingly well-documented evidence of high genetic, ethnic, and linguistic diversity amongst African populations, there is limited data on human leukocyte antigen (HLA) diversity in these populations. HLA is part of the host defense mechanism mediated through antigen presentation to effector cells of the immune system. With the high disease burden in southern Africa, HLA diversity data is increasingly important in the design of population-specific vaccines and the improvement of transplantation therapeutic interventions. This review highlights the paucity of HLA diversity data amongst southern African populations and defines a need for information of this kind. This information will support disease association studies, provide guidance in vaccine design, and improve transplantation outcomes

Human Leukocyte Antigen-A, B, C, DRB1, and DQB1 Allele and Haplotype Frequencies in a Subset of 237 Donors in the South African Bone Marrow Registry

Human leukocyte antigen- (HLA-) A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 allele and haplotype frequencies were studied in a subset of 237 volunteer bone marrow donors registered at the South African Bone Marrow Registry (SABMR). Hapl-o-Mat software was used to compute allele and haplotype frequencies from individuals typed at various resolutions, with some alleles in multiple allele code (MAC) format. Four hundred and thirty-eight HLA-A, 235 HLA-B, 234 HLA-DRB1, 41 HLA-DQB1, and 29 HLA-C alleles are reported. The most frequent alleles were A∗02:02g (0.096), B∗07:02g (0.082), C∗07:02g (0.180), DQB1∗06:02 (0.157), and DRB1∗15:01 (0.072). The most common haplotype was A∗03:01g~B∗07:02g~C∗07:02g~DQB1∗06:02~DRB1∗15:01 (0.067), which has also been reported in other populations. Deviations from Hardy-Weinberg equilibrium were observed in A, B, and DRB1 loci, with C~DQB1 being the only locus pair in linkage disequilibrium. This study describes allele and haplotype frequencies from a subset of donors registered at SABMR, the only active bone marrow donor registry in Africa. Although the sample size was small, our results form a key resource for future population studies, disease association studies, and donor recruitment strategies

High resolution HLA ∼A, ∼B, ∼C, ∼DRB1, ∼DQA1, and ∼DQB1 diversity in South African populations

BACKGROUND : Lack of HLA data in southern African populations hampers disease association studies and our understanding of genetic diversity in these populations. We aimed to determine HLA diversity in South African populations using high resolution HLA ~A, ~B, ~C, ~DRB1, ~DQA1 and ~DQB1 data, from 3005 previously typed individuals. METHODS : We determined allele and haplotype frequencies, deviations from HardyWeinberg equilibrium (HWE), linkage disequilibrium (LD) and neutrality test. South African HLA class I data was additionally compared to other global populations using non-metrical multidimensional scaling (NMDS), genetic distances and principal component analysis (PCA). RESULTS : All loci strongly (p < 0.0001) deviated from HWE, coupled with excessive heterozygosity in most loci. Two of the three most frequent alleles, HLA ~DQA1*05:02 (0.2584) and HLA ~C*17:01 (0.1488) were previously reported in South African populations at lower frequencies. NMDS showed genetic distinctness of South African populations. Phylogenetic analysis and PCA clustered our current dataset with previous South African studies. Additionally, South Africans seem to be related to other subSaharan populations using HLA class I allele frequencies. DISSCUSSION AND CONCLUSION : Despite the retrospective nature of the study, data missingness, the imbalance of sample sizes for each locus and haplotype pairs, and induced methodological difficulties, this study provides a unique and large HLA dataset of South Africans, which might be a useful resource to support anthropological studies, disease association studies, population based vaccine development and donor recruitment programs. We additionally provide simulated high resolution HLA class I data to augment the mixed resolution typing results generated from this study.The South African Medical Research Council (SAMRC) in terms of the MRC’s Flagships Awards Project (SAMRC-RFA-UFSP-01-2013/STEM CELLS), the SAMRC Extramural Unit for stem cell Research and Therapy, the Institute for Cellular and Molecular Medicine of the University of Pretoria, and the National Research Foundation.https://www.frontiersin.org/journals/geneticsdm2022Immunolog