Interferon gamma (IFN-γ) negative CD4+ and CD8+ T-cells can produce immune mediators in response to viral antigens.

Evaluation of antigen-specific T-cell responses to viral antigens is frequently performed on IFN-γ secreting cells. However, T-cells are capable of producing many more functions than just IFN-γ, some of which, like Perforin, are associated with immune protection in HIV-1 disease elite controllers. We evaluated the extent of missed T-cell functions when IFN-γ secretion is used as a surrogate marker for further evaluation of T-cell functions. Intracellular cytokine staining assay and flow cytometry were used to assess peripheral blood mononuclear cells (PBMCs) from 31 HIV-infected ART-naive individuals for the extent to which gated CD4+ and CD8+ IFN-γ producing and non-producing T-cells also secreted IL-2, Perforin, and TNF-α functions. Similarly, the extent of missed virus-specific responses in IFN-γ ELISpot assay negative T-cells from 5 HIV-1 uninfected individuals was evaluated. Cells from HIV-infected individuals were stimulated with pooled consensus group M (Con M) peptides; and those from healthy individuals were stimulated with pooled adenovirus (Ad) peptides. Overall, frequencies of virus-specific IFN-γ secreting CD4+ and CD8+ cells were low. Proportions of IFN-γ negative CD4+ expressing IL-2, Perforin, or TNF-α to Con M were significantly higher (5 of 7 functional profiles) than the corresponding IFN-γ positive CD4+ (0 of 7) T-cell phenotype, p = 0.02; Fisher's Exact test. Likewise, proportions of CD8+ T-cells expressing other functions were significantly higher in 4 of the 7 IFN-γ negative CD8+ T-cells. Notably, newly stimulated Perforin, identified as Perforin co-expression with IL-2 or TNF-α, was significantly higher in IFN-γ negative CD8+ T-cell than in the positive CD8+ T-cells. Using SEB, lower responses in IFN-γ positive cells were most associated with CD4+ than CD8+ T-cells. These findings suggest that studies evaluating immunogenicity in response to HIV and Adenovirus viral antigens should not only evaluate T-cell responsiveness among IFN-γ producing cells but also among those T-cells that do not express IFN-γ

Meta-analysis of African ancestry genome-wide association studies identified novel locus and validates multiple loci associated with kidney function

Despite recent efforts to increase diversity in genome-wide association studies (GWASs), most loci currently associated with kidney function are still limited to European ancestry due to the underlying sample selection bias in available GWASs. We set out to identify susceptibility loci associated with estimated glomerular filtration rate (eGFRcrea) in 80027 individuals of African-ancestry from the UK Biobank (UKBB), Million Veteran Program (MVP), and Chronic Kidney Disease genetics (CKDGen) consortia. We identified 8 lead SNPs, 7 of which were previously associated with eGFR in other populations. We identified one novel variant, rs77408001 which is an intronic variant mapped to the ELN gene. We validated three previously reported loci at GATM-SPATA5L1, SLC15A5 and AGPAT3. Fine-mapping analysis identified variants rs77121243 and rs201602445 as having a 99.9% posterior probability of being causal. Our results warrant designing bigger studies within individuals of African ancestry to gain new insights into the pathogenesis of Chronic Kidney Disease (CKD), and identify genomic variants unique to this ancestry that may influence renal function and disease

Molecular Dynamic Simulation Reveals Structure Differences in APOL1 Variants and Implication in Pathogenesis of Chronic Kidney Disease.

BACKGROUND: According to observational studies, two polymorphisms in the apolipoprotein L1 (APOL1) gene have been linked to an increased risk of chronic kidney disease (CKD) in Africans. One polymorphism involves the substitution of two amino-acid residues (S342G and I384M; known as G1), while the other involves the deletion of two amino-acid residues in a row (N388 and Y389; termed G2). Despite the strong link between APOL1 polymorphisms and kidney disease, the molecular mechanisms via which these APOL1 mutations influence the onset and progression of CKD remain unknown. METHODS: To predict the active site and allosteric site on the APOL1 protein, we used the Computed Atlas of Surface Topography of Proteins (CASTp) and the Protein Allosteric Sites Server (PASSer). Using an extended molecular dynamics simulation, we investigated the characteristic structural perturbations in the 3D structures of APOL1 variants. RESULTS: According to CASTp's active site characterization, the topmost predicted site had a surface area of 964.892 Å2 and a pocket volume of 900.792 Å3. For the top three allosteric pockets, the allostery probability was 52.44%, 46.30%, and 38.50%, respectively. The systems reached equilibrium in about 125 ns. From 0-100 ns, there was also significant structural instability. When compared to G1 and G2, the wildtype protein (G0) had overall high stability throughout the simulation. The root-mean-square fluctuation (RMSF) of wildtype and variant protein backbone Cα fluctuations revealed that the Cα of the variants had a large structural fluctuation when compared to the wildtype. CONCLUSION: Using a combination of different computational techniques, we identified binding sites within the APOL1 protein that could be an attractive site for potential inhibitors of APOL1. Furthermore, the G1 and G2 mutations reduced the structural stability of APOL1

Uganda Genome Resource : A rich research database for genomic studies of communicable and non-communicable diseases in Africa

Summary The Uganda Genome Resource (UGR) is a well-characterized genomic database with a range of phenotypic communicable and non-communicable diseases and risk factors generated from the Uganda General Population Cohort (GPC), a population-based open cohort established in 1989. The UGR comprises genotype data on ∼5,000 and whole-genome sequence data on ∼2,000 Ugandan GPC individuals from 10 ethno-linguistic groups. Leveraging other platforms at MRC/UVRI and LSHTM Uganda Research Unit, there is opportunity for additional sample collection to expand the UGR to advance scientific discoveries. Here, we describe UGR and highlight how it is providing opportunities for discovery of novel disease susceptibility genetic loci, refining association signals at new and existing loci, developing and testing polygenic scores to determine disease risk, assessing causal relations in diseases, and developing capacity for genomics research in Africa. The UGR has the potential to develop to a comparable level of European and Asian large-scale genomic initiatives

Strengthening Bioinformatics and Genomics Analysis Skills in Africa for Attainment of the Sustainable Development Goals Report of the 2nd Conference of the Nigerian Bioinformatics and Genomics Network

The second conference of the Nigerian Bioinformatics and Genomics Network (NBGN21) was held from October 11 to October 13, 2021. The event was organized by the Nigerian Bioinformatics and Genomics Network. A 1-day genomic analysis workshop on genome-wide association study and polygenic risk score analysis was organized as part of the conference. It was organized primarily as a research capacity building initiative to empower Nigerian researchers to take a leading role in this cutting-edge field of genomic data science. The theme of the conference was “Leveraging Bioinformatics and Genomics for the attainments of the Sustainable Development Goals.” The conference used a hybrid approach—virtual and in-person. It served as a platform to bring together 235 registered participants mainly from Nigeria and virtually, from all over the world. NBGN21 had four keynote speakers and four leading Nigerian scientists received awards for their contributions to genomics and bioinformatics development in Nigeria. A total of 100 travel fellowships were awarded to delegates within Nigeria. A major topic of discussion was the application of bioinformatics and genomics in the achievement of the Sustainable Development Goals (SDG3—Good Health and Well-Being, SDG4—Quality Education, and SDG 15—Life on Land [Biodiversity]). In closing, most of the NBGN21 conference participants were interviewed and interestingly they agreed that bioinformatics and genomic analysis of African genomes are vital in identifying population-specific genetic variants that confer susceptibility to different diseases that are endemic in Africa. The knowledge of this can empower African healthcare systems and governments for timely intervention, thereby enhancing good health and well-bein

Genome-wide association analysis of cystatin-C kidney function in continental Africa

BACKGROUND: Chronic kidney disease is becoming more prevalent in Africa, and its genetic determinants are poorly understood. Creatinine-based estimated glomerular filtration rate (eGFR) is commonly used to estimate kidney function, modelling the excretion of the endogenous biomarker (creatinine). However, eGFR based on creatinine has been shown to inadequately detect individuals with low kidney function in Sub-Saharan Africa, with eGFR based on cystatin-C (eGFRcys) exhibiting significantly superior performance. Therefore, we opted to conduct a GWAS for eGFRcys. METHODS: Using the Uganda Genomic Resource, we performed a genome-wide association study (GWAS) of eGFRcys in 5877 Ugandans and evaluated replication in independent studies. Subsequently, putative causal variants were screened through Bayesian fine-mapping. Functional annotation of the GWAS loci was performed using Functional Mapping and Annotation (FUMA). FINDINGS: Three independent lead single nucleotide polymorphisms (SNPs) (P-value 99%. The rs911119 SNP maps to the cystatin C gene and has been previously associated with eGFRcys among Europeans. With gene-set enrichment analyses of the olfactory receptor family 51 overlapping genes, we identified an association with the G-alpha-S signalling events. INTERPRETATION: Our study found two previously unreported associated SNPs for eGFRcys in continental Africans (rs59288815 and rs4277141) and validated a previously well-established SNP (rs911119) for eGFRcys. The identified gene-set enrichment for the G-protein signalling pathways relates to the capacity of the kidney to readily adapt to an ever-changing environment. Additional GWASs are required to represent the diverse regions in Africa. FUNDING: Wellcome (220740/Z/20/Z)

Noncommunicable Disease (NCD) strategic plans in low- and lower-middle income Sub-Saharan Africa: framing and policy response

Background Global efforts to address NCDs focus primarily on 4-by-4 interventions – interventions to prevent and treat four groups of conditions affecting mainly older adults (some cardiovascular disease and cancers, type 2 diabetes, chronic respiratory disease) and four associated risk factors (alcohol, tobacco, poor diets, and physical inactivity). However, the NCD burden in Sub-Saharan Africa (SSA) is composed of a more diverse set of conditions, driven by a more complex group of risks, and impacting all segments of the population. Objective To document the NCD priorities identified by NCD strategic plans, to characterize the proposed policy response, and to assess the alignment between the two. Methods Using a two-part conceptual framework, we undertook a descriptive study to characterize the framing and overall policy response of strategic plans from 24 low- and lower-middle-income countries across SSA. Results The national situation assessments that ground strategic plans emphasize a diversity of conditions that range in terms of severity and frequency. These assessments also highlight a wide diversity of factors that shape this burden. Most include discussions of a broad range of behavioral, structural, genetic, and infectious risk factors. Plans endorse a more narrow response to this diverse burden, with a focus on primary and secondary prevention that is generally convergent with the objectives established in global policy documents. Conclusions Broadly, we observe that plans developed by countries in SSA recognize the heterogeneity of the NCD burden in this region. However, they emphasize interventions that are consistent with global strategies focused on preventing a narrower set of cardiometabolic risk factors and their associated diseases. In comparison, relatively few countries detail plans to prevent, treat, and palliate the full scope of the needs they identify. There is a need for increased support for bottom-up planning efforts to address local priorities

Transferability of genetic risk scores in African populations

A new study reveals that polygenic scores for lipid traits derived from data of African American individuals have high predictive value in a South African Zulu cohort but are poor predictors in a cohort from Uganda, further highlighting the need to improve polygenic predictions in populations of African ancestries. The poor transferability of genetic risk scores (GRSs) derived from European ancestry data in diverse populations is a cause of concern. We set out to evaluate whether GRSs derived from data of African American individuals and multiancestry data perform better in sub-Saharan Africa (SSA) compared to European ancestry-derived scores. Using summary statistics from the Million Veteran Program (MVP), we showed that GRSs derived from data of African American individuals enhance polygenic prediction of lipid traits in SSA compared to European and multiancestry scores. However, our GRS prediction varied greatly within SSA between the South African Zulu (low-density lipoprotein cholesterol (LDL-C), R-2 = 8.14%) and Ugandan cohorts (LDL-C, R-2 = 0.026%). We postulate that differences in the genetic and environmental factors between these population groups might lead to the poor transferability of GRSs within SSA. More effort is required to optimize polygenic prediction in Africa

Transferability of genetic risk scores in African populations.

The poor transferability of genetic risk scores (GRSs) derived from European ancestry data in diverse populations is a cause of concern. We set out to evaluate whether GRSs derived from data of African American individuals and multiancestry data perform better in sub-Saharan Africa (SSA) compared to European ancestry-derived scores. Using summary statistics from the Million Veteran Program (MVP), we showed that GRSs derived from data of African American individuals enhance polygenic prediction of lipid traits in SSA compared to European and multiancestry scores. However, our GRS prediction varied greatly within SSA between the South African Zulu (low-density lipoprotein cholesterol (LDL-C), R2 = 8.14%) and Ugandan cohorts (LDL-C, R2 = 0.026%). We postulate that differences in the genetic and environmental factors between these population groups might lead to the poor transferability of GRSs within SSA. More effort is required to optimize polygenic prediction in Africa