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In sub-Saharan Africa, Kaposi's sarcoma-associated herpesvirus (KSHV) is endemic, and Kaposi's sarcoma (KS) is a significant public health problem. Until recently, KSHV genotype analysis was performed using variable gene regions, representing a small fraction of the genome, and thus the contribution of sequence variation to viral transmission or pathogenesis are understudied. We performed near full-length KSHV genome sequence analysis on samples from 43 individuals selected from a large Cameroonian KS case-control study. KSHV genomes were obtained from 21 KS patients and 22 control participants. Phylogenetic analysis of the K1 region indicated the majority of sequences were A5 or B1 subtypes and all three K15 alleles were represented. Unique polymorphisms in the KSHV genome were observed including large gene deletions. We found evidence of multiple distinct KSHV genotypes in three individuals. Additionally, our analyses indicate that recombination is prevalent suggesting that multiple KSHV infections may not be uncommon overall. Most importantly, a detailed analysis of KSHV genomes from KS patients and control participants did not find a correlation between viral sequence variations and disease. Our study is the first to systematically compare near full-length KSHV genome sequences between KS cases and controls in the same endemic region to identify possible sequence variations associated with disease risk.

Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targets) consortium aims to identify the genomic and molecular basis of heart failure.Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of >1.10 for common variants (allele frequency > 0.05) and >1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 x 10(-8) under an additive genetic model.Conclusions HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.

BackgroundType 2 diabetes is highly prevalent in British Pakistanis and Bangladeshis (BPB). The Genes & Health (G&H) cohort offers means to explore genetic determinants of disease in BPBs.MethodsWe assessed whether common genetic loci associated with type 2 diabetes in European-ancestry individuals (EUR) replicate in G&H. We constructed a type 2 diabetes polygenic risk score (PRS) and combined it with a clinical risk instrument (QDiabetes) to build a novel, integrated risk tool (IRT). We compared IRT performance using net reclassification index (NRI) versus QDiabetes alone.We compared PRS distribution between type 2 diabetes subgroups identified by clinical features at diagnosis.FindingsWe replicated fewer loci in G&H (n = 76/338, 22%) than would be expected given power if all EUR-ascertained loci were transferable (n = 95, 28%) (p-value = 0.01). In 13,648 patients free from type 2 diabetes followed up for 10 years, NRI was 3.2% for IRT versus QDiabetes (95% confidence interval 2.0 - 4.4%). IRT performed best in reclassification of young adults deemed low risk by QDiabetes as high risk. PRS was independently associated with progression to type 2 diabetes after gestational diabetes (p = 0.028). Mean type 2 diabetes PRS differed between phenotypically-defined type 2 diabetes subgroups (p = 0.002).InterpretationThe type 2 diabetes PRS has broad potential clinical application in BPB, improving identification of type 2 diabetes risk (especially in the young), and characterisation of subgroups at diagnosis.FundingWellcome Trust, MRC, NIHR, and others.Research in ContextEvidence before this studyPeople of south Asian origin are disproportionately affected by type 2 diabetes, yet are underrepresented in genetic studies assessing its causation. To date, there have been no published studies that systematically assess how type 2 diabetes genetic risk loci identified in European individuals can be transferred into south Asians, taking into account power and differences in linkage disequilibrium, nor has the clinical utility of a type 2 diabetes polygenic risk score (PRS) been evaluated in this ethnic group. For coronary artery disease, integration of PRS with clinical risk tools has been shown to enhance the prediction of incident disease, in multiple ancestral groups. For type 2 diabetes, whilst it is known from multiple studies of Europeans that PRS can enhance prediction of incident disease, no study has examined PRS performance when integrated with an existing clinical risk tool, although it has potentially significant clinical impact. The identification of type 2 diabetes subgroups at disease presentation has now been studied extensively, but the influence of polygenic risk in characterising these subgroups has not been tested. We examined prior evidence using multiple updated searches across MEDLINE, CINAHL, EMBASE, MEDRXIV and BIORXIV on 29/6/2021 with terms including “type 2 diabetes” and “polygenic risk scor$,” “genetic risk scor$”, “subgroup”, and “cluster” did not identify similar published work.Added value of this studyIn the first study to systematically assess the transferability of genetic loci associated with type 2 diabetes in European ancestry individuals into a British Pakistanis and Bangladeshis (BPBs), we find fewer transferable loci than would be expected, accounting for power. We also construct a type 2 diabetes PRS for BPBs and show that its integration with QDiabetes enhances 10-year prediction of incident type 2 diabetes, especially in individuals aged less than 40 years deemed low risk by QDiabetes alone, who tended to be free from comorbidities, and relatively slim. Additionally, we find the PRS is independently associated with progression from gestational diabetes mellitus to type 2 diabetes in BPBs, replicating previous findings in European individuals. We replicate previously-reported subgroups of type 2 diabetes in BPBs, including Mild Age-Related Diabetes, Mild Obesity-Related Diabetes, and Insulin-Resistant Diabetes, and show that PRS distribution differs between clinically-defined clusters. In a novel clustering approach integrating PRS with clinical features, we identify a previously unreported subgroup we name “Clinically Undifferentiated High Polygenic Susceptibility Diabetes”, and observe differences in rates of progression to micro- and macrovascular complications between subgroups.Implications of all the available evidenceA single, low-cost genotyping array can now determine the polygenic risk of multiple diseases in parallel at any point in the life course. We build on existing genomic resources to build a type 2 diabetes PRS that can be used to predict incident disease in a specific ancestral group that is disproportionately affected by the condition. We show that a PRS, when integrated with an established and well-validated clinical risk algorithm, has significant potential clinical utility as both a means to better estimate individual disease risk, and to elucidate the influence of genetics on disease subgroups to aid future efforts to stratify care and treatment of the disease.

BackgroundIndividuals with South Asian ancestry have higher risk of heart disease than other groups in Western countries; however, most genetic research has focused on European-ancestry (EUR) individuals. It is unknown whether reported genetic loci and polygenic scores (PGSs) for cardiometabolic traits are transferable to South Asians, and whether PGSs have utility in clinical settings.MethodsUsing data from 22,000 British Pakistani and Bangladeshi individuals with linked electronic health records from the Genes & Health cohort (G&H), we conducted genome-wide association studies (GWAS) and characterised the genetic architecture of coronary artery disease (CAD), body mass index (BMI), lipid biomarkers and blood pressure. We applied a new technique to assess the extent to which loci from GWAS in EUR samples were transferable. We tested how well existing findings from EUR studies performed in genetic risk prediction and Mendelian randomisation in G&H.ResultsTrans-ancestry genetic correlations between G&H and EUR samples for the tested traits were not significantly lower than 1, except for BMI (rg=0.85, p=0.02). We found evidence for transferability for the vast majority of loci from EUR discovery studies that were sufficiently powered to replicate in G&H. PGSs showed variable transferability in G&H, with the relative accuracy compared to EUR (ratio of incremental r2/AUC) ≥0.95 for HDL-C, triglycerides, and blood pressure, but lower for BMI (0.78) and CAD (0.42). We observed significant improvement in categorical net reclassification in G&H (NRI=3.9%; 95% CI 0.9–7.0) when adding a previously developed CAD PGS to clinical risk factors (QRISK3). We used transferable loci as genetic instruments in trans-ancestry Mendelian randomisation and found evidence of an increased CAD risk for higher LDL-C and BMI, and for lower HDL-C in G&H, consistent with our findings for EUR samples.ConclusionsThe genetic loci for CAD and its risk factors are largely transferable from EUR studies to British Pakistanis and Bangladeshis, whereas the transferability of PGSs varies greatly between traits. Our analyses suggest clinical utility for addition of PGS to existing clinical risk prediction tools for this population.Clinical PerspectiveWhat is new?This is the first study to explore the transferability of GWAS findings and PGSs for CAD and related cardiometabolic traits in British Pakistani and Bangladeshi individuals from a cohort with real-world electronic clinical data.We propose a new approach to assessing transferability of GWAS loci between populations, which can serve as a new methodological standard in this developing field.We find evidence of overall high transferability of GWAS loci in British Pakistanis and Bangladeshis. BMI, lipids and blood pressure show the highest transferability of loci, and CAD the lowest.The transferability of PGSs varied between traits, being high for HDL-C, triglycerides and blood pressure but more modest for CAD, BMI and LDL-C.Our results suggest that, for some traits, the use of transferable GWAS loci improves the robustness of Mendelian randomisation estimates in non-Europeans.What are the clinical implications?The polygenic score for CAD derived from genetic studies of European individuals improves reclassification on top of clinical risk factors in British Pakistanis and Bangladeshis. The improvement was driven by identification of more cases in younger individuals (25–54 years old), and of controls in older individuals (55–84 years old).Incorporation of the polygenic score for CAD into risk prediction models is likely to prevent cardiovascular events and deaths in this population.

BackgroundHelicobacter pylori (H. pylori) establishes life-long infection in humans in the absence of treatment and has been associated with a variety of gastrointestinal conditions including peptic ulcer and gastric cancer. Antibody responses to H. pylori antigens are found to be associated with disease risk, however, data from Africa are scarce.MethodsTo assess the seroprevalence of H. pylori and characterise antibody response patterns, we measured serum IgG antibody levels to 14 antigens among 7,211 individuals in a rural Ugandan population cohort. Multivariate-adjusted linear regression models were fitted to investigate the influence of age, sex, and co-infection on antibody seroreactivity levels.ResultsH. pylori seroprevalence was 95% in our study population, with 94% of individuals seropositive in childhood (H. pylori positive individuals, we found a markedly high seroprevalence (~99%) and antibody levels to the high-risk antigens CagA and VacA, in addition to Cagδ. HSV-2 co-infection was significantly associated with higher IgG levels of CagA and VacA (OR=1.10, 95% C. I=1.05-1.16). HIV infection was associated with lowered IgG levels to CagA (OR=0.86, 95% C.I.=0.80-0.93), and HPV infection was associated with increased IgG levels to VacA (OR=1.16, 95% C.I.=1.11-1.21).ConclusionsH. pylori in this population is ubiquitous from childhood, with a high prevalence and high seroreactivity levels of high-risk antigens, suggesting chronic active inflammatory responses in individuals that are indicative of risk of disease. Further investigation is warranted to fully understand the relationship between host, immunogenicity, and clinical outcomes to better stratify by risk and improve treatment.Key MessagesAntibody responses to H. pylori antigens are found to be associated with risk of gastric cancer, however, despite the high seroprevalence in African populations, data from Africa are scarce. This is the first study of antibody response patterns and their determinants from an African population.Our study shows a population where H. pylori is ubiquitous from childhood, and seroprevalence of virulent antigens is distinctively high suggesting an increased of disease compared to other populations.We observe inter-individual variation in virulent antibody responses partly influenced by co-infection.We highlight crucial insights into antibody-based biomarkers of disease risk and reinforce the need for population-based H. pylori screening and treatment programmes for gastric cancer control.

Kawasaki disease (KD) is a paediatric vasculitis associated with coronary artery aneurysms (CAA). Genetic variants influencing susceptibility to KD have been previously identified, but no risk alleles have been validated that influence CAA formation. We conducted a genome-wide association study (GWAS) for CAA in KD patients of European descent with 200 cases and 276 controls. A second GWAS for susceptibility pooled KD cases with healthy paediatric controls from vaccine trials in the UK (n = 1609). Logistic regression mixed models were used for both GWASs. The susceptibility GWAS was meta-analysed with 400 KD cases and 6101 controls from a previous European GWAS, these results were further meta-analysed with Japanese GWASs at two putative loci. The CAA GWAS identified an intergenic region of chromosome 20q13 with multiple SNVs showing genome-wide significance. The risk allele of the most associated SNV (rs6017006) was present in 13% of cases and 4% of controls; in East Asian 1000 Genomes data, the allele was absent or rare. Susceptibility GWAS with meta-analysis with previously published European data identified two previously associated loci (ITPKC and FCGR2A). Further meta-analysis with Japanese GWAS summary data from the CASP3 and FAM167A genomic regions validated these loci in Europeans showing consistent effects of the top SNVs in both populations. We identified a novel locus for CAA in KD patients of European descent. The results suggest that different genes determine susceptibility to KD and development of CAA and future work should focus on the function of the intergenic region on chromosome 20q13.

Neisseria meningitidis, the causative agent of meningococcal disease (MD), evades complement-mediated clearance upon infection by ‘hijacking’ the human complement regulator factor H (FH). The FH protein family also comprises the homologous FH-related (FHR) proteins, hypothesized to act as antagonists of FH, and FHR-3 has recently been implicated to play a major role in MD susceptibility. Here, we show that, next to FH and FHR-3, the circulating levels of all FH family proteins are equally decreased during pediatric MD. We did not observe a specific consumption of FH or FHR-3 by N. meningitidis during the first days of infection and the levels recovered over time. MD severity associated predominantly with a loss of FH. Strikingly, loss of FH and FHRs associated strongly with renal failure, suggesting insufficient protection of host tissue by the FH protein family. Retaining higher levels of FH family proteins may thus limit tissue injury during MD.

Kaposi’s sarcoma-associated herpesvirus (KSHV) and Epstein-Barr Virus (EBV) establish life-long infections and are associated with malignancies. Striking geographic variation in incidence and the fact that virus alone is insufficient to cause disease, suggests other co-factors are involved. Here we present epidemiological analysis and genome-wide association study (GWAS) in 4365 individuals from an African population cohort, to assess the influence of host genetic and non-genetic factors on virus antibody responses. EBV/KSHV co-infection (OR = 5.71(1.58–7.12)), HIV positivity (OR = 2.22(1.32–3.73)) and living in a more rural area (OR = 1.38(1.01–1.89)) are strongly associated with immunogenicity. GWAS reveals associations with KSHV antibody response in the HLA-B/C region (p = 6.64 × 10−09). For EBV, associations are identified for VCA (rs71542439, p = 1.15 × 10−12). Human leucocyte antigen (HLA) and trans-ancestry fine-mapping substantiate that distinct variants in HLA-DQA1 (p = 5.24 × 10−44) are driving associations for EBNA-1 in Africa. This study highlights complex interactions between KSHV and EBV, in addition to distinct genetic architectures resulting in important differences in pathogenesis and transmission., Disease prognosis after infection with Kaposi’s sarcoma-associated herpesvirus and Epstein-Barr Virus is highly variable. Here the authors carry out epidemiological and genetic analysis of a Ugandan cohort and suggest complex interactions may influence pathogenesis and transmission.

This study presents 45 new KSHV genomes sequenced from Uganda, a KSHV endemic region. We present new evidence for the presence of inter- and intragenic recombination across genomes contributing to the diversification of KSHV strains into at least 5 types., Background Kaposi sarcoma-associated herpesvirus (KSHV) establishes lifelong infection in the human host and has been associated with a variety of malignancies. KSHV displays striking geographic variation in prevalence, which is highest in sub-Saharan Africa. The current KSHV genome sequences available are all tumor cell line-derived or primary tumor-associated viruses, which have provided valuable insights into KSHV genetic diversity. Methods Here, we sequenced 45 KSHV genomes from a Ugandan population cohort in which KSHV is endemic; these are the only genome sequences obtained from nondiseased individuals and of KSHV DNA isolated from saliva. Results Population structure analysis, along with the 25 published genome sequences from other parts of the world, showed whole-genome variation, separating sequences and variation within the central genome contributing to clustering of genomes by geography. We reveal new evidence for the presence of intragenic recombination and multiple recombination events contributing to the divergence of genomes into at least 5 distinct types. Discussion This study shows that large-scale genome-wide sequencing from clinical and epidemiological samples is necessary to capture the full extent of genetic diversity of KSHV, including recombination, and provides evidence to suggest a revision of KSHV genotype nomenclature.

Epstein Barr virus (EBV) infects 95% of the global population and is associated with up to 2% of cancers globally. Immunoglobulin G (IgG) antibody levels to EBV have been shown to be heritable and associated with developing malignancies. We, therefore, performed a pilot genome-wide association analysis of anti-EBV IgG traits in an African population, using a combined approach including array genotyping, whole-genome sequencing and imputation to a panel with African sequence data. In 1562 Ugandans, we identify a variant in human leukocyte antigen (HLA)-DQA1, rs9272371 (p = 2.6 × 10−17) associated with anti-EBV nuclear antigen-1 responses. Trans-ancestry meta-analysis and fine-mapping with European-ancestry individuals suggest the presence of distinct HLA class II variants driving associations in Uganda. In addition, we identify four putative, novel, very rare African-specific loci with preliminary evidence for association with anti-viral capsid antigen IgG responses which will require replication for validation. These findings reinforce the need for the expansion of such studies in African populations with relevant datasets to capture genetic diversity.

Rotavirus is the leading cause of diarrhea in children5 years of age. In light of the implementation of rotavirus vaccines of limited valency, it is important to characterize the genotypic diversity of circulating rotavirus in sub-Saharan Africa.We collected stool samples from children 0-59 months of age who presented at the health centres as cases with moderate-to-severe diarrhea in the Upper River Region of The Gambia. Stool samples were also collected from age, sex and area-matched healthy controls. All stool samples were assayed for rotavirus antigens by enzyme-linked immunosorbent assay and genotyping was done using reverse transcriptase polymerase chain reaction.We enrolled 1029 cases and 1569 controls during the 3-year study period (2008-2010). The detection rate of rotavirus among the cases was 20% (204/1029) and 3% (42/1569) among controls. At least 18 genotypes were found and the predominant genotypes were G2P[6] (28%), G1P[8] (26%) and G1P[10] (10%). The rare identified genotypes (1%) were G2P[14], G8P[6], G9P[6] and G4P[10]. There was also a strong positive association between rotavirus infection and the dry season (odds ratio: 9.83, 95% confidence interval: 6.18-15.63, P0.001). A significant increase in the odds of rotavirus and G1P[8] detection with the use of untreated water and the presence of cats, rodents and cows in the child's residence was also found.This study provides important baseline data for the genotypes circulating before vaccine implementation. The wide diversity of genotypes circulating in The Gambia implies the need for vigilant effectiveness surveillance following the implementation of RotaTeq in August 2013.

In West Africa, Mycobacterium tuberculosis strains co-circulate with M. africanum, and both pathogens cause pulmonary tuberculosis in humans. Given recent findings that M. tuberculosis T-cell epitopes are hyperconserved, we hypothesized that more immunogenic strains have increased capacity to spread within the human host population. We investigated the relationship between the composition of the mycobacterial population in The Gambia, as measured by spoligotype analysis, and the immunogenicity of these strains as measured by purified protein derivative-induced interferon-γ release in ELISPOT assays of peripheral blood mononuclear cells. We found a positive correlation between strains with superior spreading capacity and their relative immunogenicity. Although our observation is true for M. tuberculosis and M. africanum strains, the association was especially pronounced in 1 M. africanum sublineage, characterized by spoligotype shared international type 181, which is responsible for 20% of all tuberculosis cases in the region and therefore poses a major public health threat in The Gambia.

Background Chrysomya spp are common blowflies in Africa, Asia and parts of South America and some species can reproduce in prodigious numbers in pit latrines. Because of their strong association with human feces and their synanthropic nature, we examined whether these flies are likely to be vectors of diarrheal pathogens. Methodology/Principal Findings Flies were sampled using exit traps placed over the drop holes of latrines in Gambian villages. Odor-baited fly traps were used to determine the relative attractiveness of different breeding and feeding media. The presence of bacteria on flies was confirmed by culture and bacterial DNA identified using PCR. A median of 7.00 flies/latrine/day (IQR = 0.0–25.25) was collected, of which 95% were Chrysomya spp, and of these nearly all were Chrysomya putoria (99%). More flies were collected from traps with feces from young children (median = 3.0, IQR = 1.75–10.75) and dogs (median = 1.50, IQR = 0.0–13.25) than from herbivores (median = 0.0, IQR = 0.0–0.0; goat, horse, cow and calf; p, Author Summary While it is well recognized that the house fly can transmit enteric pathogens, here we show the common African latrine fly, Chrysomya putoria, is likely to be an important vector of these pathogens, since an average latrine can produce 100,000 latrine flies each year. Our behavioral studies of flies in The Gambia show that latrine flies are attracted strongly to human feces, raw beef and fish, providing a clear mechanism for faecal pathogens to be transferred from faeces to food. We used PCR techniques to demonstrate that these flies are carrying Shigella, Salmonella and E. coli, all important causes of diarrhea. Moreover our culture work shows that these pathogens are viable. Latrine flies are likely to be important vectors of diarrheal disease, although further research is required to determine what proportion of infections are due to this fly.