Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

Delayed mucosal anti-viral responses despite robust peripheral inflammation in fatal COVID-19

Background While inflammatory and immune responses to SARS-CoV-2 infection in peripheral blood are extensively described, responses at the upper respiratory mucosal site of initial infection are relatively poorly defined. We sought to identify mucosal cytokine/chemokine signatures that distinguished COVID-19 severity categories, and relate these to disease progression and peripheral inflammation. Methods We measured 35 cytokines and chemokines in nasal samples from 274 patients hospitalised with COVID-19. Analysis considered the timing of sampling during disease, as either the early (0-5 days post-symptom onset) or late (6-20 days post-symptom onset). Results Patients that survived severe COVID-19 showed IFN-dominated mucosal immune responses (IFN-γ, CXCL10 and CXCL13) early in infection. These early mucosal responses were absent in patients that would progress to fatal disease despite equivalent SARS-CoV-2 viral load. Mucosal inflammation in later disease was dominated by IL-2, IL-10, IFN-γ, and IL-12p70, which scaled with severity but did not differentiate patients who would survive or succumb to disease. Cytokines and chemokines in the mucosa showed distinctions from responses evident in the peripheral blood, particularly during fatal disease. Conclusions Defective early mucosal anti-viral responses anticipate fatal COVID-19 but are not associated with viral load. Early mucosal immune responses may define the trajectory of severe COVID-19

Predictive utility of a genetic risk score of common variants associated with type 2 diabetes in a black South African population

Aims To determine the predictive utility of polygenic risk scores of common variants associated with type 2 diabetes derived from the European and Asian ethnicities among a black South African population. Method Our study was a case-control study nested within the Prospective Urban and Rural Epidemiological (PURE) study of 178 male and female cases, matched for age and gender with 178 controls. Four types of genetic risk scores (GRS) were developed from 66 selected SNPs. These comprised of beta cell related variants (GRSb), variants which had significant associations with T2D in our study (GRSn), variants from the trans-ethnic meta-analysis (GRStrans) and all the 66 selected SNPs (GRSt). Results Of the GRS’s, only GRSn was associated with increased risk of T2D as indicated by an OR (95CI) of 1.21 (1.02–1.43) p-value = 0.015. Stratified analysis of age and BMI, indicated the GRSn to be significantly associated with T2D among the non-obese and participants less than 50 years. The area under the ROC of the T2D risk factors only was 0.652 (p value < 0.001) and with the addition of GRSn it was 0.665 (p value < 0.001). Conclusions The GRS of European and Asian derived variants have limited clinical utility in the black South African population. The inclusion of population specific variants in the GRS is pivotal

A Linear Programming Model for Blending

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Leveraging information between multiple population groups and traits improves fine-mapping resolution

Statistical fine-mapping helps to pinpoint likely causal variants underlying genetic association signals. Its resolution can be improved by (i) leveraging information between traits; and (ii) exploiting differences in linkage disequilibrium structure between diverse population groups. Using association summary statistics, MGflashfm jointly fine-maps signals from multiple traits and population groups; MGfm uses an analogous framework to analyse each trait separately. We also provide a practical approach to fine-mapping with out-of-sample reference panels. In simulation studies we show that MGflashfm and MGfm are well-calibrated and that the mean proportion of causal variants with PP > 0.80 is above 0.75 (MGflashfm) and 0.70 (MGfm). In our analysis of four lipids traits across five population groups, MGflashfm gives a median 99% credible set reduction of 10.5% over MGfm. MGflashfm and MGfm only require summary level data, making them very useful fine-mapping tools in consortia efforts where individual-level data cannot be shared

Nutrient Patterns Associated with Fasting Glucose and Glycated Haemoglobin Levels in a Black South African Population

Type 2 diabetes (T2D) burden is increasing globally. However, evidence regarding nutrient patterns associated with the biomarkers of T2D is limited. This study set out to determine the nutrient patterns associated with fasting glucose and glycated haemoglobin the biomarkers of T2D. Factor analysis was used to derive nutrient patterns of 2010 participants stratified by urban/rural status and gender. Principal Component Analysis (PCA) was applied to 25 nutrients, computed from the quantified food frequency questionnaires (QFFQ). Three nutrient patterns per stratum, which accounted for 73% of the variation of the selected nutrients, were identified. Multivariate linear regression models adjusted for age, BMI, smoking, physical activity, education attained, alcohol intake, seasonality and total energy intake were computed. Starch, dietary fibre and B vitamins driven nutrient pattern was significantly associated with fasting glucose (β = −0.236 (−0.458; −0.014); p = 0.037) and glycated haemoglobin levels (β = −0.175 (−0.303; −0.047); p = 0.007) in rural women. Thiamine, zinc and plant protein driven nutrient pattern was associated with significant reductions in glycated haemoglobin and fasting glucose ((β = −0.288 (−0.543; −0.033); p = 0.027) and (β = −0.382 (−0.752; −0.012); p = 0.043), respectively) in rural men. Our results indicate that plant driven nutrient patterns are associated with low fasting glucose and glycated haemoglobin levels

Sex Differences in the Associations of Nutrient Patterns with Total and Regional Adiposity: A Study of Middle-Aged Black South African Men and Women

The study evaluated the association between nutrient patterns with body fat and regional adiposity in middle-aged black South African (SA) men and women and determined if this differed by sex. Body fat and regional adiposity (dual-energy x-ray absorptiometry), and dietary intake (7-day quantified food frequency questionnaire) were measured in black SA men (n = 414) and women (n = 346). Using principal component analysis, nutrient patterns were computed from 25 nutrients in the combined sample. Four nutrient patterns were extracted, explaining 67% of the variance in nutrient intake. Animal and fat, as well as the vitamin C, sugar, and potassium driven patterns, were positively associated with total adiposity. In contrast, the retinol and vitamin B12 pattern was associated with the centralisation of fat. Notably, the strength of the association between the animal-driven nutrient pattern and BMI was greater in men (1.14 kg/m2, 95% CI (0.63&ndash;1.66)) than in women (0.81 kg/m2, 95% CI (0.25&ndash;1.36)) (Pint = 0.017). In contrast, the plant-driven pattern was associated with higher abdominal subcutaneous adipose tissue (SAT) in women (44 cm2, 95% CI (22&ndash;67)) but not men (Pint = 1.54 &times; 10&minus;4). These differences suggest that although men and women have similar nutrient patterns, their associations with the whole body and regional body fat are different