A5056550697- Diabetes and associated disorders
- Pancreatic function and diabetes
- Genetic Associations and Epidemiology
- Diabetes Management and Research
- T-cell and B-cell Immunology
- HIV Research and Treatment
- HIV/AIDS Research and Interventions
- HIV-related health complications and treatments
- Immune Cell Function and Interaction
- HIV/AIDS drug development and treatment
- Diet, Metabolism, and Disease
- Liver Disease Diagnosis and Treatment
- RNA modifications and cancer
- Viral gastroenteritis research and epidemiology
- Genetic Mapping and Diversity in Plants and Animals
- Hepatitis C virus research
- Molecular Biology Techniques and Applications
- Respiratory viral infections research
- Celiac Disease Research and Management
- Immunodeficiency and Autoimmune Disorders
- Pharmacological Effects and Toxicity Studies
- Rheumatoid Arthritis Research and Therapies
- Cytomegalovirus and herpesvirus research
- Hepatitis B Virus Studies
- Galectins and Cancer Biology
University of Oxford
2017-2025
Centre for Human Genetics
2017-2022
MRC Clinical Trials Unit at UCL
2013-2018
Medical Research Council
2016
University College London
2014-2016
OBJECTIVE Immunohistological analyses of pancreata from patients with type 1 diabetes suggest distinct autoimmune islet β-cell pathology between those diagnosed at <7 years (<7 group) and age ≥13 (≥13 group), both B- T-lymphocyte inflammation common in children the group, whereas B cells are rare group. Based on these observations, we sought to identify differences genetic susceptibility prespecified age-at-diagnosis groups inform etiology most aggressive form that initiates...
Given the potential shared aetiology between type 1 and 2 diabetes, we aimed to identify any genetic regions associated with both diseases. For associations where there is a signal allele that increases risk one disease also other, inference about could be made, develop therapeutic strategies treat or prevent diseases simultaneously. Alternatively, if co-localises divergent effect directions, it provide valuable biological insight into how association affects two differently.
C-peptide declines in type 1 diabetes, although many long-duration patients retain low, but detectable levels. Histological analyses confirm that β-cells can remain following diabetes onset. We explored the trends observed decline UK Genetic Resource Investigating Diabetes (UK GRID) cohort (N = 4,079), with β-cell loss pancreas donors from network for Pancreatic Organ (nPOD) biobank and Exeter Archival Biobank (EADB) (combined N 235), stratified by recently reported age at diagnosis...
Introduction Despite normalization of total CD4 counts, ongoing immune dysfunction is noted amongst those on antiretroviral therapy (ART). Low CD4/CD8 ratio associated with a high risk AIDS and non‐AIDS events may act as marker senescence [ 1 ]. This improved by ART although uncommon (~7%) 2 The probability count immediate initiation in primary HIV infection (PHI) 3 We examined whether similarly normalized vs. deferred at PHI. Material Methods Using data from the SPARTAC trial UK Register...
Total CD4 T-cell counts predict HIV disease progression but do not necessarily reflect normalization of immune function. CD4/CD8 ratio is a marker dysfunction, prognostic indicator for non-AIDS mortality, and reflects viral reservoir size. Despite antiretroviral therapy (ART), recovery in chronic infection incomplete; we hypothesize enhanced with earlier treatment initiation recently infected individuals.CD4 count were analyzed using data from 2 cohorts: SPARTAC trial the UK Seroconverters...
Biological datasets often consist of thousands or millions variables, e.g. genetic variants biomarkers, and when sample sizes are large it is common to find many associated with an outcome interest, for example, disease risk in a GWAS, at high levels statistical significance, but very small effects. The False Discovery Rate (FDR) used identify effects interest based on ranking variables according their significance. Here, we develop complementary measure the FDR, priorityFDR, that ranks by...
The genetic risk of type 1 diabetes has been extensively studied. However, the determinants age at diagnosis (AAD) remain relatively unexplained. Identification AAD genes and pathways could provide insight into earliest events in disease process.Using ImmunoChip data from 15,696 cases, we aimed to identify regions genome associated with AAD.Two were convincingly (p < 5 × 10-8): MHC on 6p21, 6q22.33. Fine-mapping 6q22.33 identified two AAD-associated haplotypes region nearest encoding protein...
Abstract We report the largest and most ancestrally diverse genetic study of type 1 diabetes (T1D) to date (61,427 participants), yielding 152 regions associated false discovery rate < 0.01, including 36 genome-wide significance for first time. Credible sets disease-associated variants are specifically enriched in immune cell accessible chromatin, particularly CD4 + effector T cells. Colocalization with chromatin accessibility quantitative trait loci (QTL) cells identified five where...
Transcriptome imputation has become a popular method for integrating genotype data with publicly available expression to investigate the potentially causal role of genes in complex traits. Here, we compare three approaches (PrediXcan, MetaXcan and FUSION) via application genome-wide association study (GWAS) Crohn's disease type 1 diabetes from Wellcome Trust Case Control Consortium. We investigate: (i) how results each approach other those standard GWAS analysis; (ii) variants models used by...
For human immunodeficiency virus (HIV)-infected adolescents facing lifelong antiretroviral therapy (ART), short-cycle (SCT) with long-acting agents offers the potential for drug-free weekends, less toxicity, better adherence and cost savings. To determine whether or not efavirenz (EFV)-based ART in short cycles of 5 days on 2 off is as efficacious (in maintaining virological suppression) continuous EFV-based (continuous therapy; CT). Secondary objectives included occurrence new clinical HIV...
Defective alleles within the PRF1 gene, encoding pore-forming protein perforin, in combination with environmental factors, cause familial type 2 hemophagocytic lymphohistiocytosis (FHL2), a rare, severe autosomal recessive childhood disorder characterized by massive release of cytokines-cytokine storm.The aim this study was to determine function hypomorph PRF1:p.A91V g.72360387 G > A on multiple sclerosis (MS) and 1 diabetes (T1D).We cross-compare association data for mutation derived from...
Abstract For polygenic traits, associations with genetic variants can be detected over many chromosome regions, owing to the availability oflarge sample sizes. Most variants, however, have small effects on disease risk and, therefore, unravelling causal target genes, and biology of these is challenging. Here, we define Bigger or False Discovery Rate (BFDR) as probability that either a variant false-positive randomly drawn, true-positive association exceeds it in effect size. Using BFDR,...
ABSTRACT Genome-wide association studies (GWAS) have identified over 150,000 links between common genetic variants and human traits or complex diseases. Over 80% of these associations map to polymorphisms in non-coding DNA. Therefore, the challenge is identify disease-causing variants, genes they affect, cells which effects occur. We developed a platform using ATAC-seq, DNaseI footprints, NG Capture-C machine learning address this challenge. Applying approach red blood cell identifies...
There are few data on the frequency of virological remission in African individuals after treatment with antiretroviral therapy (ART) primary HIV infection (PHI).
Lopinavir/ritonavir (LPV/r) pediatric tablets (100/25 mg) are approved by the United States Food and Drug Administration (FDA) European Medicines Agency (EMA) as part of combination antiretroviral therapy. Dosing is based on body weight bands or surface area under FDA approval only EMA. This can lead to a different recommended dose. In addition, band-based dosing has not been formally studied in target population. We evaluated pharmacokinetics (PK) LPV/r children, administered twice daily...
Introduction The effect of HCV infection on HIV disease progression remains unclear; the duration is unknown. Methods We used data from a cohort seroconverters to investigate time seroconversion CD4 <350cells/mm3, AIDS or death, censoring at earlier cART initiation last clinic visit, adjusting for confounders and splitting into follow up periods (<2, 2–4 >4 years). additionally compared cell decline following that mono-infected individuals with similar by fitting random effects model. In...
Abstract We recently mapped a genetic susceptibility locus on chromosome 6q22.33 for type 1 diabetes (T1D) diagnosed below the age of 7 years between PTPRK and thymocyte-selection-associated ( THEMIS) genes. As thymus plays central role in shaping T cell repertoire, we aimed to identify most likely causal factors behind this association using thymocyte genomic data. In four populations, identified 253 DNA sequence motifs underlying histone modifications. The G insertion allele rs138300818,...
Abstract Background The rising prevalence of childhood obesity has been postulated as an explanation for the increasing rate individuals diagnosed with type 1 diabetes (T1D). However, robust causal evidence supporting this claim extremely challenging to uncover, particularly given typical early onset T1D. Methods In study, we used genetic variation separate direct effect body size on T1D risk from effects at different stages in life course using univariable and multivariable Mendelian...
Abstract Aims/hypothesis Given the potential shared aetiology between type 1 and 2 diabetes, we aimed to identify any genetic regions associated with both diseases. For associations where there is a signal allele that increases risk one disease also other, inference about could be made, develop therapeutic strategies treat or prevent diseases simultaneously. Alternatively, if colocalises divergent effect directions, it provide valuable biological insight into how association affects two...