A5073926232- Genetic Associations and Epidemiology
- Metabolism, Diabetes, and Cancer
- Nutrition and Health in Aging
- GDF15 and Related Biomarkers
- COVID-19 Clinical Research Studies
- Diabetes and associated disorders
- Congenital Heart Disease Studies
- Adipose Tissue and Metabolism
- Hyperglycemia and glycemic control in critically ill and hospitalized patients
- Congenital Diaphragmatic Hernia Studies
- Cholesterol and Lipid Metabolism
- Diabetes Treatment and Management
- Macrophage Migration Inhibitory Factor
- Gene expression and cancer classification
- Diabetes Management and Research
- Chronic Disease Management Strategies
- Complement system in diseases
- Lipid metabolism and biosynthesis
- SARS-CoV-2 and COVID-19 Research
- Cancer, Lipids, and Metabolism
- Regulation of Appetite and Obesity
- Genetics, Bioinformatics, and Biomedical Research
- Cancer, Hypoxia, and Metabolism
- Diabetes Management and Education
- RNA modifications and cancer
Wellcome/MRC Institute of Metabolic Science
2019-2025
University of Cambridge
2019-2025
Queen's University Belfast
2015-2025
Medical Research Council
2019-2024
Addenbrooke's Hospital
2021-2024
Cambridge University Hospitals NHS Foundation Trust
2021-2024
Wellcome Trust
2019-2024
University of Graz
2024
MRC Epidemiology Unit
2022-2023
Harvard University
2016-2022
GDF15, a hormone acting on the brainstem, has been implicated in nausea and vomiting of pregnancy, including its most severe form, hyperemesis gravidarum (HG), but full mechanistic understanding is lacking
Significance Circulating hormones must cross the vascular endothelium to elicit their actions in target tissues via either transcytosis or paracellular diffusion. Insulin receptors on endothelial cells are believed mediate of circulating insulin, but how this affects insulin action vivo is unknown. Here, we demonstrate that knockout delays kinetics activation signaling skeletal muscle, fat, and several regions brain not liver olfactory bulb. This alters induces tissue-specific resistance...
Significance GDF15, a hormone produced by wide variety of cells undergoing different types stress, acts on receptor in the brain where it transmits signals that are perceived organism as aversive. We now report an action whereby activates endocrine stress response and increases circulating levels principal glucocorticoid (a “stress” steroid). By studying mice genetically deficient we also demonstrate GDF15 is key signal through which damage due to toxic chemicals steroid response. currently...
Background: Statins lower low-density lipoprotein cholesterol (LDL-C) and reduce the risk of coronary artery disease (CAD). However, they also increase type 2 diabetes (T2D). Methods: We consider genetic variants in region HMGCR gene, which encodes target statins, their associations with downstream consequences statins. use various statistical methods to identify causal pathways influencing CAD T2D, investigate whether these are same or different for two diseases. Results: Colocalization...
Type 2 diabetes (T2D) is a heritable metabolic disorder. While population studies have identified hundreds of common genetic variants associated with T2D, the role rare (frequency < 0.1%) protein-coding variation less clear. We performed exome sequence analysis in 418,436 (n = 32,374 T2D cases) individuals UK Biobank. previously reported genes (
Glucagon-like peptide-1 (GLP-1) is an insulin-releasing hormone clinically exploited for glycaemic control in diabetes, which also confers acute cardioprotection and benefits experimental/clinical heart failure. We specifically investigated the role of GLP-1 mimetic, exendin-4, post-myocardial infarction (MI) remodelling, a key contributor to Adult female normoglycaemic mice underwent coronary artery ligation/sham surgery prior infusion with exendin-4/vehicle 4 weeks. Metabolic parameters...
Abstract Liver X receptor-α (LXRα) regulates cellular cholesterol abundance and potently activates hepatic lipogenesis. Here we show that at least 1 in 450 people the UK Biobank carry functionally impaired mutations LXRα, which is associated with biochemical evidence of dysfunction. On a western diet, male female mice homozygous for dominant negative mutation LXRα have elevated liver cholesterol, diffuse crystal accumulation develop severe hepatitis fibrosis, despite reduced triglyceride no...
A series of 467 cases congenital heart disease detected in prenatal life were analyzed to identify the forms cardiac malformation associated with karyotypic defects and calculate incidence chromosomal abnormalities such malformations. Of these, 77 proved have anomalies although not all karyotyped. The results two ways. First, whole was examined order describe form found association as, many known be defects, several unexpected. In which positive, there other abnormal findings on ultrasound,...
The emotional distress associated with adjusting to and living diabetes has been termed distress. Diabetes is glycaemic control but interventions reduce have failed consistently improve control. Various illness perceptions previously linked both interrelationships between these features not investigated. We hypothesised that mediate the relationship glycaemia. Participants type 2 attending outpatient clinics (n = 84) provided demographic clinical information completed Distress Scale-17 Brief...
Glucagon-like peptide-1 (GLP-1) therapies are routinely used for glycaemic control in diabetes and their emerging cardiovascular actions have been a major recent research focus. In addition to GLP-1 receptor activation, the metabolically-inactive breakdown product, GLP-1(9-36)amide, also appears exert notable effects, including protection against acute cardiac ischaemia. Here, we specifically studied influence of GLP-1(9-36)amide on chronic post-myocardial infarction (MI) remodelling, which...
Clinical case-based studies have identified rare pathogenic variants in several genes as causes of severe early-onset obesity, but their penetrance and interaction with polygenic susceptibility the general population remain unclear. We analysed UK Biobank (UKBB) whole exome sequence data to assess effects heterozygous nine previously reported on adult BMI recalled childhood adiposity. Among 419,581 UKBB participants, we carriers coding that were i) experimentally-characterised...
Populations of Black African (BA) ancestry are disproportionately affected by cardiometabolic diseases, possibly due to dysregulation the complement system. This study aimed determine 1) relationships between fasting markers and risk in BA White European (WE) men, 2) whether postprandial response differs ethnicity. Eighty-eight 97 WE men (age=44.4 [42.0-47.6] years, BMI=29.2±4.5 kg/m2) were assessed for plasma factors. A second cohort (n=20 10 BA) (age=31.0±1.1 BMI=27.1 [26.0-28.6] underwent...
Our understanding of the genetic architecture obesity has primarily been shaped by observations from adult populations with relatively few studies on childhood obesity. To address this gap, we conduct a longitudinal association study in up to ~600,000 individuals objectively measured or recalled adiposity-related traits. We identify 624 common variant signals (only 7% are previously reported) associated adiposity, which one third have no concordant BMI. Signals linked leptin-melanocortin...
The diagnosis of structural heart disease before birth is associated with a poor prognosis. Of 222 continuing pregnancies seen in 10 year period, there has been 79% mortality. This inconsistent published results and current concepts the outcome for children cardiac malformation. 222, death occurred intrauterine life 57, 87 died as neonates, 31 infancy or childhood. There are 47 survivors whom only five have survived beyond 4 years. Factors influencing these cases were examined further. A...
Alcohol dehydrogenase 1B (ADH1B) is a primate-specific enzyme which, uniquely among the ADH class 1 family, highly expressed both in adipose tissue and liver. Its expression reduced obesity increased by insulin stimulation. Interference with ADH1B has also been reported to impair adipocyte function. To better understand role of adipocytes, we used CRISPR/Cas9 delete human stem cells (ASC). Cells lacking failed differentiate into mature adipocytes manifested minimal triglyceride accumulation...
Accelerated migration and proliferation of vascular smooth muscle cells (VSMCs) enhances arterial restenosis after angioplasty in insulin resistance diabetes. Elevation Src homology 2-containing protein tyrosine phosphatase 1 (SHP-1) induces apoptosis the microvasculature. However, role SHP-1 intimal hyperplasia has not been clarified diabetes.We used a femoral artery wire injury mouse model, rodent models with diabetes, patients type 2 Further, we modulated expression using transgenic that...
Abstract Type 2 diabetes (T2D) is a chronic metabolic disorder with significant genetic component. While large-scale population studies have identified hundreds of common variants associated T2D susceptibility, the role rare (minor allele frequency < 0.1%) protein coding variation less clear. To this end, we performed gene burden analysis 18,691 genes in 418,436 (n=32,374 cases) individuals sequenced by UK Biobank (UKBB) study to assess impact on risk. Our associations at exome-wide...
In patients with atherosclerotic complications of diabetes, impaired neovascularization ischemic tissue in the myocardium and lower limb limits ability these tissues to compensate for poor perfusion. We identified 10 novel insulin-regulated genes, among them Adm, Cited2, Ctgf, which were downregulated endothelial cells by insulin through FoxO1. CBP/p300-interacting transactivator ED-rich tail 2 (CITED2), was up 54%, is an important negative regulator hypoxia-inducible factor (HIF) HIF...
Angiotensin-converting enzyme 2 (ACE2) and serine protease TMPRSS2 have been implicated in cell entry for severe acute respiratory syndrome coronavirus (SARS-CoV-2), the virus responsible disease 2019 (COVID-19). The expression of ACE2 lung epithelium might implications risk SARS-CoV-2 infection severity COVID-19. We use human genetic variants that proxy angiotensin-converting (ACE) inhibitor drug effects cardiovascular factors to investigate whether these exposures affect gene circulating...