Scientific Business Abstracts of the 113th Annual Meeting of the Association of Physicians of Great Britain and Ireland

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Biography Tessa M. Cacciottolo graduated from the University of Malta Medical School, then moved to the UK to further her clinical training in general medicine, gastroenterology and hepatology. During this time she became interested in the interface between liver disease and metabolism. She joined Professor Farooqi’s group at the Institute of Metabolic Science in Cambridge, to study the mechanisms which are disrupted in people with severe obesity, and how these could be associated with liver and metabolic disease. Aim The prevalence of obesity and associated cardiometabolic complications has risen sharply in recent years. Within the Genetics of Obesity Study (n = 7000) we identified 15 rare loss of function variants in SRC-1 associated with obesity and liver cirrhosis at a young age. We hypothesized that SRC-1 plays a crucial role in human peripheral lipid metabolism. Methods To test the effect of SRC-1 on lipid metabolism, we knocked down SRC-1 in hepG2 cells, quantified expression of key enzymes using qPCR and measured exogenous fatty acid oxidation using the Seahorse Bioscience flux analyser. In human variant carriers, we performed open adipose tissue biopsies and assessed histology for fibrosis using Sirius red stain. Hepatic fibrosis was quantified using magnetic resonance elastography. Results SRC-1 knock-down caused 75% reduction in expression of CYP7A1 and 80% reduction in expression of CPT1a, the rate limiting enzymes for cholesterol catabolism and fatty acid oxidation, respectively; and significant reduction in exogenous palmitate oxidation. In humans, we found significant insulin resistance (mean HOMA-IR = 3.2), severe fibrosis in 40% adipose tissue biopsies and advanced liver fibrosis or cirrhosis in 27% of cases. Conclusions SRC-1 variants are associated with a high risk of adipose tissue fibrosis. The inability of hepatocytes to handle excess lipid may lead to lipotoxicity and accelerated liver fibrosis. Biography Dr Gennadiy Tenin started his scientific career as a researcher in the University of Dundee (Scotland, UK) studying the termination of body axis elongation in chick embryo, followed by the short period in King’s College London investigating molecular control of head mesoderm patterning in chick. He then moved to the University of Manchester to work with Dr Kathryn Hentges, working on several projects, studying different aspects of heart development using mouse as a model organism. As the next step in his career, he started working with Prof Bernard Keavney to identify new genes involved in cardiovascular development and congenital heart disease, using GWAS data in Tetralogy of Fallot patients as the starting point. He currently continues his research in the area, studying the function of the one of the newly identified genes during cardiogenesis. Congenital heart diseases (CHD) are the commonest birth defects and present in 9 out of 1000 live births. Tetralogy of Fallot (TOF) is the commonest cyanotic CHD; some 80% of TOF cases are sporadic and not due to a recognized genetic syndrome. Sporadic, non-syndromic TOF nonetheless exhibits significant heritability, and is considered to be a multigenic condition. Previously, a region of association on chr 13q31 (P = 3.03 × 10–11) was discovered through genome-wide association studies (GWAS) in TOF patients but no causative gene identified. Integration of population genetics data, regional chromosomal interactions and embryonic expression data suggested that the nearby located gene Glypican-6 (GPC6) was the strongest candidate. GPC6 was found to be expressed exclusively in the endocardial cushions, transitory structures critical for cardiac septation. We used mouse gene knock-out to investigate the functional significance of Gpc6 in heart. Mice carrying a hypomorphic allele of Gpc6 displayed abnormalities in cushion development, leading to lower cell density in cardiac valves, thinner great vessels and, in some cases, a ventricular septal defect. The complete knock-out of Gpc6 resulted in double outlet right ventricle with mal-positioned aorta, a phenotype closely related to human TOF. The previously uncharacterized gene GPC6 was confirmed to be a novel causative gene for CHD, and is the first such gene to be identified from a GWAS approach. The glypicans, of which GPC6 is one, are heparan sulfate proteoglycans involved in a number of cell signalling pathways; this work newly identifies the role of the glypican gene family in heart development. Biography Dr Eilise Ryan currently works as a Clinical Research Fellow with Professors Moira Whyte and Sarah Walmsley at the Centre for Inflammation Research Edinburgh. She was awarded a Wellcome Research Grant for her PhD, exploring mechanisms for impaired macrophage function in chronic obstructive pulmonary disease (COPD), with a particular focus on cellular energetics. COPD patients have defective innate immunity, characterized in part by macrophage dysfunction with impaired macrophage phagocytosis of bacteria and apoptotic cells (efferocytosis). We hypothesized that defective macrophage function in COPD may share a common mechanism related to altered metabolism, and or, as previously suggested in the literature, failure to upregulate the Nrf2-mediated antioxidant response. AM and MDM were isolated from patients with established COPD (GOLD stages 1–3). Macrophage efferocytosis rates were correlated with bacterial internalization of Streptococcus pneumoniae. Seahorse technology was utilized to metabolically profile cells in real time. Efferocytosis assays were performed +/− Sulforaphane (a non-specific Nrf2 agonist) and Compound 7, a highly specific Nrf2 agonist (GSK). Both COPD MDM and AM have significantly impaired bacterial phagocytosis and efferocytosis compared to Healthy Controls (P < 0.05). Moreover, there was a correlation between COPD macrophage phagocytosis and efferocytosis (r = 0.71). Both Glycolytic Reserve and Spare Respiratory Capacity were significantly reduced in AM and MDM from COPD donors (P < 0.05). In vitro studies using Sulforaphane and Compound 7 enhanced efferocytosis of apoptotic cells in both COPD AM and MDM (P < 0.01). In summary, we observe a correlation between macrophage phagocytosis and efferocytosis in COPD, suggesting a common mechanism. We demonstrate an altered metabolic profile in COPD macrophages, with potential consequences for high energy requiring processes such as efferocytosis. The partial rescue of defective COPD MDM and AM efferocytosis via specific activation of the Nrf2 pathway, suggests that activation of the Nrf2 module may enable metabolic reprogramming in COPD macrophages, leading to enhanced efferocytosis. Biography Yingjuan Liu was recently awarded her PhD degree at November 2018 from The University of Manchester. She is currently appointed as a research associate working with Professor Bernard Keavney in Division of Cardiovascular Sciences, The University of Manchester. She is focusing on the genetics of Congenital Heart Diseases with particular efforts in investigating the functional roles of long noncoding RNAs during cardiovascular development. Objectives To identify the gene and mechanism responsible for the Genome-wide association studies (GWAS) signal (OR = 1.46; P = 2.61 × 10−10) which we previously identified at chromosome 4p16 for atrial septal defect (ASD). To date, while a number of risk variants have been identified from GWAS of congenital heart disease (CHD), none has been functionally confirmed. Methods and Results The linkage disequilibrium in the region indicated association was restricted to the long noncoding RNA STX18-AS1. Since STX18-AS1 is not conserved beyond primates, all experiments were conducted in human tissues and cell lines. In 108 RNA samples from right atrial appendages and corresponding DNA, we first confirmed the risk SNPs of ASD were eQTLs for STX18-AS1 in cardiac tissues. Using qPCR, the transcription of STX18-AS1 in embryonic hearts was detected to be t

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