👤 Alison M J Buchan

Cardiovascular disease (CVD) remains a major global health concern and a leading cause of morbidity and mortality worldwide. Early-diagnosis and prompt medical attention are crucial in managing and reducing overall impact on health-and-wellbeing, necessitating the development of innovative diagnostics, which transcend traditional methodologies. Raman spectroscopy uniquely provides molecular fingerprinting and structural information, offering insights into biochemical composition. Integration of Raman spectroscopy with advanced machine learning is established as a powerful clinical adjunct for point-of-care detection of CVDs. A non-invasive, label-free spectroscopic platform coupled with neural network algorithm, 'SKiNET' has been developed to accurately detect the biomolecular changes within plasma of CVD versus healthy cohorts, enabling rapid diagnosis and longer-term monitoring, where the real-time capabilities provide dynamic assessment of progression, aligning treatment strategies with evolving states. CVD has been detected and classified via SKiNET with 88.6 %-accuracy, 92.9 %-specificity and 85.1 %-sensitivity and with 83.8 %-accuracy. The hybrid RS-SKiNET bio-molecularly specific detection signposted a comprehensive panel of CVD-indicative biomarkers, including SIL-6, IL-9, LpA, ApoB, PCSK9 and NT-ProBNP, offering important insights into disease mechanisms and risk-stratification. This multidimensional technique holds potential for improved patient-and-healthcare management for CVDs, laying the platform toward high-throughput biomolecular profiling of CVD-indicative macromolecular biomarkers, particularly vital for widespread point-of-care diagnostics and monitoring. Show less

Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. Here, we report results from a large genome-wide association study and multitrait analysis including 5,900 HCM cases, 68,359 controls and 36,083 UK Biobank participants with cardiac magnetic resonance imaging. We identified 70 loci (50 novel) associated with HCM and 62 loci (20 novel) associated with relevant left ventricular traits. Among the prioritized genes in the HCM loci, we identify a novel HCM disease gene, SVIL, which encodes the actin-binding protein supervillin, showing that rare truncating SVIL variants confer a roughly tenfold increased risk of HCM. Mendelian randomization analyses support a causal role of increased left ventricular contractility in both obstructive and nonobstructive forms of HCM, suggesting common disease mechanisms and anticipating shared response to therapy. Taken together, these findings increase our understanding of the genetic basis of HCM, with potential implications for disease management. Show less

The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young, otherwise healthy, individuals. We conducted genome-wide association studies and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases) and nine left ventricular (LV) traits (19,260 UK Biobank participants with structurally normal hearts). We identified 16 loci associated with HCM, 13 with DCM and 23 with LV traits. We show strong genetic correlations between LV traits and cardiomyopathies, with opposing effects in HCM and DCM. Two-sample Mendelian randomization supports a causal association linking increased LV contractility with HCM risk. A polygenic risk score explains a significant portion of phenotypic variability in carriers of HCM-causing rare variants. Our findings thus provide evidence that polygenic risk score may account for variability in Mendelian diseases. More broadly, we provide insights into how genetic pathways may lead to distinct disorders through opposing genetic effects. Show less

The incretins glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are gut hormones that act via the enteroinsular axis to potentiate insulin secretion from the pancreas in a glucose-dependent manner. Both GLP-1 receptor and GIP receptor knockout mice (GLP-1R(-/-) and GIPR(-/-), respectively) have been generated to investigate the physiological importance of this axis. Although reduced GIP action is a component of type 2 diabetes, GIPR-deficient mice exhibit only moderately impaired glucose tolerance. The present study was directed at investigating possible compensatory mechanisms that take place within the enteroinsular axis in the absence of GIP action. Although serum total GLP-1 levels in GIPR knockout mice were unaltered, insulin responses to GLP-1 from pancreas perfusions and static islet incubations were significantly greater (40-60%) in GIPR(-/-) than in wild-type (GIPR(+/+)) mice. Furthermore, GLP-1-induced cAMP production was also elevated twofold in the islets of the knockout animals. Pancreatic insulin content and gene expression were reduced in GIPR(-/-) mice compared with GIPR(+/+) mice. Paradoxically, immunocytochemical studies showed a significant increase in beta-cell area in the GIPR-null mice but with less intense staining for insulin. In conclusion, GIPR(-/-) mice exhibit altered islet structure and topography and increased islet sensitivity to GLP-1 despite a decrease in pancreatic insulin content and gene expression. Show less