Investigating the Role of Inflammatory Biomarkers and Incretins in the Aetiology of Type 2 Diabetes and Coronary Heart Disease using Human Genetics

Background: The relevance of inflammatory and incretin-related signalling pathways in the aetiology of cardiometabolic diseases is of considerable pharmacological interest but remains uncertain. Evidence from animal models and epidemiological studies point to a role for chronic inflammation for the pathophysiology of type 2 diabetes (T2D), with interleukin-6 (IL-6) proposed as a key player. Incretins such as glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) are hormones that stimulate a decrease in blood glucose. Their receptors are existing T2D drug targets, yet the efficacy and safety of GIP mono- and dual agonists e.g. tirzepatide are still unknown. Genetic approaches can help to address limitations of earlier studies and systematically assess the roles of IL-6 and GIP mediated signalling for cardiometabolic diseases. Aims: To investigate the potential causal roles of IL-6 and GIP receptor signalling for the risk of cardiometabolic diseases, specifically T2D and coronary heart disease (CHD), through analysis of large-scale genetic data from patient and population-based studies. Methods: 1) Systematic literature searches were conducted for each topic and the existing evidence summarised in the introduction. 2) A partial loss-of-function missense variant (Asp358Ala) in the IL-6 receptor gene (IL6R) was used to estimate the effect of IL-6R inhibition on T2D risk in 260,614 cases and 1,350,640 controls. 3) An observational meta-analysis of new unpublished and published studies (5,421 T2D cases, 31,562 non-cases) was conducted to compare observational and genetically predicted effects of IL6 levels on T2D. 4) The specificity of the IL6R variant was tested by including genetic and observational associations from a range of other inflammatory markers. 5) Large-scale genomic data from 23 cardiometabolic diseases as well as anthropometric, lipid, glycaemic and ~6,000 ‘omic (metabolomic and proteomic) traits were brought together to systematically assess associations of a known missense variant in GIPR, E354, and infer specificity and potential beneficial or harmful effects of GIPR mono agonism. Bayesian multi-trait colocalisation was used to distinguish trait clusters driven by shared causal variants to identify independent causal variants driving specific trait associations. Findings: IL-6 levels (both measured and genetically predicted) were associated with T2D risk, with a small but significant effect (odds ratio (OR) 95% confidence interval (CI) for the Asp358Ala partial loss of function variant 0.98 (0.97, 0.99); p=2x10-7). Genetic mediation analyses estimated that IL-6 levels mediated up to 5% of the association between BMI and T2D. Colocalisation results at the GIPR locus identify E354 as the driver of a shared signal for GIP (higher), T2D and related traits (lower risk), and adiposity (higher) with high posterior probability (>0.97), and demonstrate that this is distinct from cardiovascular and lipid associations nearby in APOE (rs7412; PP >0.99). Interpretation: Large-scale genetic and prospective observational data provide evidence that IL-6 mediated inflammation is implicated in T2D aetiology but suggest that the impact of this pathway on disease risk in the general population is likely to be small. At the GIPR locus, distinct genetic signals were shown to drive associations of glycaemic and adiposity traits versus CHD and lipid traits. This study provides evidence that inclusion of GIPR agonists in dual agonists could potentiate the protective effect of GLP1 agonists on diabetes without undue cardiovascular risk, while the effects of GIP on weight gain are counteracted by GLP-1

Experimental analysis of submerged flapping foils; implications for autonomous surface vehicles (ASVs)

Autonomous surface vehicles (ASVs) have proven effective as ocean observing platforms for maritime operations. In most cases it is advantageous to operate ASVs for extensive missions in order to maximize their cost effectiveness. Such long endurance missions require ASVs to be capable of scavenging ambient energy from the surrounding ocean environment. Submerged flapping foils are currently utilized as an effective mechanism to convert ocean wave energy directly into propulsion.The authors propose a novel setup whereby these foils can heave relative to the surface vehicle and, through the application of a power take off (PTO) system, can recover a proportion of the incoming wave energy.Experiments were performed to investigate the coupled response between a surface vehicle and submerged flapping foils within the context of generating power and propulsion from incoming waves onboard ASVs. Results show that the response of a surface vehicle with submerged flapping foils is particularly sensitive to design parameters such as the longitudinal location of the foils and the seakeeping characteristics of the surface vehicle.Through optimising the PTO system, this setup could recover a useful proportion of wave energy for ASV platforms

Experimental study of a wave energy scavenging system onboard autonomous surface vessels (ASVs)

Autonomous Surface Vehicles (ASV) have many potential applications in the maritime industry and ocean science. To subsist in the ocean space, an ASV must have the ability to scavenge energy from the surrounding environment. Waves are an abundant source of energy on the ocean surface and a suitable resource for an ASV to scavenge. Flapping foils have been shown to generate thrust in a wavy flow and power in a uniform flow. The aim of this experimental study is to investigate the relationship between flapping foil propulsion and power generation in the context of ASVs. Initial experiments incorporating fully passive flapping foils submerged at the bow and stern of a surface vessel in head waves were performed in a towing tank. The spring-loaded foils were located at the end of rigid pivot arms protruding at the bow and abaft of the vessel. The pivot arms were free to rotate about a location beneath the keel line and restrained by adjustable rotational dampers. In this free condition, wave energy is recovered in the form of work applied by the flapping foils through the rotary dampers which were used to simulate the damping effects of a power take-off device. Thrust was generated under conditions when the pivot arm was fixed. This system, referred to as the Flapping Energy Utilization and Recovery (FLEUR) system, could serve as a dualpurpose wave energy scavenging propulsor and power generator for long-endurance ASVs

Information sciences experiment system

The rapid expansion of remote sensing capability over the last two decades will take another major leap forward with the advent of the Earth Observing System (Eos). An approach is presented that will permit experiments and demonstrations in onboard information extraction. The approach is a non-intrusive, eavesdropping mode in which a small amount of spacecraft real estate is allocated to an onboard computation resource. How such an approach allows the evaluation of advanced technology in the space environment, advanced techniques in information extraction for both Earth science and information science studies, direct to user data products, and real-time response to events, all without affecting other on-board instrumentation is discussed

Associations between callous-unemotional traits and peer-rated social behaviors in elementary and middle school

There is strong evidence that peers are of central importance to children’s and adolescents’ social and emotional adaptation and success in school. However, it remains an open question as to whether callous-unemotional (CU) traits, or interpersonal and affective deficits that pose risk for antisocial behaviors and psychopathy, are related to social-behavioral outcomes as assessed by those who are believed to have the most accurate perspectives on such outcomes – young adolescents’ peers. Using data from a longitudinal and multi-method study of peer relations (N = 379, % female = 51.90, Mage = 10.24 at Time 1), the current study addressed this gap by examining the links between teacher-reports of CU traits and conduct problems (CP) and peer-reports of the extent to which young adolescents are aggressive, victimized, excluded, prosocial, and sociable during the Fall and Spring semesters in Grade 5 (Times 1and 2) and Grade 6 (Times 3 and 4). Results revealed that teacher-rated CP, but not CU traits, was associated positively with peer-reports of aggression. CU traits, but not CP, was associated positively with victimization/exclusion and associated negatively with prosociality. CU traits and CP demonstrated opposite relations with sociability, with CU traits demonstrating a negative association. Findings are discussed in the context of the broader literature examining the social-behavioral correlates of CU traits.Accepted manuscrip

Evidence for Shared Genetic Aetiology Between Schizophrenia, Cardiometabolic, and Inflammation-Related Traits: Genetic Correlation and Colocalization Analyses.

Funder: MQ: Transforming Mental Health; Grant(s): MQDS17/40BACKGROUND: Schizophrenia commonly co-occurs with cardiometabolic and inflammation-related traits. It is unclear to what extent the comorbidity could be explained by shared genetic aetiology. METHODS: We used GWAS data to estimate shared genetic aetiology between schizophrenia, cardiometabolic, and inflammation-related traits: fasting insulin (FI), fasting glucose, glycated haemoglobin, glucose tolerance, type 2 diabetes (T2D), lipids, body mass index (BMI), coronary artery disease (CAD), and C-reactive protein (CRP). We examined genome-wide correlation using linkage disequilibrium score regression (LDSC); stratified by minor-allele frequency using genetic covariance analyzer (GNOVA); then refined to locus-level using heritability estimation from summary statistics (ρ-HESS). Regions with local correlation were used in hypothesis prioritization multi-trait colocalization to examine for colocalisation, implying common genetic aetiology. RESULTS: We found evidence for weak genome-wide negative correlation of schizophrenia with T2D (rg = -0.07; 95% C.I., -0.03,0.12; P = .002) and BMI (rg = -0.09; 95% C.I., -0.06, -0.12; P = 1.83 × 10-5). We found a trend of evidence for positive genetic correlation between schizophrenia and cardiometabolic traits confined to lower-frequency variants. This was underpinned by 85 regions of locus-level correlation with evidence of opposing mechanisms. Ten loci showed strong evidence of colocalization. Four of those (rs6265 (BDNF); rs8192675 (SLC2A2); rs3800229 (FOXO3); rs17514846 (FURIN)) are implicated in brain-derived neurotrophic factor (BDNF)-related pathways. CONCLUSIONS: LDSC may lead to downwardly-biased genetic correlation estimates between schizophrenia, cardiometabolic, and inflammation-related traits. Common genetic aetiology for these traits could be confined to lower-frequency common variants and involve opposing mechanisms. Genes related to BDNF and glucose transport amongst others may partly explain the comorbidity between schizophrenia and cardiometabolic disorders

Genetically Predicted Glucose-Dependent Insulinotropic Polypeptide (GIP) Levels and Cardiovascular Disease Risk Are Driven by Distinct Causal Variants in the GIPR Region.

There is considerable interest in GIPR agonism to enhance the insulinotropic and extrapancreatic effects of GIP, thereby improving glycemic and weight control in type 2 diabetes (T2D) and obesity. Recent genetic epidemiological evidence has implicated higher GIPR-mediated GIP levels in raising coronary artery disease (CAD) risk, a potential safety concern for GIPR agonism. We therefore aimed to quantitatively assess whether the association between higher GIPR-mediated fasting GIP levels and CAD risk is mediated via GIPR or is instead the result of linkage disequilibrium (LD) confounding between variants at the GIPR locus. Using Bayesian multitrait colocalization, we identified a GIPR missense variant, rs1800437 (G allele; E354), as the putatively causal variant shared among fasting GIP levels, glycemic traits, and adiposity-related traits (posterior probability for colocalization [PPcoloc] > 0.97; PP explained by the candidate variant [PPexplained] = 1) that was independent from a cluster of CAD and lipid traits driven by a known missense variant in APOE (rs7412; distance to E354 ∼770 Kb; R 2 with E354 = 0.004; PPcoloc > 0.99; PPexplained = 1). Further, conditioning the association between E354 and CAD on the residual LD with rs7412, we observed slight attenuation in association, but it remained significant (odds ratio [OR] per copy of E354 after adjustment 1.03; 95% CI 1.02, 1.04; P = 0.003). Instead, E354's association with CAD was completely attenuated when conditioning on an additional established CAD signal, rs1964272 (R 2 with E354 = 0.27), an intronic variant in SNRPD2 (OR for E354 after adjustment for rs1964272: 1.01; 95% CI 0.99, 1.03; P = 0.06). We demonstrate that associations with GIP and anthropometric and glycemic traits are driven by genetic signals distinct from those driving CAD and lipid traits in the GIPR region and that higher E354-mediated fasting GIP levels are not associated with CAD risk. These findings provide evidence that the inclusion of GIPR agonism in dual GIPR/GLP1R agonists could potentiate the protective effect of GLP-1 agonists on diabetes without undue CAD risk, an aspect that has yet to be assessed in clinical trials

Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity.

The melanocortin 4 receptor (MC4R) is a G protein-coupled receptor whose disruption causes obesity. We functionally characterized 61 MC4R variants identified in 0.5 million people from UK Biobank and examined their associations with body mass index (BMI) and obesity-related cardiometabolic diseases. We found that the maximal efficacy of β-arrestin recruitment to MC4R, rather than canonical Gαs-mediated cyclic adenosine-monophosphate production, explained 88% of the variance in the association of MC4R variants with BMI. While most MC4R variants caused loss of function, a subset caused gain of function; these variants were associated with significantly lower BMI and lower odds of obesity, type 2 diabetes, and coronary artery disease. Protective associations were driven by MC4R variants exhibiting signaling bias toward β-arrestin recruitment and increased mitogen-activated protein kinase pathway activation. Harnessing β-arrestin-biased MC4R signaling may represent an effective strategy for weight loss and the treatment of obesity-related cardiometabolic diseases

Advancing critical chemical processes for a sustainable future: challenges for industry and the Max Planck-Cardiff centre on the fundamentals of heterogeneous catalysis (funcat)

Catalysis is involved in around 85 % of manufacturing industry and contributes an estimated 25 % to the global domestic product, with the majority of the processes relying on heterogeneous catalysis. Despite the importance in different global segments, the fundamental understanding of heterogeneously catalysed processes lags substantially behind that achieved in other fields. The newly established Max Planck–Cardiff Centre on the Fundamentals of Heterogeneous Catalysis (FUNCAT) targets innovative concepts that could contribute to the scientific developments needed in the research field to achieve net zero greenhouse gas emissions in the chemical industries. This Viewpoint Article presents some of our research activities and visions on the current and future challenges of heterogeneous catalysis regarding green industry and the circular economy by focusing explicitly on critical processes. Namely, hydrogen production, ammonia synthesis, and carbon dioxide reduction, along with new aspects of acetylene chemistry

Association of Genetic Variants Related to Gluteofemoral vs Abdominal Fat Distribution With Type 2 Diabetes, Coronary Disease, and Cardiovascular Risk Factors.

IMPORTANCE: Body fat distribution, usually measured using waist-to-hip ratio (WHR), is an important contributor to cardiometabolic disease independent of body mass index (BMI). Whether mechanisms that increase WHR via lower gluteofemoral (hip) or via higher abdominal (waist) fat distribution affect cardiometabolic risk is unknown. OBJECTIVE: To identify genetic variants associated with higher WHR specifically via lower gluteofemoral or higher abdominal fat distribution and estimate their association with cardiometabolic risk. DESIGN, SETTING, AND PARTICIPANTS: Genome-wide association studies (GWAS) for WHR combined data from the UK Biobank cohort and summary statistics from previous GWAS (data collection: 2006-2018). Specific polygenic scores for higher WHR via lower gluteofemoral or via higher abdominal fat distribution were derived using WHR-associated genetic variants showing specific association with hip or waist circumference. Associations of polygenic scores with outcomes were estimated in 3 population-based cohorts, a case-cohort study, and summary statistics from 6 GWAS (data collection: 1991-2018). EXPOSURES: More than 2.4 million common genetic variants (GWAS); polygenic scores for higher WHR (follow-up analyses). MAIN OUTCOMES AND MEASURES: BMI-adjusted WHR and unadjusted WHR (GWAS); compartmental fat mass measured by dual-energy x-ray absorptiometry, systolic and diastolic blood pressure, low-density lipoprotein cholesterol, triglycerides, fasting glucose, fasting insulin, type 2 diabetes, and coronary disease risk (follow-up analyses). RESULTS: Among 452 302 UK Biobank participants of European ancestry, the mean (SD) age was 57 (8) years and the mean (SD) WHR was 0.87 (0.09). In genome-wide analyses, 202 independent genetic variants were associated with higher BMI-adjusted WHR (n = 660 648) and unadjusted WHR (n = 663 598). In dual-energy x-ray absorptiometry analyses (n = 18 330), the hip- and waist-specific polygenic scores for higher WHR were specifically associated with lower gluteofemoral and higher abdominal fat, respectively. In follow-up analyses (n = 636 607), both polygenic scores were associated with higher blood pressure and triglyceride levels and higher risk of diabetes (waist-specific score: odds ratio [OR], 1.57 [95% CI, 1.34-1.83], absolute risk increase per 1000 participant-years [ARI], 4.4 [95% CI, 2.7-6.5], P < .001; hip-specific score: OR, 2.54 [95% CI, 2.17-2.96], ARI, 12.0 [95% CI, 9.1-15.3], P < .001) and coronary disease (waist-specific score: OR, 1.60 [95% CI, 1.39-1.84], ARI, 2.3 [95% CI, 1.5-3.3], P < .001; hip-specific score: OR, 1.76 [95% CI, 1.53-2.02], ARI, 3.0 [95% CI, 2.1-4.0], P < .001), per 1-SD increase in BMI-adjusted WHR. CONCLUSIONS AND RELEVANCE: Distinct genetic mechanisms may be linked to gluteofemoral and abdominal fat distribution that are the basis for the calculation of the WHR. These findings may improve risk assessment and treatment of diabetes and coronary disease.This study was funded by the United Kingdom’s Medical Research Council through grants MC_UU_12015/1, MC_PC_13046, MC_PC_13048 and MR/L00002/1. This work was supported by the MRC Metabolic Diseases Unit (MC_UU_12012/5) and the Cambridge NIHR Biomedical Research Centre and EU/EFPIA Innovative Medicines Initiative Joint Undertaking (EMIF grant: 115372). EPIC-InterAct Study funding: funding for the InterAct project was provided by the EU FP6 program (grant number LSHM_CT_2006_037197). D.B.S. and S.O’R. are supported by the Wellcome Trust (WT107064 and WT095515 respectively) the MRC Metabolic Disease Unit, the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre and the NIHR Rare Disease Translational Research Collaboration