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of IL-6R inhibition on T2D risk in 260,614 cases and 1,350,640 controls. 3) An observational meta-analysis of new unpublished and published studies (5,421 T2D cases, 31,562 non-cases) was conducted to compare observational and genetically predicted effects of IL6 levels on T2D. 4) The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.
Human Genetics, Epidemiology, Inflammation, Metabolic disease
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