Investigating the Role of Inflammatory Biomarkers and Incretins in the Aetiology of Type 2 Diabetes and Coronary Heart Disease using Human Genetics
type: CreativeWork
description: 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of IL-6R inhibition on T2D risk in 260,614 cases and 1,350,640 controls. 3) An observational meta-analysis of new unpublished and published studies (5,421 T2D cases, 31,562 non-cases) was conducted to compare observational and genetically predicted effects of IL6 levels on T2D. 4) The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 as…
abstract: 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 as…
author: Bowker, Nicholas
language: eng
keywords: Human Genetics, Epidemiology, Inflammation, Metabolic disease
license: https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/95291016-c47d-43d4-8d8c-9e728c3edd0a/download
license: https://www.rioxx.net/licenses/all-rights-reserved/
date published: 2020-11-18
date modified: 2026-07-22T22:24:08Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.70467