Dose–response relationship between genetically proxied average blood glucose levels and incident coronary heart disease in individuals without diabetes mellitus

AIMS/HYPOTHESIS: Our aim was to investigate the relationship between average blood glucose levels and incident CHD in individuals without diabetes mellitus. METHODS: To investigate average blood glucose levels, we studied HbA(1c) as predicted by 40 variants previously shown to be associated with both type 2 diabetes and HbA(1c). Linear and non-linear Mendelian randomisation analyses were performed to investigate associations with incident CHD risk in 324,830 European ancestry individuals from the UK Biobank without diabetes mellitus. RESULTS: Every one mmol/mol increase in genetically proxied HbA(1c) was associated with an 11% higher CHD risk (HR 1.11, 95% CI 1.05, 1.18). The dose–response curve increased at all levels of HbA(1c), and there was no evidence favouring a non-linear relationship over a linear one. CONCLUSIONS/INTERPRETATIONS: In individuals without diabetes mellitus, lowering average blood glucose levels may reduce CHD risk in a dose-dependent way. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version of this article (10.1007/s00125-020-05377-0) contains peer-reviewed but unedited supplementary material.