Assessing the linear and non-linear association of HbA_1c with cardiovascular disease: a Mendelian randomisation study

Aims/hypothesis: We aimed to evaluate whether genetically predicted HbA_1c has an effect on the risk of cardiovascular diseases and investigate the shape of the relationship of genetically predicted HbA_1c with cardiovascular diseases. Methods: We performed linear univariable, multivariable and non-linear Mendelian randomisation analyses in 373,571 white British participants (mean age 56.9) from the UK Biobank. Results: In univariable linear Mendelian randomisation analysis, a 1 mmol/mol increase in genetically predicted HbA_1c was associated with higher risk of coronary artery disease (OR 1.03, 95% CI 1.02, 1.05), stroke (OR 1.02, 95% CI 1.00, 1.05) and hypertension (OR 1.02, 95% CI 1.01, 1.03). Multivariable Mendelian randomisation adjusted for the effect of haemoglobin gave a consistent conclusion for coronary artery disease. The associations with stroke and hypertension were directionally similar but with wider CI overlapping the null. Non-linear Mendelian randomisation indicated that the shape of the effect of genetically predicted HbA_1c on cardiovascular outcomes was likely linear. Conclusions/interpretation: The study suggests a detrimental effect of HbA_1c on coronary artery disease in both men and women, and the effect is via a glycaemic characteristic. The shape of the genetic association of HbA_1c with these cardiovascular outcomes, in particular coronary artery disease, is likely to be linear. Graphical abstract: [Figure not available: see fulltext.]