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

AIMS/HYPOTHESIS: We aimed to evaluate whether genetically predicted HbA has an effect on the risk of cardiovascular diseases and investigate the shape of the relationship of genetically predicted HbA 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 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 on cardiovascular outcomes was likely linear.

CONCLUSIONS/INTERPRETATION: The study suggests a detrimental effect of HbA 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 with these cardiovascular outcomes, in particular coronary artery disease, is likely to be linear.