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. 2021 Apr;64(4):845-849.
doi: 10.1007/s00125-020-05377-0. Epub 2021 Jan 26.

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

Stephen Burgess  1   2 , Rainer Malik  3 , Bowen Liu  2 , Amy M Mason  2 , Marios K Georgakis  3 , Martin Dichgans  3   4   5 , Dipender Gill  6   7   8   9
Affiliations

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

Stephen Burgess et al. Diabetologia. 2021 Apr.

Abstract

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 HbA1c as predicted by 40 variants previously shown to be associated with both type 2 diabetes and HbA1c. 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 HbA1c 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 HbA1c, 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.

Keywords: Average blood glucose levels; CHD; Mendelian randomisation.

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Figures

Fig. 1
Fig. 1
Non-linear Mendelian randomisation investigating the relationship between genetically proxied average blood glucose levels (measured by HbA1c) and risk of incident CHD in individuals without diabetes mellitus: (a) men and women combined; (b) men only; and (c) women only. The x-axis depicts HbA1c levels in mmol/mol. The y-axis depicts the hazard ratio for coronary heart disease (HR for CHD) with respect to the reference, plotted on a log scale. Reference is set to an HbA1c of 30 mmol/mol (4.9%). The grey lines represent the 95% CIs. The fractional polynomial test is a goodness-of-fit test that assesses whether any improvement of fit when using a non-linear function to model the association, compared with a linear function, is greater than would be expected due to chance (a significant p value indicates that a non-linear model is preferred to a linear model)
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