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. 2022 Oct 1;71(10):2222-2232.
doi: 10.2337/db21-0905.

Differentiating Associations of Glycemic Traits With Atherosclerotic and Thrombotic Outcomes: Mendelian Randomization Investigation

Shuai Yuan  1 , Amy M Mason  2 , Stephen Burgess  3   4 , Susanna C Larsson  1   5
Affiliations

Differentiating Associations of Glycemic Traits With Atherosclerotic and Thrombotic Outcomes: Mendelian Randomization Investigation

Shuai Yuan et al. Diabetes. .

Abstract

We conducted a Mendelian randomization analysis to differentiate associations of four glycemic indicators with a broad range of atherosclerotic and thrombotic diseases. Independent genetic variants associated with fasting glucose (FG), 2 h glucose after an oral glucose challenge (2hGlu), fasting insulin (FI), and glycated hemoglobin (HbA1c) at the genome-wide significance threshold were used as instrumental variables. Summary-level data for 12 atherosclerotic and 4 thrombotic outcomes were obtained from large genetic consortia and the FinnGen and UK Biobank studies. Higher levels of genetically predicted glycemic traits were consistently associated with increased risk of coronary atherosclerosis-related diseases and symptoms. Genetically predicted glycemic traits except HbA1c showed positive associations with peripheral artery disease risk. Genetically predicted FI levels were positively associated with risk of ischemic stroke and chronic kidney disease. Genetically predicted FG and 2hGlu were positively associated with risk of large artery stroke. Genetically predicted 2hGlu levels showed positive associations with risk of small vessel stroke. Higher levels of genetically predicted glycemic traits were not associated with increased risk of thrombotic outcomes. Most associations for genetically predicted levels of 2hGlu and FI remained after adjustment for other glycemic traits. Increase in glycemic status appears to increase risks of coronary and peripheral artery atherosclerosis but not thrombosis.

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Conflict of interest statement

Duality of Interest

No potential conflicts of interest relevant to this article were reported.

Figures

Figure 1
Figure 1
Associations of genetically predicted FG with atherosclerotic and thrombotic outcomes. The combined estimates are indicated with boldface type. The ORs were scaled to 1 mmol/L increase in genetically predicted FG. UKBB, UK Biobank.
Figure 2
Figure 2
Associations of genetically predicted 2hGlu with atherosclerotic and thrombotic outcomes. The combined estimates are indicated with boldface type. The ORs were scaled to 1 unit in log-transformed millimoles per liter increase in genetically predicted levels of 2hGlu. UKBB, UK Biobank.
Figure 3
Figure 3
Associations of genetically predicted FI with atherosclerotic and thrombotic outcomes. The combined estimates are indicated with boldface type. The ORs were scaled to 1 unit in log-transformed picomoles per liter increase in genetically predicted FI levels. UKBB, UK Biobank.
Figure 4
Figure 4
Associations of genetically predicted HbA1c with atherosclerotic and thrombotic outcomes. The combined estimates are indicated with boldface type. The ORs were scaled to 1 percentage increase in genetically predicted HbA1c levels. UKBB, UK Biobank.
Figure 5
Figure 5. Summary of associations of genetically predicted glycemic traits with 12 atherosclerotic and 4 thrombotic outcomes.
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