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Type 2 Diabetes, Metabolic Traits, and Risk of Heart Failure: A Mendelian Randomization Study

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posted on 04.06.2021, 17:50 by Ify R Mordi, R Thomas Lumbers, Colin NA Palmer, Ewan R Pearson, Naveed Sattar, Michael V Holmes, Chim C Lang, the HERMES Consortium
Objective

The aim of this study was to use Mendelian randomization (MR) techniques to estimate the causal relationships between genetic liability to type 2 diabetes, glycaemic traits and risk of HF.

Research Design and Methods

Summary-level data were obtained from genome-wide association studies (GWAS) of type 2 diabetes, insulin resistance (IR), glycated haemoglobin, fasting insulin and glucose and HF. MR was conducted using the inverse variance weighted (IVW) method. Sensitivity analyses included MR-Egger, weighted median and mode methods, and multivariable MR conditioning on potential mediators.

Results

Genetic liability to type 2 diabetes was causally related to higher risk of HF (OR: 1.13 per 1 log-unit higher risk of type 2 diabetes; 95% CI 1.11-1.14, p<0.001), however sensitivity analysis revealed evidence of directional pleiotropy. The relationship between type 2 diabetes and HF was attenuated when adjusted for coronary disease, body mass index, LDL-cholesterol and blood pressure. Genetically-instrumented higher IR was associated with higher risk of HF (OR 1.19 per 1 log-unit higher risk of IR; 95% CI 1.00-1.41, p=0.041). There were no notable associations identified between fasting insulin, glucose or glycated haemoglobin and risk of HF. Genetic liability to HF was causally linked to higher risk of type 2 diabetes (OR 1.49; 95% CI 1.01-2.19, p=0.042) though again with evidence of pleiotropy.

Conclusions

These findings suggest a causal role of type 2 diabetes and IR in HF aetiology, though both the presence of bidirectional effects and directional pleiotropy highlight potential sources of bias that need to be considered.

Funding

IM was supported by an NHS Education for Scotland/Chief Scientist Office Postdoctoral Clinical Lectureship (PCL 17/07). MH is supported by a British Heart Foundation Intermediate Clinical Fellowship (FS/18/23/33512). He has also received grant funding from Boehringer Ingelheim. He is also supported by a British Heart Foundation Center of Research Excellence Grant (RE/18/6/34217)

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