The Impact of Glycated Hemoglobin (HbA1c) on Cardiovascular Disease Risk: A Mendelian Randomization Study Using UK
Shiu Lun Au Yeung1, Shan Luo2, C Mary Schooling2,3
1School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China ayslryan@hku.hk.
Insights
Glycated hemoglobin (HbA1c) likely causes coronary artery disease (CAD), but not overall cardiovascular disease (CVD). Further research is needed to understand the mechanisms behind this association.
Area of Science:
- Genetics
- Cardiovascular Medicine
- Metabolic Health
Background:
- Glycated hemoglobin (HbA1c) is linked to cardiovascular disease (CVD), but evidence is mainly observational.
- Previous Mendelian randomization studies focused on CVD subtypes.
- The causal relationship between HbA1c and CVD requires further investigation.
Purpose of the Study:
- To investigate the causal relationship between HbA1c and CVD, including its subtypes.
- To utilize Mendelian randomization in the UK Biobank for robust analysis.
- To validate findings using external datasets like CARDIoGRAMplusC4D.
Main Methods:
- Employed Mendelian randomization using 38 genetic variants for HbA1c in UK Biobank participants (n=392,038).
- Utilized inverse variance weighting (IVW) and sensitivity analyses (MR-Egger, weighted median).
- Validated coronary artery disease (CAD) findings in the CARDIoGRAMplusC4D study (n=184,305).
Main Results:
- HbA1c was not associated with overall CVD (OR 1.11 per %, 95% CI 0.83-1.48).
- A significant positive association was found between HbA1c and CAD risk (OR 1.50 per %, 95% CI 1.08-2.11), consistent across sensitivity analyses and validated externally.
- The association with stroke subtypes was inconclusive due to limited case numbers.
Conclusions:
- Glycated hemoglobin (HbA1c) is likely a causal factor for coronary artery disease (CAD).
- The specific biological mechanisms underlying the HbA1c-CAD link require further elucidation.
- These findings strengthen the evidence for managing HbA1c levels to prevent CAD.
Objective:
Glycated hemoglobin (HbA1c) is positively associated with cardiovascular disease (CVD), although evidence is primarily observational. Mendelian randomization studies have only examined its relation with subtypes of CVD. We examined the relation of HbA1c with CVD and its subtypes in the UK Biobank using Mendelian randomization.
Research Design And Methods:
We used 38 genetic variants strongly and independently related to HbA1c (n = 123,665) applied to the UK Biobank (n = 392,038). We used inverse variance weighting (IVW) to obtain the associations of HbA1c with CVD, coronary artery disease (CAD), and stroke (overall and stroke subtypes). Sensitivity analyses included Mendelian randomization (MR)-Egger, a weighted median, and exclusion of potentially invalid single nucleotide polymorphisms (SNPs). We also applied the same genetic instruments to CARDIoGRAMplusC4D (Coronary ARtery DIsease Genome wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) 1000 Genomes-based genome-wide association study (n = 184,305) as a validation for CAD.
Results:
In the UK Biobank, HbA1c was not associated with CVD using IVW (odds ratio [OR] 1.11 per %, 95% CI 0.83-1.48). However, HbA1c was associated with increased CAD risk (OR 1.50 per %, 95% CI 1.08-2.11) with directionally consistent results from MR-Egger and weighted median. The positive association with CAD was more pronounced when we excluded potentially invalid SNPs (OR 2.24 per %, 95% CI 1.55-3.25). The positive association was replicated in CARDIoGRAM (OR 1.52 per %, 95% CI 1.03-2.26). The association of HbA1c with stroke and its subtypes was less clear given the low number of cases.
Conclusions:
HbA1c likely causes CAD. The underlying mechanisms remain to be elucidated.
Related Concept Videos
01:27Psychoneuroimmunology: Cardiovascular Disease
A key area of focus in PNI is the relationship between stress and coronary...
01:24Hemoglobin
When all four heme groups are bound to oxygen, the resulting molecule is called oxyhemoglobin. As a result, arterial blood...
01:17Imaging Studies for Cardiovascular System I:Echocardiography
Indications: Echocardiography is utilized to diagnose heart failure, valve disorders, and myocardial infarction. It also assesses cardiac structures' size, shape, and motion,...
01:28Imaging Studies for Cardiovascular System V: CT
01:20Bioequivalence Experimental Study Designs: Completely Randomized and Randomized Block Designs
01:20Imaging Studies for Cardiovascular System II:Types of Echocardiography
Types of Echocardiography
Transthoracic Echocardiography (TTE)
TTE is the most common type of echocardiogram which involves placing a transducer on the patient's chest, emitting sound waves to create heart images. TTE is invaluable for evaluating the heart's size, structure, and motion, making it particularly useful for...