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HbA1c Is Associated With Increased Risk for CAD
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In this study, Mendelian randomization was used to evaluate the association between HbA1c and cardiovascular disease (CVD) and its subtypes (N = 392,038). Using inverse variance weighting, HbA1c was not associated with CVD. HbA1c was found to be associated with an increased risk for coronary artery disease (CAD), which was more pronounced after excluding potentially invalid single nucleotide polymorphisms.
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Further studies are necessary to understand the underlying contributing mechanisms of HbA1c to CAD.
abstract
This abstract is available on the publisher's site.
Access this abstract nowOBJECTIVE
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), stroke, and its 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.
Additional Info
Disclosure statements are available on the authors' profiles:
The Impact of Glycated Hemoglobin (HbA1c) on Cardiovascular Disease Risk: A Mendelian Randomization Study Using UK Biobank
Diabetes Care 2018 Jun 27;[EPub Ahead of Print], SL Au Yeung, S Luo, CM SchoolingFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Hemoglobin A1c (HbA1c) is a convenient test of long-term blood glucose concentrations1,2 and also serves as a marker of risk for diabetes-related complications, including cardiovascular disease (CVD).3 However, the association between HbA1c and CVD risk has been primary observational.4,5 This study uses Mendelian randomization,6 an application of the method of instrumental variables using genetic data in the UK Biobank, to examine the causal effect of HbA1c on the risk of CVD and its subtypes, including coronary artery disease (CAD). Researchers found that HbA1c was not associated with CVD as a combined outcome but was associated specifically with CAD risk. Sensitivity analyses using various statistical approaches support the hypothesis that HbA1c has a causal role in CAD, where the odds of CAD are 1.5 to 2 times higher for every percent increase in HbA1c.
Results from this study have several implications. First, modern large-scale genotype and phenotype datasets, such as the UK Biobank, can be used to design well-powered studies that strengthen the causal interpretation of epidemiological associations. Second, interventions that lower glycemia, and in doing so lower HbA1c, may reduce CAD risk. However, mechanisms underlying the HbA1c–CAD relationship remain to be elucidated, especially those that are independent of glycemia. Third, the causal evidence for an association with stroke risk is less compelling, although null findings could be explained by phenotype heterogeneity and the low number of stroke cases in the UK Biobank.
References