The impact of glycated hemoglobin (HbA_1c) on cardiovascular disease risk: A mendelian randomization study using UK Biobank

OBJECTIVE: Glycated hemoglobin (HbA_1c) 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 HbA_1c 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 HbA_1c (n = 123, 665) applied to the UK Biobank (n = 392,038). We used inverse variance weighting (IVW) to obtain the associations of HbA_1c 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, HbA_1c was not associated with CVD using IVW (odds ratio [OR] 1.11 per %, 95% CI 0.83-1.48). However, HbA_1c 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 HbA_1c with stroke and its subtypes was less clear given the low number of cases. CONCLUSIONS: HbA_1c likely causes CAD. The underlying mechanisms remain to be elucidated.