The Impact of Glycated Hemoglobin (HbA1c) on Cardiovascular Disease Risk: A Mendelian Randomization Study Using UK Biobank

OBJECTIVEGlycated 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 METHODSWe 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.RESULTSIn 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.CONCLUSIONSHbA(1c) likely causes CAD. The underlying mechanisms remain to be elucidated.