The impact of glycated hemoglobin on risk of hypertension: a Mendelian randomization study using UK Biobank

Background: Observational studies suggest higher glycated hemoglobin (HbA1c) associated with higher hypertension risk although these associations could be confounded. We examined the relation using a Mendelian randomization design in a large Biobank, the UK Biobank. Methods: We identified 38 single nucleotide polymorphisms (SNPs) strongly and independently related to HbA1c from a large genome wide association study (n = 123 665) and applied them to the UK Biobank (n = 376 644). We used inverse variance weighting (IVW) to assess the relation of HbA1c with risk of hypertension (defined using the American College of Cardiology/American Heart Association 2017 guidelines), and SBP and DBP. Sensitivity analyses included Mendelian randomization-Egger, weighted median, Mendelian randomization pleiotropy residual sum and outlier and exclusion of pleiotropic SNPs. Results: HbA1c was not clearly associated with hypertension risk using IVW (odds ratio 1.11, 95% confidence interval 0.76-1.62) in the main analysis. However, Mendelian randomization pleiotropy residual sum and outlier suggested potential horizontal pleiotropy. After excluding potentially invalid SNPs, HbA1c was associated with hypertension risk (IVW odds ratio 1.22 per %, 95% confidence interval 1.01-1.46), with consistent estimates from sensitivity analyses. HbA1c was positively associated with SBP in some, but not all analyses, albeit with directionally consistent estimates. The relation with DBP was unclear. Conclusion: Our study suggests HbA1c may increase hypertension risk and could be one underlying mechanistic pathway between HbA1c and coronary artery disease risk.