Causal associations between HbA1c and multiple diseases unveiled through a Mendelian randomization phenome-wide association study in East Asian populations

Most analyses of hemoglobin A1c (HbA1c) and multiple common diseases have focused on European populations, thus there is a need for Mendelian randomization phenome-wide association study (MR-PheWAS) in East Asian populations. We used MR-PheWAS to investigate the potential causal associations between HbA1c and 159 types of diseases in the Biobank Japan dataset, employing the inverse variance weighted as the primary statistical approach, supplemented by MR-Egger and weighted median analyses. Additionally, multiple sensitivity analyses were conducted to assess heterogeneity and pleiotropy. High HbA1c levels are associated with an increased risk of type 1 diabetes (odds ratio [OR] = 4.07; 95% confidence interval [CI]: 2.34~7.07), type 2 diabetes (OR = 4.76; 95% CI: 3.01~7.55), cataract (OR = 1.33; 95% CI: 1.18~1.51), diabetic nephropathy (OR = 5.70; 95% CI: 2.24~14.46), and peripheral arterial disease (OR = 1.62; 95% CI: 1.29~2.04). Conversely, elevated HbA1c levels are associated with a reduced risk of asthma (OR = 0.76; 95% CI: 0.67~0.86), breast cancer (OR = 0.75; 95% CI: 0.65~0.87), and cerebral aneurysm (OR = 0.71; 95% CI: 0.57~0.88). The results of the causal association between HbA1c and numerous diseases in East Asian populations provides insights for the region's specialized glycemic control and disease prevention programs, as well as new preventive and treatment options.