Abstract
BACKGROUND: Although existing studies have reported associations between blood group A and cardiometabolic diseases (CMD), most have focused on dominant inheritance models. However, genome-wide association studies have mostly been based on additive genotypes. This study aims to investigate the association between the blood group A allele and 15 CMD using recessive, dominant, and additive models and identify potential mediators. METHODS: This study leveraged data from over 320,000 participants with O and A blood groups in the UK Biobank to investigate the association between blood group A allele and 15 major CMD under recessive, dominant, and gene dosage (additive) models. Protein data from nearly 30,000 participants were used to analyze the association between ABO protein levels and CMD. Mediation analysis further explored whether blood cell count traits and blood biochemistry mediate the association between the number of A allele and CMD. RESULTS: The additive model demonstrates a dose-response association of the blood group A allele with venous thromboembolism (VTE), myocardial infarction (MI), ischemic stroke (IS), type 2 diabetes mellitus (T2DM), and heart failure (HF), among others. Each additional A allele increased disease risk, particularly for VTE (HR = 1.273, P[FDR] = 4.43 × 10(-96)). ABO protein levels also correlated with five CMD outcomes, particularly VTE and coronary artery disease (CAD). Mediation analyses revealed that blood cell traits (e.g., hemoglobin, hematocrit) and biochemistries (e.g., aspartate aminotransferase to alanine aminotransferase ratio, apolipoprotein B) significantly mediated the associations for specific CMD, suggesting shared biological mechanisms. CONCLUSIONS: Our findings reveal that blood group A allele is associated with an increased risk of multiple CMD, particularly under the additive model. Some blood cell count traits and blood biochemistries play significant mediating roles.