Abstract
BACKGROUND: The ABO blood group system is associated with differential susceptibility to thrombotic vascular diseases. ABO is also known to be a strong trans-protein quantitative trait locus for plasma proteins involved in cell adhesion and hemostasis. STUDY DESIGN AND METHOD: To further investigate these associations, we integrated epigenomic, genomic, and proteomic data from the Milieu Intérieur cohort. We used the rs8176719 SNP to classify donors as either type O or non-O, and used linear models to compare levels of 229 plasma proteins in 400 donors, including age, sex, cytomegalovirus serostatus, and secretor status as covariates. RESULTS: We observed increased levels of soluble E-selectin and decreased levels of von Willebrand Factor (vWF) in O donors compared with non-O donors. By performing an epigenome-wide association study, we identified 23 differentially methylated CpG sites between blood types, which were all located in the ABO gene. Notably, CpG sites in the ABO promoter region of type O donors were less methylated than those of the non-O donors. Using mediation analysis, we found that these differences in DNA methylation partially explained the effects of blood group on differential E-selectin and vWF plasma levels. DISCUSSION: We find differentially methylated CpG sites between blood types and provide new evidence that ABO blood group status affects circulating levels of specific proteins.