Clinical and Population Studies Genome-Wide Association Identifies the ABO Blood Group as a Major Locus Associated With Serum Levels of Soluble E-Selectin

Background—Elevated serum soluble E-selectin levels have been associated with a number of diseases. Although E-selectin levels are heritable, little is known about the specific genetic factors involved. E-selectin levels have been associated with the ABO blood group phenotype. Methods and Results—We performed a high-resolution genome-wide association study of serum soluble E-selectin levels in 685 white individuals with type 1 diabetes from the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Intervention and Complications (EDIC) study to identify major loci influencing levels. Highly significant evidence for association (Pϭ10 Ϫ29) was observed for rs579459 near the ABO blood group gene, accounting for 19% of the variance in E-selectin levels. Levels of E-selectin were higher in O/O than O/A heterozygotes, which were likewise higher than A/A genotypes. Analysis of subgroups of A alleles reveals heterogeneity in the association, and even after this was accounted for, an intron 1 SNP remained significantly associated. We replicate the ABO association in nondiabetic individuals. Conclusion—ABO is a major locus for serum soluble E-selectin levels. We excluded population stratification, fine-mapped the association to sub-A alleles, and also document association with additional variation in the ABO region. E ndothelial cells express leukocyte-specific cell adhesion molecules both constitutively and in response to cyto-kines and other mediators. 1,2 Cellular adhesion molecules mediate the attachment and transmigration of leukocytes across the endothelial surface and are hypothesized to play an important role in the initiation of atherosclerosis. 3,4 Binding of leukocytes to the endothelium requires the interaction of integrins on the surface of leukocytes with intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and the selectins on the endothelial cells. Soluble forms of these adhesion molecules are present in endothelial cell culture supernatants and human sera and there is correlation of levels of soluble cell adhesion molecules 5 with their membrane-bound expression. Serum soluble E-selectin levels have been variably associated with a number of common diseases, including atherosclerosis, 3,4,6,7 Type 1, 7–9 and Type 2 diabetes. 10 Investigations into the relationship of E-selectin levels to long-term diabetic complications have however produced inconsistent results. In a nested case-control analysis of the EURODIAB Prospective Complications Study (nϭ543), patients with macro-or microvascular complications had higher E-selectin levels than those without long-term complications. 11 In another report from EURODIAB (nϭ540), soluble E-selectin levels were positively associated with retinopathy, albuminuria, and cardiovascular disease in univariate analysis. for other risk factors, including HbA1c, the association between E-selectin levels …