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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1958.)
© 2009 American Heart Association, Inc.

Clinical and Population Studies

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

Andrew D. Paterson; Maria F. Lopes-Virella; Daryl Waggott; Andrew P. Boright; S. Mohsen Hosseini; Rickey E. Carter; Enqing Shen; Lucia Mirea; Bhupinder Bharaj; Lei Sun; Shelley B. Bull; the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group^*

From the Program in Genetics and Genome Biology (A.D.P., S.M.H., B.B.), Hospital for Sick Children, Toronto, Canada; the Samuel Lunenfeld Research Institute of Mount Sinai Hospital (D.W., E.S., L.M., S.B.B.), Prosserman Centre for Health Research, Toronto, Canada; the Department of Medicine (A.P.B.), University Health Network, and the Dalla Lana School of Public Health (A.D.P., L.M., L.S., S.B.B.), University of Toronto, Canada; the Department of Medicine and Laboratory Services (M.F.L.-V.), Medical University of South Carolina and Ralph H. Johnson VA Medical Center, Charleston; and the Department of Biostatistics, Bioinformatics, and Epidemiology (R.E.C.), Medical University of South Carolina, Charleston.

Correspondence to Dr Andrew Paterson, Program in Genetics and Genome Biology, the Hospital for Sick Children, TMDT Building East Tower, Rm 15-707, 101 College Street, Toronto, Ontario, M5G 1L7, Canada. E-mail andrew.paterson{at}utoronto.ca

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 (P=10^–29) 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.

Previous studies have identified various biomarkers and diseases that are associated with ABO, but the physiological mechanisms are mostly unclear. Here, we show the ABO gene locus accounts for 19% of the variance in serum soluble E-selectin levels, which is produced by damage to endothelial cells, and an inflammatory marker.

Key Words: E-selectin • ABO blood group • genome-wide association • SNP