on September 3, 2009
Published online before print September 3, 2009, doi: 10.1161/ATVBAHA.109.192971
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Submitted on August 15, 2008
Accepted on August 20, 2009
Genome-Wide Association Identifies the ABO Blood Group as a Major Locus Associated With Serum Levels of Soluble E-Selectin
Andrew D. Paterson *;
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.
* To whom correspondence should be addressed. 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, excluded population stratification, fine-mapped the association to sub-A alleles, and also document association with additional variation in the ABO region.
Key words: E-selectin • ABO blood group • genome-wide association • SNP