Novel Association of ABO Histo-Blood Group Antigen with Soluble ICAM-1: Results of a Genome-Wide Association Study of 6,578 Women

Abstract

While circulating levels of soluble Intercellular Adhesion Molecule 1 (sICAM-1) have been associated with diverse conditions including myocardial infarction, stroke, malaria, and diabetes, comprehensive analysis of the common genetic determinants of sICAM-1 is not available. In a genome-wide association study conducted among 6,578 participants in the Women's Genome Health Study, we find that three SNPs at the ICAM1 (19p13.2) locus (rs1799969, rs5498 and rs281437) are non-redundantly associated with plasma sICAM-1 concentrations at a genome-wide significance level (P−8), thus extending prior results from linkage and candidate gene studies. We also find that a single SNP (rs507666, P = 5.1×10⁻²⁹) at the ABO (9q34.2) locus is highly correlated with sICAM-1 concentrations. The novel association at the ABO locus provides evidence for a previously unknown regulatory role of histo-blood group antigens in inflammatory adhesion processes. Soluble Intercellular Adhesion Molecule 1 (sICAM-1) is an inflammatory marker that has been associated with several common diseases such as diabetes, heart disease, stroke, and malaria. While it is known that blood concentrations of sICAM-1 are at least partially genetically determined, our current knowledge of which genes mediate this effect is limited. Taking advantage of new technologies allowing us to interrogate genetic variation on a whole genome basis, we found that a variation in the ABO gene is an important determinant of sICAM-1 blood concentrations. Since the ABO gene is responsible for the ABO blood groups, this discovery sheds light on a new role for blood groups and offers novel mechanisms to explain the association between sICAM-1 blood concentrations and various common diseases.