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<5x10(-8)), thus extending prior results from linkage and candidate gene studies. We also find that a single SNP (rs507666, P = 5.1x10(-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.

Figure 1. Genetic Context of Genome-Wide Significant Associations.

Genomic context for each of two loci with genome-wide association with sICAM-1 levels. The ICAM1 locus (19p13.2) is shown in Figure 1-A and the ABO locus (9q34.2) in Figure 1-B. Upper panel: Genes from RefSeq release 25. Only one isoform is shown when multiple splicing variants are known. Middle Panel: SNPs are shown according to their physical location and P-values (red dots). Also shown is the genetic distance in cM from the lowest P-value SNP (light grey line) along with the position of recombination hotspots (light grey vertical bars). Recombination rates and hotspots are based on HapMap data, as described by McVean et al. and Winckler et al. . Lower panel: Pair wise linkage disequilibrium (D′ and R²) between SNPs based on WGHS data.