Abstract 17304: Dense Genotyping of Candidate Gene Loci Identifies Variants Associated with Soluble E-Selectin Levels

Abstract

Background: Elevated soluble (s) E-selectin levels have been associated with various cardiovascular diseases. Recently, genetic variants in the ABO blood group have been related to E-selectin levels in a small cohort of patients with type 1 diabetes. We evaluated whether this association is reproducible in a population-based sample. Methods: We used a high-density genotyping array containing single-nucleotide polymorphisms (SNPs) from E-selectin candidate genes (50K IBC Chip) selected on known biology of E-selectin metabolism, mouse genetic studies, and human genetic association studies. SNP selection was based on tagging SNPs and included low-frequency nonsynonymous SNPs. 1,508 men and women from a randomly drawn subsample of the baseline examination of the MONICA/KORA Augsburg Cohort Study, conducted between 1984 and 1995, with measurements of sE-selectin and genotyping by the 50K IBC Chip comprised the study population. Linear regression analysis with adjustment for age, sex and survey was applied to assess associations between gene variants and sE-selectin levels. The significance level was defined as 5.0e-6 accounting for multiple testing. Results: Twelve SNPs, all from the ABO blood group candidate gene (ABO) were significantly associated with levels of E-selectin. The strongest association was observed for rs651007 with a change of E-selectin level per one copy of the minor allele of -18.59 ng/ml (p=5.79*10-56). All twelve SNPs had minor allele frequencies above 20% showing a substantial gene variation. Conclusions: Our findings indicate that the genetic variants at the ABO locus affect sE-selectin levels. These findings may not only enhance our understanding of adhesion molecule biology, but may also provide a focus for several novel research avenues.