Genome-wide association study revealed novel candidate gene loci associated with soluble E-selectin levels in a Taiwanese population

Background and aims: Increase soluble E-selectin (sE-selectin) levels are associated with various inflammation and cardiometabolic disorders. Methods: This study aimed to investigate the genetic determinants of circulating sE-selectin levels by genome-wide association study (GWAS) in 4,525 Taiwan Biobank (TWB) participants and genotype-phenotype association analysis for sE-selectin level-determining alleles in over 80,000 TWB participants. Results: By GWAS, ABO, SELE, and FUT6 gene variants were identified as the determinants of sE-selectin levels, which reach genome-wide significance (maximum p = 3.25 × 10⁻²⁷¹, 4.81 × 10⁻¹⁴, and 9.64 × 10⁻¹², respectively). After further adjustment for the lead ABO rs2519093 genotypes, three novel gene loci, EVI5, FER and DMAC1, were associated with sE-selectin levels at p < 5 × 10⁻⁷. Three other previously reported gene loci, CELSR2, ST3GAL6-AS1, and HNF1A-AS1, also showed supportive evidence for the association with sE-selectin levels (maximum p < 0.0073). A multivariate analysis revealed age, body mass index, current smoking, hemoglobin A1C, hematocrit, leukocyte and platelet counts, serum alanine aminotransferase, triglycerides, and uric acid levels were independently associated with sE-selectin levels, in which the above ten gene loci contribute to 27.68% of the variance. For genotype-phenotype association analysis, a pleiotropic effect was demonstrated with genome-wide significant association between ABO gene variants and total and low-density-lipoprotein cholesterol levels, leukocyte counts and hematocrit. Conclusions: Our data provide novel insight into the regulation of sE-selectin levels. These results may open new avenues in understanding the critical role of E-selectin on the pathogenesis of inflammatory and cardiometabolic disorders.