Functional impact of IgA nephropathy-associated selectin gene haplotype on leukocyte-endothelial interaction

Immunogenetics. 2006 Jun;58(5-6):355-61. doi: 10.1007/s00251-006-0120-7. Epub 2006 Apr 28.

Abstract

Previously, we discovered single-nucleotide polymorphisms (SNPs) associated with Immunoglobulin A (IgA) nephropathy in selectin genes, which were 712C>T(P238S) in L selectin, -642A>G in the promoter region of L selectin, and 1402C>T(H468Y) in E selectin. Interestingly, these SNPs were in nearly complete linkage disequilibrium, thus two haplotypes, disease-associated TGT and wild-type (Wt) CAC, were constructed. To investigate the functional significance of TGT haplotype, a stable CHO transfectant expressing a P238S-L-selectin variant (CHO-varL) and a recombinant adenovirus vector containing an H468Y-E-selectin variant (Ad-varE) were established and compared to their Wt counterparts. Under flow, CHO-varL exhibited significantly less adhesion over IL-1beta-activated HUVEC monolayers compared to CHO-wtL. Furthermore, a luciferase reporter construct, containing a promoter region of the L-selectin variant (luc-varL), exhibited significantly less transcription activity compared to Wt (luc-wtL). These results suggest that the adhesive interactions and expression level of L selectin in disease-associated haplotypes are significantly compromised, indicating a potential role of these SNPs in the pathogenesis of inflammatory diseases, including IgA nephropathy.

MeSH terms

  • Amino Acid Substitution
  • Animals
  • CHO Cells
  • Cell Adhesion / genetics*
  • Cell Adhesion / immunology
  • Cricetinae
  • Cricetulus
  • E-Selectin / genetics
  • E-Selectin / metabolism
  • Endothelium, Vascular / immunology
  • Glomerulonephritis, IGA / genetics*
  • Glomerulonephritis, IGA / immunology
  • HL-60 Cells
  • Haplotypes
  • Humans
  • L-Selectin / genetics
  • L-Selectin / metabolism*
  • Leukocytes / immunology*
  • Mutation
  • Polymorphism, Single Nucleotide / genetics*
  • Promoter Regions, Genetic

Substances

  • E-Selectin
  • L-Selectin