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

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.

l‐selectin gene polymorphisms in Graves' disease

“…This hypothesis was supported by a recent study by Takei et al. , which showed that the l ‐selectin gene promoter carried with –642T allele exhibited more active transcription than the one with –642C allele 34 . We also investigated the correlation of serum s l ‐seletin concentrations with C‐642T genotypes in 131 subjects.…”

Association of the 98T ELAM-1 Polymorphism With Increased Bleeding After Cardiac Surgery

“…Despite this LD, a third, untested SNP could actually be the conveyor of the biological effect; for example 1402C/T 37 or Leu554Phe. 38 ELAM-1 SNPs have also been noted to be in LD with other selectin molecules on the same gene, such as L-selectin, 39 further complicating the potential for LD.…”

IgA Nephropathy: Insights into Genetic Basis and Treatment Options

“…In addition, haplotype relative risk (HRR) analyses showed that these same SNP alleles were more often transmitted to patients (HRR = 1.568, P < 0.014 for the 2093C allele; HRR = 2.114, P < 0.001 for the 2180T allele) [Li YJ et al, 2004]. The same group using a similar approach recently reported that the Megsin 23167G SNP variant is associated with both susceptibility and progression of IgAN in 435 Chinese patients and their family members using TDT and HRR analyses [Takei et al, 2006]. The GG genotype was found to be associated with severe histologic lesions and disease progression.…”