Association of NKG2D gene variants with susceptibility and severity of rheumatoid arthritis

Abstract

NKG2D (KLRK1) is a C-type lectin receptor present on natural killer (NK) cells, γδ, CD8 and CD4 T cells. Upon ligand binding, NKG2D mediates activatory and co-stimulatory signals to NK cells and activated CD4 T cells, respectively. Polymorphisms in NKG2D predispose to infectious diseases, cancer, transplantation and autoimmune disorders. We studied the influence of this NK receptor polymorphism on predisposition to and modification of the disease phenotype in patients with rheumatoid arthritis (RA). Eight different single nucleotide polymorphisms (SNP) in the NKG2 gene were genotyped in 236 patients with RA and 187 controls using Taqman 5' nuclease assays. NKG2D genotype/allele frequency did not differ between patients and controls. Subgroup analysis showed that the frequency of A allele of NKG2D9 and T allele of NKG2D10 was significantly higher in patients with deformities (a marker of severe disease) [11 versus 5%, Pc = 0·03, odds ratio (OR) = 2·44, 95% confidence interval (CI) = 1·09-5·98 and 10 versus 4%, Pc = 0·04, OR = 2·45, 95% CI = 1·05-6·39, respectively], while the frequency of alleles G of NKG2D9 and A of NKG2D10 was greater in patients without deformities (Pc = 0·03, OR = 0·41, 95% CI = 0·17-0·91 and Pc = 0·04, OR = 0·41, 95% CI = 0·16-0·96). Similar trends of association were observed with deforming phenotype of RA in female patients and deforming young onset RA subgroups. Haplotype analysis revealed that the frequency of haplotype G-C-A-G-A-T-C-C was higher in patients than in controls (12 versus 8%, P = 0·04, OR = 1·61, 95% CI = 1·01-2·55), suggesting that it may predispose to RA. Our study suggests that the NKG2D gene polymorphisms may modify the risk of development and severity of RA.

NKG2D ligands in inflammatory joint diseases: analysis in human samples and mouse models

“…In joint diseases, NKG2DL were mainly investigated in RA. In line with previous reports [4] between OA and other arthritides. Interestingly, Rae1 appeared also upregulated in joints harvested from MSU crystals-injected mice, suggesting that cellular damage and /or activation following urate crystals-induced inflammation might respond to NKG2D / NKG2DLs cross talk, further supporting a regulatory role for NK or NKT cells in gout [19].…”

Increased natural killer cell subsets with inhibitory cytokines and inhibitory surface receptors in patients with recurrent miscarriage and decreased or normal subsets in kidney transplant recipients late post-transplant

“…An up-regulation of inhibiting and stimulating NKG2 receptors was observed after allogeneic or autologous haematopoietic stem cell transplantation and in patients with rheumatoid arthritis, whereby a gene polymorphism of NKG2 was found to be associated with susceptibility and severity of rheumatoid arthritis [13][14][15]. Our focus was upon NK cells, NK T cells and T cells that produce IL-4 and/or TGF-b and/or co-express the inhibitory surface receptors CD158a (KIR2DL1), CD158b (KIR2DL2/L3), CD158e (KIR3DL1) and/or NKG2A and/or the stimulating receptor NKG2D.…”

“…Our focus was upon NK cells, NK T cells and T cells that produce IL-4 and/or TGF-b and/or co-express the inhibitory surface receptors CD158a (KIR2DL1), CD158b (KIR2DL2/L3), CD158e (KIR3DL1) and/or NKG2A and/or the stimulating receptor NKG2D. An up-regulation of inhibiting and stimulating NKG2 receptors was observed after allogeneic or autologous haematopoietic stem cell transplantation and in patients with rheumatoid arthritis, whereby a gene polymorphism of NKG2 was found to be associated with susceptibility and severity of rheumatoid arthritis [13][14][15]. Certain CD158 determinants summarized as killer cell immunoglobulin-like receptors (KIR) were found to be associated with RM [16][17][18][19] as well as control of viral infection, chronic rejection and graft loss in renal transplantation [20,21].…”

Prognostic significance of high-mobility group box protein 1 genetic polymorphisms in rheumatoid arthritis disease outcome

“…Previous research has found that specific SNPs in GWAS-identified susceptibility regions are associated with RA disease progression. For instance, certain SNPs in the interleukin ( IL ) -32 , NKG2D and vascular endothelial growth factor ( VEGF ) genes are known to contribute to the progression of RA 7 - 9 .…”