Influence of NKG2D Genetic Variants on Response to Anti-TNF Agents in Patients with Rheumatoid Arthritis

Abstract

A natural killer group 2 member D (NKG2D) acts as a powerful activating and co-stimulatory receptor on immune effector cells including NK and T cells. Disruptions within the NKG2D signalling pathway may trigger an exacerbated immune response and promote autoimmune reactions. The objective of the study was to evaluate a plausible role of polymorphisms within the NKG2D gene as a predictor of how effective anti-tumor necrosis factor (TNF) therapy is in rheumatoid arthritis (RA) patients. A total of 280 RA patients receiving anti-TNF therapy were genotyped for NKG2D rs2255336 (A > G), rs1049174 (C > G), and rs1154831 (C > A). Clinical response was evaluated according to the European League against Rheumatism (EULAR) criteria at the 12th and 24th week. Both the NKG2D rs225336 and rs1049174 polymorphisms were significantly associated with efficacy of TNF inhibitors. Inefficient therapy was more frequently observed in patients with rs2255336 GG or rs1049174 CC genotype as compared to other genotypes (p-value = 0.003 and p-value = 0.004, respectively). The presence of the rs2255336 G or the rs1049174 C allele correlated with a worse EULAR response (p-value = 0.002, p-value = 0.031, respectively). Moreover, patients carrying the rs2255336 or rs1049174 heterozygous genotype achieved better EULAR responses than patients with homozygous genotypes (p-value = 0.010 and p-value = 0.002, respectively). Data from the present study provides evidence that NKG2D polymorphisms may affect response to anti-TNF inhibitors in RA patients.

Polymorphisms within the RANK and RANKL Encoding Genes in Patients with Rheumatoid Arthritis: Association with Disease Progression and Effectiveness of the Biological Treatment

“…The moderate response was defined as either ΔDAS28 > 1.2 and DAS28 at endpoint > 3.2 or 0.6 < ΔDAS28 ≤ 1.2 and DAS28 at endpoint ≤ 5.1. A lack of response was defined as ΔDAS28 ≤ 0.6 or 0.6 < ΔDAS28 ≤ 1.2 and DAS28 at endpoint > 5.1, as previously described (Iwaszko et al 2018 ).…”

“…Biologic agents successfully suppress disease symptoms, as well as stop further bone damage and reduce disability (Geiler et al 2011 ). Our previous studies showed that some genetic features may influence disease susceptibility or anti-TNF therapy outcome in RA patients (Bogunia-Kubik et al 2015 ; Gębura et al 2017 ; Iwaszko et al 2018 ; Świerkot et al 2015a ).…”

The Role of Natural Killer Group 2, Member D in Chronic Inflammation and Autoimmunity

“…Single-nucleotide polymorphisms in both MICA and NKG2D have been associated with RA, suggesting MICA and NKG2D as RA susceptibility genes ( 55 , 56 ). Moreover, a recent study evaluated the role of polymorphisms in KLRK1 gene with efficacy of α-TNF therapy in RA patients ( 57 ), identifying two polymorphisms associated with better response and two polymorphisms associated with inefficient response to therapy. More functional studies that would dissect the direct effect of the polymorphisms to the TNF production and resistance to α-TNF therapy would be beneficial to understand the impact of this association.…”

Identification of Disease Risk DNA Variations is Shaping the Future of Precision Health

“…This Special Issue on DNA Variations in Evolution and Human Diseases features a series of studies that identify new pathological and protective DNA variations in common human diseases and conditions including chronic periodontitis [11], familial adenomatous polyposis [12], asthma [13], rheumatoid arthritis [14], multiple myeloma [15], dental implant failure [16], tooth agenesis [17], tuberculosis [18], and developmental disorders [19,20].…”