Presence of the full-length KIR2DS4 gene reduces the chance of rheumatoid arthritis patients to respond to methotrexate treatment

Abstract

BackgroundKIR genes coding for natural killer cell immunoglobulin-like receptors, KIR, influence the effector and regulatory function of NK cells as well as some subpopulations of T lymphocytes (e.g. CD4+CD28-KIR+) depending on presence of ligands (particularly HLA-C molecules). KIR-KIR ligand interaction may lead to the development of autoimmune disorders, including rheumatoid arthritis (RA). However, their role in the response of RA patients to methotrexate therapy is not known.MethodsKIR genes and KIR-ligand (HLA-C C1/C2 allomorphs) genotyping was performed using the PCR-SSP method in 312 RA patients (179 classified as good responders and 133 as poor responders using DAS28 criteria). Thus, we evaluated the association of KIR genes and HLA-C allomorphs with the response to methotrexate (MTX) treatment.ResultsWe observed that patients possessing the full-length KIR2DS4 (KIR2DS4f) gene had a lower chance of responding in comparison to KIR2DS4f-negative cases. This phenomenon was observed both in erosive disease (ED) and rheumatoid factor (RF) positive and in ED- and RF-negative patients. Interestingly, the observed effect of the KIR2DS4f gene was strongest in individuals possessing medium values (20-33 mm/h) of the erythrocyte sedimentation rate (ESR). Patients with high ESR values had low probability and, in contrast, patients with low ESR had a high probability of MTX response, and the presence of KIR2DS4f did not affect their outcome. Additionally, we show that the KIR2DS4f effect did not depend on the presence of either C1 or C2 allomorphs.ConclusionOur results suggest that the response of RA patients with medium ESR values to MTX treatment may be dependent on the full-length KIR2DS4 gene.

KIR/HLA Gene Profile Implication in Systemic Sclerosis Patients from Mexico

“…In SSc patients, the 2DS4del presence was associated with risk to SSc, while 2DS4full was associated with reduced risk. In autoimmune diseases, 2DS4full was associated with a lower chance of response to methotrexate in RA patients [39]. In other medical conditions like a kidney transplant, KIR2DS4 gene variants are associated with the risk of rejection to kidney transplantation [40].…”

HLA-Cw6-positive patients with psoriasis show improved response to methotrexate treatment

“…For example, the response rate to MTX has recently been shown to be a associated with another genetic marker (KIR2DS4 alleles) in rheumatoid arthritis (RA). 8 The genetic association of HLA-Cw6 with the response of PsA to MTX has not been reported to date.…”

“…Alternatively, the presence of systemic inflammatory arthritis itself may well affect not only psoriasis severity but also response to treatment. For example, the response rate to MTX has recently been shown to be a associated with another genetic marker ( KIR2DS4 alleles) in rheumatoid arthritis (RA) . The genetic association of HLA‐Cw6 with the response of PsA to MTX has not been reported to date.…”

Association of Killer Cell Immunoglobulin- Like Receptor Genes in Iranian Patients with Rheumatoid Arthritis

“…As important determinants of NKC response, KIR profile not only affects the risk for developing RA but also modulates the special clinical feature by which RA presents in each patient for example, studies have revealed that the presence of KIR2DS2 improves responsiveness to anti-TNF-α therapy [ 10 ] and the presence of KIR2DS4 reduces RA patients’ responsiveness to methotrexate therapy [ 15 ]. KIR genotyping has therefore been a subject of interest and replication studies have revealed various KIR genotypes which render the individual susceptible to RA.…”