Comprehensive association study of genetic variants in the IL-1 gene family in systemic juvenile idiopathic arthritis

Abstract

Patients with systemic juvenile idiopathic arthritis (sJIA) have a characteristic daily spiking fever and elevated levels of inflammatory cytokines. Members of the interleukin-1 (IL-1) gene family have been implicated in various inflammatory and autoimmune diseases, and treatment with the IL-1 receptor antagonist, Anakinra, shows remarkable improvement in some patients. This work describes the most comprehensive investigation to date of the involvement of the IL-1 gene family in sJIA. A two-stage case-control association study was performed to investigate the two clusters of IL-1 family genes using a tagging single nucleotide polymorphism (SNP) approach. Genotyping data of 130 sJIA patients and 151 controls from stage 1 highlighted eight SNPs in the IL1 ligand cluster region and two SNPs in the IL1 receptor cluster region as showing a significant frequency difference between the populations. These 10 SNPs were typed in an additional 105 sJIA patients and 184 controls in stage 2. Meta-analysis of the genotypes from both stages showed that three IL1 ligand cluster SNPs (rs6712572, rs2071374 and rs1688075) and one IL1 receptor cluster SNP (rs12712122) show evidence of significant association with sJIA. These results indicate that there may be aberrant control of the activity of the IL-1 family in sJIA patients causing the increased susceptibility to the disease.

Pathogenesis of adult-onset Still’s disease: new insights from the juvenile counterpart

“…Polymorphisms have been described in genes encoding innate immunity-associated factors and cytokines, such as IL-6, IL-1a, IL1-RN, macrophage inhibitory factor (MIF), or TNF in patients with sJIA [28][29][30] and IL-18, or MIF in patients with AOSD [31,32]. Loss-of-function variants in P2RX7, which encodes an ATP receptor that regulates IL-1 processing and secretion, have also been reported [33].…”

Cytokines of the Immune System

“…6 Meta-analysis of the risk for systemic juvenile idiopathic arthritis showed that three IL-1 gene cluster SNPs (rs6712572, rs2071374, and rs1688075) and one IL-1 receptor cluster SNP (rs12712122) are associated with disease. 7 The genetic susceptibility for ankylosing spondylitis may be associated with the IL1A gene polymorphisms. 8 According to meta-analysis the following polymorphisms in the IL-1 gene cluster contribute to increased risk: IL-1RN (VNTR), IL-1A (rs1800587), and IL36B (rs1900287), with a distinct discrepancy for these associations among races.…”

Caspase-1 als Regulator der Autoinflammation bei rheumatischen Erkrankungen

“…Es wurden jedoch eine gesteigerte Aktivierung von Inflammasomen und eine daraus resultierende gesteigerte Sekretion von IL-1β und abhängigen Zytokinen (IL-6, TNF-α) beschrieben [76][77][78]. Die gut dokumentierte Assoziation mit Punktmutationen in regulatorischen Regionen IL-1-assoziierter Gene, weiterer proinflammatorischer Gene (IL-6, TNF) sowie dem IL-10-Promoter (aber auch vielen anderen Genen) deutet auf eine genetische Komponente in der Pathophysiologie hin [79][80][81][82][83]. Letztendlich könnte die Akkumulation verschiedener genomischer Varianten zu einem Ungleichgewicht zwischen Caspase-1-abhängigen proinflammatorischen Botenstoffen und antiinflammatorischen Regulatoren führen und Entzündungs-prozesse bei der sJIA auslösen und/oder unterhalten [70].…”