Identification of a new putative functional IL18 gene variant through an association study in systemic lupus erythematosus

Abstract

Interleukin-18 (IL-18) is a proinflammatory cytokine that plays an important role in chronic inflammation and autoimmune disorders. In this study, we aimed to determine the potential role of the IL18 gene in SLE. To define the genetic association of the IL18 and SLE, we have genotyped nine SNPs in an independent set of Spanish cases and controls. The IL18 polymorphisms were genotyped by PCR, using a predeveloped TaqMan allele discrimination assay. Two SNPs were still significant after fine mapping of the IL18 gene. The SNP (rs360719) surviving correction for multiple tests was genotyped in two replication cohorts from Italy and Argentina. After the analysis, a significance with rs360719 C-allele remained across the sets and after the meta-analysis (Pooled OR = 1.37, 95% CI 1.21-1.54, combined P = 3.8E-07, Pc = 1.16E-06). Quantitative real-time PCR was performed to assess IL18 mRNA expression in PBMC from subjects with different IL18 rs360719 genotypes. We tested the effect of the IL18 rs360719 polymorphism on the transcription of IL18 by electrophoretic mobility shift assay and western blot. We found a significant increase in the relative expression of IL18 mRNA in individuals carrying the rs360719 C-risk allele; in addition we show that the polymorphism creates a binding site for the transcriptional factor OCT-1. These findings suggest that the novel IL18 rs360719 variant may play an important role in determining the susceptibility to SLE and it could be a key factor in the expression of the IL18 gene.

Absence of Association ofInterleukin-18Gene Polymorphisms with Primary Immune Thrombocytopenia in a Chinese Han Population

“…It was reported that the -607 C and -137 G alleles could induce higher IL-18 expression at transcription levels through favoring the binding of cAMP-responsive element protein and histone 4 transcription factor-1, respectively (Giedraitis et al, 2001;Smith and Humphries, 2009). Recently, these promoter SNPs have been found associated with genetic susceptibility to many autoimmune diseases, such as systemic lupus erythematosus, type 1 diabetes, and rheumatoid arthritis (Dong et al, 2007;Sánchez et al, 2009;Wen et al, 2014).…”

Polimorfismos genéticos de interleuquina 6 (IL6), IL6R e IL18: asociación con componentes del síndrome metabólico en niños chilenos con obesidad

“…Es así como los portadores del alelo C de rs360719 muestran un incremento en la expresión del RNA mensajero de este gen versus el alelo T 36 . En el caso de rs187238, el alelo G se correlaciona con una mayor actividad transcripcional del promotor 33 .…”

IL18 rs360719 A>G, IL18R1 rs13015714 G>T, IL18RAP rs917997 C>T and IL28B rs8099917 T>G polymorphisms and risk of gastric cardiac adenocarcinoma

“…OCT-1 is known to be a ubiquitously expressed factor and is involved in the regulation of several genes; it may also repress the expression of certain cytokines (22). Allele A of rs917997, a SNP 1.5 kb downstream of IL18RAP, was found to be strongly associated with coeliac disease susceptibility (23).…”