Elsevier

Cytokine

Volume 38, Issue 2, May 2007, Pages 84-89
Cytokine

Molecular screening and association study of IL15 gene polymorphisms in rheumatoid arthritis

https://doi.org/10.1016/j.cyto.2007.05.005Get rights and content

Abstract

Interleukin 15 (IL-15) is a pleiotropic pro-inflammatory cytokine known to play a relevant role in rheumatoid arthritis (RA) pathogenesis. In this study we aimed to investigate for the first time the contribution of IL15 gene to RA susceptibility. We screened 13 single nucleotide polymorphisms (SNPs) localised within IL15 regulatory regions (promoter, 5′ UTR region and 3′ UTR region) in a total of 420 individuals, who were genotyped by direct sequencing of PCR products. In addition, an association study of these IL15 SNPs was conducted in three independent case-control cohorts of Spanish Caucasian origin, including a total of 645 RA patients and 656 healthy controls. The presence of the 13 selected IL15 SNPs in our population was confirmed and no new genetic variants were found. The distribution of the IL15 selected SNPs in RA patients and controls showed no statistically significant deviation in any of the populations studied. Additionally, we performed a haplotype analysis that revealed three IL15 haplotype blocks. None of the haplotype blocks was associated with RA susceptibility or severity in the three cohorts analysed. Our results suggest that the IL15 gene polymorphisms do not appear to play a major role in RA genetic predisposition in our population.

Introduction

Clinical features of active rheumatoid arthritis (RA) such as articular pain, cartilage erosions, swelling and joint deformity are thought to be mediated in part by an aberrant cytokine regulation that results in the altered pro-inflammatory response observed in RA patients [1]. In this regard, one of the most relevant cytokines that plays a pivotal role in RA pathogenesis is interleukin (IL) 15 [2].

IL-15 expression was demonstrated in the synovial membrane and synovial T cells of RA patients with active RA [3]. IL-15 exerts a potent chemo-attractant effect and can both recruit and activate T cells in the synovial compartment [4]. IL-15-activated T cells from RA patients are able to stimulate monocytes to produce tumor necrosis factor α (TNF-α) in a cell-contact-dependent mechanism [5]. Thus, IL-15 has been suggested as an important enhancer of TNF-α production in RA synovial membranes [2]. Furthermore, IL-15 may be implicated in the perpetuation of synovial inflammation in RA by generating a positive-feedback loop, in which IL-15 synthesis by activated synovial macrophages or fibroblasts could induce a continuous T-cell recruitment [2]. Another interesting finding is the potential therapeutic role of IL-15 in RA. The use of IL-15 inhibitors suppresses the development of collagen-induced arthritis (CIA) while a human monoclonal antibody targeting IL-15 (HuMax-IL15) has beneficial effects for RA in vitro and in vivo [6], [7]. On this basis, IL-15 could be proposed as an interesting candidate gene for RA.

The IL15 gene is located at the 4q31 chromosomal region and its expression is regulated both at the transcriptional and translational levels [2]. It was observed that RA patients present an increased expression of the IL-15 protein when compared to patients affected by other rheumatic diseases [3], [4], [5], [6], [7], [8]. Genetic polymorphisms affecting cytokines can lead to variations in the production and level of the protein, as reported for polymorphisms affecting TNF-α and gamma interferon (IFNγ) [9]. Thus, the presence of genetic polymorphisms in the IL15 gene regulatory regions might affect IL15 expression and could provide an explanation for the differences in IL-15 levels observed among individuals.

Having in mind all these evidences, we aimed to investigate, through the analysis of different genetic variants affecting IL15 gene regulatory regions, the possible involvement of IL15 gene in RA susceptibility and severity.

Section snippets

Subjects

A two-stage case-control association study was design to analyze the role of IL15 gene in RA genetic predisposition. First we performed an initial screening and association study of IL15 gene polymorphisms in a cohort including 200 RA patients and 220 healthy controls recruited at “Hospital Virgen de las Nieves” in Granada, Southern Spain. In addition, two independent case-control cohorts from Madrid, Central Spain (“Hospital La Paz”, 215 RA patients and 210 healthy controls) and Lugo, North

Screening IL15 SNPs

The IL15promoter, 5′ UTR and 3′ UTR regions were sequenced in a first cohort from Granada (420 individuals). We could confirm that the 13 SNPs selected from the public database were present in our study population. However, SNP 1 and SNP 8 were not polymorphic in our population and therefore were excluded for the association study (Table 3). The allelic frequencies of the tested SNPs were similar to those reported for Caucasian populations in the public database and in previous studies (//www.ncbi.nlm.nih.gov/

Discussion

IL-15 was described in 1994 as a T cell activating factor belonging to the 4α helix cytokine superfamily with structural homology to IL-2 [11]. IL-15 has pleiotropic and physiological activities in both the innate and acquired immune responses. This cytokine is implicated in the induction of T cell proliferation, the activation of cytotoxic effector cells, the co-stimulation of immunoglobulin synthesis by B cells and the activation of monocytes [18]. In addition, IL-15 plays an essential role

Acknowledgments

This work was supported by Grant SAF2003-03460 and SAF2006-0000398 from Plan Nacional de I+D (CICYT).

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