Dataset Information

A candidate gene approach identifies an IL33 genetic variant as a novel genetic risk factor for GCA.

ABSTRACT:

Introduction

Increased expression of IL-33 and its receptor ST2, encoded by the IL1RL1 gene, has been detected in the inflamed arteries of giant cell arteritis (GCA) patients. The aim of the present study was to investigate for the first time the potential influence of the IL33 and IL1RL1 loci on GCA predisposition.

Methods

A total of 1,363 biopsy-proven GCA patients and 3,908 healthy controls from four European cohorts (Spain, Italy, Germany and Norway) were combined in a meta-analysis. Six genetic variants: rs3939286, rs7025417 and rs7044343, within the IL33 gene, and rs2058660, rs2310173 and rs13015714, within the IL1RL1 gene, previously associated with immune-related diseases, were genotyped using predesigned TaqMan assays.

Results

A consistent association between the rs7025417 polymorphism and GCA was evident in the overall meta-analysis, under both allele (P(MH) = 0.041, OR = 0.88, CI 95% 0.78-0.99) and recessive (P(MH) = 3.40E-03, OR = 0.53, CI 95% 0.35-0.80) models. No statistically significant differences between allele or genotype frequencies for the other IL33 and IL1RL1 genetic variants were detected in this pooled analysis.

Conclusions

Our results clearly evidenced the implication of the IL33 rs7025417 polymorphism in the genetic network underlying GCA.

SUBMITTER: Marquez A

PROVIDER: S-EPMC4237421 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Publications

A candidate gene approach identifies an IL33 genetic variant as a novel genetic risk factor for GCA.

Márquez Ana A Solans Roser R Hernández-Rodríguez José J Cid Maria C MC Castañeda Santos S Ramentol Marc M Rodriguez-Rodriguez Luis L Narváez Javier J Blanco Ricardo R Ortego-Centeno Norberto N Palm Oyvind O Diamantopoulos Andreas P AP Braun Niko N Moosig Frank F Witte Torsten T Beretta Lorenzo L Lunardi Claudio C Cimmino Marco A MA Vaglio Augusto A Salvarani Carlo C González-Gay Miguel A MA Martín Javier J

PloS one 20141119 11

<h4>Introduction</h4>Increased expression of IL-33 and its receptor ST2, encoded by the IL1RL1 gene, has been detected in the inflamed arteries of giant cell arteritis (GCA) patients. The aim of the present study was to investigate for the first time the potential influence of the IL33 and IL1RL1 loci on GCA predisposition.<h4>Methods</h4>A total of 1,363 biopsy-proven GCA patients and 3,908 healthy controls from four European cohorts (Spain, Italy, Germany and Norway) were combined in a meta-an ...[more]

PMID: 25409453

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Project description:BackgroundRheumatoid arthritis (RA) is a chronic autoimmune disorder affecting approximately 1% of the population. The disease results from the interplay between an individual's genetic background and unknown environmental triggers. Although human leukocyte antigens (HLAs) account for approximately 30% of the heritable risk, the identities of non-HLA genes explaining the remainder of the genetic component are largely unknown. Based on functional data in mice, we hypothesized that the immune-related genes complement component 5 (C5) and/or TNF receptor-associated factor 1 (TRAF1), located on Chromosome 9q33-34, would represent relevant candidate genes for RA. We therefore aimed to investigate whether this locus would play a role in RA.Methods and findingsWe performed a multitiered case-control study using 40 single-nucleotide polymorphisms (SNPs) from the TRAF1 and C5 (TRAF1/C5) region in a set of 290 RA patients and 254 unaffected participants (controls) of Dutch origin. Stepwise replication of significant SNPs was performed in three independent sample sets from the Netherlands (ncases/controls = 454/270), Sweden (ncases/controls = 1,500/1,000) and US (ncases/controls = 475/475). We observed a significant association (p < 0.05) of SNPs located in a haplotype block that encompasses a 65 kb region including the 3' end of C5 as well as TRAF1. A sliding window analysis revealed an association peak at an intergenic region located approximately 10 kb from both C5 and TRAF1. This peak, defined by SNP14/rs10818488, was confirmed in a total of 2,719 RA patients and 1,999 controls (odds ratiocommon = 1.28, 95% confidence interval 1.17-1.39, pcombined = 1.40 x 10(-8)) with a population-attributable risk of 6.1%. The A (minor susceptibility) allele of this SNP also significantly correlates with increased disease progression as determined by radiographic damage over time in RA patients (p = 0.008).ConclusionsUsing a candidate-gene approach we have identified a novel genetic risk factor for RA. Our findings indicate that a polymorphism in the TRAF1/C5 region increases the susceptibility to and severity of RA, possibly by influencing the structure, function, and/or expression levels of TRAF1 and/or C5.

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Dataset Information

A candidate gene approach identifies an IL33 genetic variant as a novel genetic risk factor for GCA.

Introduction

Methods

Results

Conclusions

Publications

A candidate gene approach identifies an IL33 genetic variant as a novel genetic risk factor for GCA.

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