IL1RN genetic variations and risk of IPF: a meta-analysis and mRNA expression study

Nicoline M Korthagen,Jan C Grutters,Henk J T Ruven,Karin M Kazemier,Coline H M Van Moorsel

doi:10.1007/s00251-012-0604-6

Abstract

Idiopathic pulmonary fibrosis (IPF) is a rare and devastating lung disease of unknown aetiology. Genetic variations in the IL1RN gene, encoding the interleukin-1 receptor antagonist (IL-1Ra), have been associated with IPF susceptibility. Several studies investigated the variable number tandem repeat (VNTR) or single nucleotide polymorphisms rs408392, rs419598 and rs2637988, with variable results. The aim of this study was to elucidate the influence of polymorphisms in IL1RN on IPF susceptibility and mRNA expression. We performed a meta-analysis of the five case–control studies that investigated an IL1RN polymorphism in IPF in a Caucasian population. In addition, we investigated whether IL1RN mRNA expression was influenced by IL1RN polymorphisms. The VNTR, rs408392 and rs419598 were in tight linkage disequilibrium, with D′ > 0.99. Furthermore, rs2637988 was in linkage disequilibrium with the VNTR (D′ = 0.90). A haploblock of VNTR*2 and the minor alleles of rs408392and rs419598 was constructed. Meta-analysis revealed that this VNTR*2 haploblock is associated with IPF susceptibility both with an allelic model (odds ratio = 1.42, p = 0.002) and a carriership model (odds ratio = 1.60, p = 0.002). IL1RN mRNA expression was significantly influenced by rs2637988, with lower levels found in carriers of the (minor) GG genotype (p < 0.001). From this meta-analysis, we conclude that the VNTR*2 haploblock is associated with susceptibility to IPF. In addition, polymorphisms in IL1RN influence IL-1Ra mRNA expression, suggesting that lower levels of IL-1Ra predispose to developing IPF. Together these findings demonstrate that the cytokine IL-1Ra plays a role in IPF pathogenesis.

Highlights

Idiopathic pulmonary fibrosis (IPF) is a rapidly progressing lung disease with unknown cause and a median survival of only 2.5 to 3.5 years (Gribbin et al 2006; Mapel et al 1998; Rudd et al 2007)
Analysis of European HapMap population genotypes showed that the two biallelic single nucleotide polymorphism (SNP) rs408392 and rs419598 are in complete linkage disequilibrium (D′ 0 1)
We observed in the Dutch cohort, that in all individuals, the longer variable number tandem repeat (VNTR) alleles with three or more repeats corresponded completely to the major allele of rs408392 and of rs419598, while the VNTR allele 2 (VNTR*2) allele corresponded to the minor alleles of these SNPs

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is a rapidly progressing lung disease with unknown cause and a median survival of only 2.5 to 3.5 years (Gribbin et al 2006; Mapel et al 1998; Rudd et al 2007). IPF is a rare disease with a prevalence of 14 per 100,000 persons, but the incidence continues to rise and it is an important cause of respiratory mortality (Navaratnam et al 2011; Raghu et al 2006). Familial and ethnic clustering support the theory that genetic variations influence IPF disease susceptibility, and identification of the genes involved can increase understanding of this complex disease (Grutters and du Bois 2005). Because no effective treatment for IPF is available at present, genetic analysis may reveal a novel target for therapy.

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