Role of the IL33 and IL1RL1 pathway in the pathogenesis of Immunoglobulin A vasculitis

D Prieto-Peña ,E Galíndez-Agirregoikoa ,Javier Llorca,Santos Castañeda ,Esteban Rubio ,Oreste Gualillo,Ana Márquez ,Emilio Rodrigo,Miguel A González‐Gay ,Verónica Pulito‐Cueto ,Luis Caminal-Montero,R Blanco ,D De Argila ,Norberto Ortego‐Centeno ,Sara Remuzgo‐Martínez ,José A Miranda‐Filloy ,Belén Atienza‐Mateo ,Juan María Blanco-Madrigal ,Leticia Lera‐Gómez ,Fernanda Genre,Ana Peñalba ,Javier Narváez ,María Teresa Leonardo ,Javier Sánchez Pérez ,Luis Martín-Penagos ,Manuel León Luque ,Javier Martı́n ,Belén Sevilla‐Perez ,Paz Collado,Raquel López‐Mejías

doi:10.1038/s41598-021-95762-5

Abstract

Cytokines signalling pathway genes are crucial factors of the genetic network underlying the pathogenesis of Immunoglobulin-A vasculitis (IgAV), an inflammatory vascular condition. An influence of the interleukin (IL)33- IL1 receptor like (IL1RL)1 signalling pathway on the increased risk of several immune-mediated diseases has been described. Accordingly, we assessed whether the IL33-IL1RL1 pathway represents a novel genetic risk factor for IgAV. Three tag polymorphisms within IL33 (rs3939286, rs7025417 and rs7044343) and three within IL1RL1 (rs2310173, rs13015714 and rs2058660), that also were previously associated with several inflammatory diseases, were genotyped in 380 Caucasian IgAV patients and 845 matched healthy controls. No genotypes or alleles differences were observed between IgAV patients and controls when IL33 and IL1RL1 variants were analysed independently. Likewise, no statistically significant differences were found in IL33 or IL1RL1 genotype and allele frequencies when IgAV patients were stratified according to the age at disease onset or to the presence/absence of gastrointestinal (GI) or renal manifestations. Similar results were disclosed when IL33 and IL1RL1 haplotypes were compared between IgAV patients and controls and between IgAV patients stratified according to the clinical characteristics mentioned above. Our results suggest that the IL33-IL1RL1 signalling pathway does not contribute to the genetic network underlying IgAV.

Highlights

Cytokines signalling pathway genes are crucial factors of the genetic network underlying the pathogenesis of Immunoglobulin-A vasculitis (IgAV), an inflammatory vascular condition
We genotyped three tag genetic variants within IL33 and three tag polymorphisms within IL1RL1, which cover the major variability of these loci and that were previously associated with several inflammatory diseases, in the largest series of Caucasian IgAV patients ever assessed for genetic studies
In this study we aimed to determine whether the IL33-IL1RL1 signalling pathway is implicated in the pathogenesis of IgAV, a small-vessel vasculitis in which cytokines signalling pathway genes are considered as an essential component in its etiology6,11–14

Summary

Introduction

Cytokines signalling pathway genes are crucial factors of the genetic network underlying the pathogenesis of Immunoglobulin-A vasculitis (IgAV), an inflammatory vascular condition. IgAV has a multifactorial aetiology in which genetics plays a relevant role in both the predisposition and clinical course of the d isease6,9,10 In this regard, outside the human leukocyte antigen region, cytokines signalling pathway genes constitute a key component of the genetic network underlying I gAV6,11–14. Taking into account all these considerations, this study aimed to determine, for the first time, the potential implication of the IL33-IL1RL1 signalling pathway in the pathogenesis of IgAV For this purpose, we genotyped three tag genetic variants within IL33 and three tag polymorphisms within IL1RL1, which cover the major variability of these loci and that were previously associated with several inflammatory diseases, in the largest series of Caucasian IgAV patients ever assessed for genetic studies

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Conclusion