Association of interleukin‐23 receptor variants with ankylosing spondylitis

Abstract

Objective. Recent studies have shown that a nonsynonymous single-nucleotide polymorphism (SNP) (Arg381Gln; rs11209026) in the interleukin-23 receptor (IL-23R) gene on chromosome 1p31 is associated with Crohn's disease and psoriasis. Given the clinical and immunologic overlap between ankylosing spondylitis (AS) and these diseases, and the potential function of this candidate SNP, this study was undertaken to examine the association of IL-23R variants with AS in multiple Canadian populations.Methods. We examined 3 cohorts of AS patients from established rheumatic disease centers in Canada. The majority of AS patients were Caucasians of northern European descent, and all patients satisfied the modified New York classification criteria for AS or for juvenile spondylarthritis. We examined 424 AS probands and 401 controls from Alberta, 251 AS probands and 122 controls from Toronto, and 121 AS probands and 219 controls from Newfoundland. Ten IL-23R SNPs were genotyped, 9 of which were incorporated in the haplotype analysis. Allele and haplotype associations were calculated using the WHAP software package. P values for haplotype associations were calculated using a permutation test.Results. The primary SNP of interest in a previous study of inflammatory bowel disease (IBD) (Arg381Gln; rs11209026) was found to be protective against AS in the Newfoundland population (P ‫؍‬ 0.04) and in the Toronto population (P ‫؍‬ 0.04) in singlemarker univariate analysis. The strongest association, however, was with SNP rs11465804 (P ‫؍‬ 0.007 for the Newfoundland population and P ‫؍‬ 0.0007 for the Toronto population). A 3-marker sliding window omnibus test revealed a significant association with markers rs10489629, rs2201841, and rs11465804 in both the Newfoundland population (P ‫؍‬ 0.04) and the Alberta population (P ‫؍‬ 0.034). Our results were independent of the IBD and psoriasis status of the AS patients.Conclusion. This concurrent analysis of 3 distinct AS populations and their regional controls demonstrates a disease association with the IL-23R locus and implicates the same polymorphisms associated with IBD and psoriasis.Spondylarthritis (SpA) is a group of inflammatory conditions of which the main clinical feature is inflammation of the spine. Ankylosing spondylitis (AS) is regarded as the prototypic SpA and is a complex multifactorial disease resulting from gene-environment interaction. Genetic factors have a substantive role in AS susceptibility and expression (1). AS is highly heritable, as evidenced by the results of population-based epidemiologic studies. The sibling recurrence risk ( s ) in AS is Ͼ80, and heritability of Ն90% for AS has been estimated from twin studies (for review, see ref. 1). HLA-B27 is the major gene associated with AS and is present in Ͼ95% of Caucasians of northern European ancestry. Despite the prominence of HLA-B27 in genetic susceptibility to AS, its contribution to overall genetic predisposition is only ϳ16-40% (1). Furthermore, since the genetic contribution of the entire major histocompatibilit...

Identification and characterization of multiple splice forms of the human interleukin-23 receptor α chain in mitogen-activated leukocytes

“…14 Subsequently, more studies have also associated this R/Q single nucleotide polymorphism with other diseases from different populations. 9,10,15,[17][18][19] Although investigating the IL23R for novel polymorphic elements, we discovered a range of novel splice variants of IL23R transcripts, greatly extending an earlier study by Zhang et al 20 from early 2006. We believe that understanding the role of these variants and how their presence is controlled will give us novel insight to the role of IL-23 in human Crohn's disease.…”

Protective role of R381Q (rs11209026) polymorphism in IL-23R gene in immune-mediated diseases: A comprehensive review

“…That suggested to the authors that IL-23R/STAT3 polymorphisms affecting T H 17 signaling efficiency were not major determinants for risk of Hashimoto's thyroiditis, at least in Croatians. Previous studies examining ankylosing spondylitis also indicated that the A allele frequency of R381Q was lower in spondylitis patients than in healthy controls (Rahman et al 2008;Duan et al 2012).…”

Interleukin‐23 Mediates the Intestinal Response to Microbial β‐1,3‐Glucan and the Development of Spondyloarthritis Pathology in SKG Mice

“…, and CARD9 downstream of the dectin 1/Syk pathway, which transduces dendritic cell (DC) interleukin-23 (IL-23) secretion by fungal products, PTGER4, which encodes a prostaglandin receptor driving IL-23 secretion by DCs, and key signaling kinases and transcription factors associated with IL-23 receptor (IL-23R) signaling (3)(4)(5)(6)(7). IL-23 is required for the expansion and maintenance of T cells and innate immune cells secreting IL-17 and IL-22, and they are both implicated in the pathogenesis of SpA and Crohn's disease (8)(9)(10)(11).…”