A Single Nucleotide Polymorphism in the Il17ra Promoter Is Associated with Functional Severity of Ankylosing Spondylitis

Abstract

The aim of this study was to identify new genetic variants associated with the severity of ankylosing spondylitis (AS). We sequenced the exome of eight patients diagnosed with AS, selected on the basis of the severity of their clinical parameters. We identified 27 variants in exons and regulatory regions. The contribution of candidate variants found to AS severity was validated by genotyping two Spanish cohorts consisting of 180 cases/300 controls and 419 cases/656 controls. Relationships of SNPs and clinical variables with the Bath Ankylosing Spondylitis Disease Activity and Functional Indices BASDAI and BASFI were analyzed. BASFI was standardized by adjusting for the duration of the disease since the appearance of the first symptoms. Refining the analysis of SNPs in the two cohorts, we found that the rs4819554 minor allele G in the promoter of the IL17RA gene was associated with AS (p<0.005). This variant was also associated with the BASFI score. Classifying AS patients by the severity of their functional status with respect to BASFI/disease duration of the 60th, 65th, 70th and 75th percentiles, we found the association increased from p60 to p75 (cohort 1: p<0.05 to p<0.01; cohort 2: p<0.01 to p<0.005). Our findings indicate a genetic role for the IL17/ILRA axis in the development of severe forms of AS.

Influence of TNF and IL17 Gene Polymorphisms on the Spondyloarthritis Immunopathogenesis, Regardless of HLA-B27, in a Brazilian Population

“…A weak association between rheumatoid arthritis and the promoter IL17A rs2275913 was found in the Norwegian population and more recently in the Brazilian population [ 7 , 32 ]. Specifically, with the risk of AS and its severity, a strong association was observed with the rs4819554 SNP in the promoter region of IL17RA in two Spanish cohorts of patients and controls, but not involving the IL17A and IL17F polymorphisms that we have studied here [ 33 ]. Therefore, in patients of Northern Italy, IL17A and IL17RA gene allelic variants were not associated with PsA susceptibility [ 34 ].…”

Role of Interleukin- (IL-) 17 in the Pathogenesis and Targeted Therapies in Spondyloarthropathies

“…Tumor necrosis factor (TNF), interleukin- (IL-) 1, IL-6, and IL-23/IL-17 are major inflammatory cytokine pathways of great interest from serial studies of single nucleotide polymorphisms, cytokine receptors, and associated intracellular signaling molecules. Among these inflammatory cytokines, IL-17 plays a dominant role in the inflammatory and proliferative cascades of human SpA [ 4 , 5 ]. In this review, we have discussed the contributing role of the IL-17 pathways in the pathophysiology of SpA from current evidence of genetic associations, studies in animal models, and expression of IL-17 in human SpA.…”

IL17A polymorphism and elevated IL17A serum levels are associated with oral lichen planus

“…We have previously demonstrated a lack of association between IL17A SNP, rheumatoid arthritis and secondary Sjögren's syndrome (Carvalho et al., ) in a study with 206 individuals, but a weak association was demonstrated in a larger sample (Nordang et al., ). In ankylosing spondylitis, a SNP in the promoter region of IL17RA was associated with an elevated risk, with a stronger association in individuals with severe forms (Vidal‐Castiñeira et al., ). Inflammatory bowel diseases seem to be influenced by IL17 SNPs, and there seems to be an interaction between the risk haplotypes in IL23R and IL17A in individuals with ulcerative colitis (Yu et al., ).…”