Association of ERAP1, IL23R and PTGER4 Polymorphisms with Radiographic Severity of Ankylosing Spondylitis

Özen, Gülşen; Deniz, Rabia; Eren, Fatih; Erzik, Can; Ünal, Ali; Yavuz, Şule; Aydın, Sibel Zehra; İnanç, Nevsun; Direşkeneli, Haner; Atagündüz, Pamir

doi:10.2174/1874312901711010001

Cited by 11 publications

(8 citation statements)

References 39 publications

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“…ERAP inhibitors) in the near future. Emerging studies explore this concept, those of which that have linked clinical response to ERAP variants [37][38][39][40]. Ultimately, understanding how to pharmacologically influence ERAP function [41] may lay the foundation for the design of effective therapeutic strategies to correct ERAP function in accordance with the patient's molecular fingerprint to tailor the treatment of MHC-I-opathy patients specifically.…”

Section: Discussionmentioning

confidence: 99%

“…The strongest association mapped to the protective haplotype rs2287987-T/rs10044354-C (meta-analysis, OR [95% CI]: =0. 39 [0.30-0.55],p=3.9 x 10 -9 ), closely followed by the risk haplotype rs2287987-C/rs10044354-T (OR [95% CI]: =2.75 [1.92-3.92], p= 2.6 x 10 -8 ), the latter present in 50% of all 130 cases and 26% of all 2,993 controls. The frequency of the CT-risk haplotype (0.24 in Dutch cases and 0.19 of Spanish cases) is ~5-6x less common in African (0.027) and Asian (0.021) populations compared to the European population (0.13, Figure 2A).…”

Section: Two Independent Variants At 5q15 Associate With Birdshotmentioning

confidence: 99%

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Functionally distinct ERAP1 and ERAP2 are a hallmark of HLA-A29-(Birdshot) Uveitis

Kuiper

Setten

Devall

et al. 2018

Preprint

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Birdshot Uveitis (Birdshot) is a rare eye condition that affects HLA-A29-positive individuals and could be considered a prototypic member of the recently proposed "MHC-I-opathy" family. Genetic studies have pinpointed the ERAP1 and ERAP2 genes as shared associations across MHC-I-opathies, which suggests ERAP dysfunction may be a root cause for MHC-I-opathies. We mapped the ERAP1 and ERAP2 haplotypes in 84 Dutch cases and 890 controls. We identified association at variant rs10044354, which mediated a marked increase in ERAP2 expression.We also identified and cloned an independently associated ERAP1 haplotype (tagged by rs2287987) present in more than half of the cases; this ERAP1 haplotype is also the primary risk and protective haplotype for other MHC- 6)) replicated and showed consistent direction of effect in an independent Spanish cohort of 46 cases and 2,103 controls. In both cohorts, the combined rs2287987-rs10044354 haplotype associated with Birdshot more strongly than either SNP alone (meta-analysis: p=3.9 × 10(-9)). Finally, we observed that ERAP2 protein expression is dependent on the ERAP1 background across three European populations (n=3,353). In conclusion, a functionally distinct combination of ERAP1 and ERAP2 are a hallmark of Birdshot and provide rationale for strategies designed to correct ERAP function for treatment of Birdshot and MHC-I-opathies more broadly.

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Section: Discussionmentioning

confidence: 99%

Section: Two Independent Variants At 5q15 Associate With Birdshotmentioning

confidence: 99%

Functionally distinct ERAP1 and ERAP2 are a hallmark of HLA-A29-(Birdshot) Uveitis

Kuiper

Setten

Devall

et al. 2018

Preprint

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“…Although the IL23/Th17 axis is an important pathway for disease development, it is also likely to influence the diverse clinical phenotype of AS. Two studies were unable to detect an effect of IL23R variants on radiographic disease severity in AS [9, 10]. As there are otherwise few data available on serological and clinical associations, we investigated whether IL23R variants impact on cytokine profiles and clinical phenotype in AS patients.…”

Section: Introductionmentioning

confidence: 99%

IL23R gene variants in relation to IL17A levels and clinical phenotype in patients with ankylosing spondylitis

Nossent

Johnsen²,

Bakland

2018

Rheumatology Advances in Practice

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Background IL23 receptor (IL23R) binding by IL23 is required for the maturation of CD4 + cells into Th17 cells and subsequent generation of IL17A and TNF. As IL23R variations contribute to AS susceptibility, we investigated the effect of IL23R variants on cytokine levels and disease measures in an AS cohort. Methods This was a cross-sectional study of AS patients ( n = 334, 90% B27 + , age 45 years). IL23R genotyping for three non-synonymous single-nucleotide polymorphisms (rs11209026, protective allele A; rs10489629, protective allele A; and rs11209032, risk allele A) was done by Taqman RT-PCR. IL23, IL17A, TNF and IL6 concentrations were determined by sandwich ELISA. Genotypic associations were analysed with non-parametric methods. Results Twenty-two AS patients (6.6%) carried the protective rs11209026 A allele, whereas 206 (61.7%) carried the rs11209032A risk allele ( P = 0.03). Two patients homozygous for rs11209026A had late onset, no co-morbidity and undetectable cytokine levels. IL23R genotypes and five common haplotypes were unrelated with age at onset, BASFI or co-morbidity (all P >0.2). There was no overall difference in the concentration of IL17A (184 vs 233 pg/ml, P > 0.2) or IL23 (276 vs 262 pg/ml, P > 0.4) between AS patients and controls, but a global haplotype association ( P = 0.01) was observed for IL23 concentrations. Conclusion Homozygosity for rs11209026A is rare in AS patients, but may ameliorate the clinical presentation. IL17A and IL23 levels are similar in controls and AS patients. IL23R variants influence IL23 levels but not IL17A levels in AS patients, suggesting that IL23R impacts more on cell types other than Th17 cells.

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“…The main variant of the gene (rs30187, K528R) interacts only with the HLA-B27 allele, and in patients who are HLA-B27 negative, ERAP1 interacts with the HLA-B40 allele 4 . The mechanism underlying the increased risk remains unclear; nevertheless, it is known that the presence of this gene is not related to the radiographic severity of the disease 5 .…”

Section: Geneticsmentioning

confidence: 99%

Recent advances in ankylosing spondylitis: understanding the disease and management

2018

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The term spondyloarthritis refers to a group of immune-mediated diseases characterised by inflammation of the axial skeleton, peripheral joints, and entheses. Ankylosing spondylitis (AS) is the most common and characteristic of these entities and even though it was first described over two centuries ago, the understanding of the underlying disease mechanism remains incomplete. It is known that around 40% of patients with AS have subclinical bowel inflammation, suggesting that the origin of the disease could be in the gut. Also, more genes and new molecules have demonstrated a role in the pathogenesis of AS. In this review, we analyse the latest therapies for spondyloarthritis and the most relevant discoveries over the last three years, together with their implications for different aspects of the disease.

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Association of ERAP1, IL23R and PTGER4 Polymorphisms with Radiographic Severity of Ankylosing Spondylitis

Cited by 11 publications

References 39 publications

Functionally distinct ERAP1 and ERAP2 are a hallmark of HLA-A29-(Birdshot) Uveitis

Functionally distinct ERAP1 and ERAP2 are a hallmark of HLA-A29-(Birdshot) Uveitis

IL23R gene variants in relation to IL17A levels and clinical phenotype in patients with ankylosing spondylitis

Recent advances in ankylosing spondylitis: understanding the disease and management

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