A single endoplasmic reticulum aminopeptidase-1 protein allotype is a strong risk factor for Behçet's disease in HLA-B*51 carriers

Takeuchi, Masaki; Ombrello, Michael J.; Kirino, Yohei; Erer, Burak; Tuğal-Tutkun, İlknur; Seyahi, Emire; Özyazgan, Yılmaz; Watts, Norman R.; Gül, Ahmet; Kastner, Daniel L.; Remmers, Elaine F.

doi:10.1136/annrheumdis-2015-209059

Cited by 62 publications

(62 citation statements)

References 17 publications

(14 reference statements)

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“…Our family study also showed haplotype frequencies very close to those predicted by imputation from the large AS association study using the Immunochip custom genotyping platform (1). They are also consistent with previous family studies on ERAP1/ERAP2 haplotypic associations with AS in Canada and recent results from a large study of ERAP1 haplotypes in Behçet's syndrome (14,15). Overall our results confirm that ERAP1 alleles with K528 predispose to AS and that 528R is protective.…”

Section: Discussionsupporting

confidence: 82%

ERAP1 association with ankylosing spondylitis is attributable to common genotypes rather than rare haplotype combinations

Roberts

Appleton

Cortés

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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We investigated the proposal that ankylosing spondylitis (AS) is associated with unusual ERAP1 genotypes. ERAP1 haplotypes were constructed for 213 AS cases and 46 rheumatoid arthritis controls using family data. Haplotypes were generated from five common ERAP1 single nucleotide polymorphisms (SNPs)—rs2287987 (M349V), rs30187 (K528R), rs10050860 (D575N), rs17482078 (R725Q), and rs27044 (Q730E). Haplotype frequencies were compared using Fisher’s exact test. ERAP1 haplotypes imputed from the International Genetics of AS Consortium (IGAS) Immunochip study were also studied. In the family study, we identified only four common ERAP1 haplotypes (“VRNQE,” “MKDRQ,” “MRDRE,” and “MKDRE”) in both AS cases and controls apart from two rare (<0.5%) previously unreported haplotypes. There were no examples of the unusual ERAP1 haplotype combination (“*001/*005”) previously reported by others in 53% of AS cases. As expected, K528-bearing haplotypes were increased in the AS family study (AS 43% vs. control 35%), due particularly to an increase in the MKDRQ haplotype (AS 35% vs. control 25%, P = 0.01). This trend was replicated in the imputed Immunochip data for the two K528-bearing haplotypes MKDRQ (AS 33% vs. controls 27%, P = 1.2 × 10–24) and MKDRE (AS 8% vs. controls 7%, P = 0.004). The ERAP1 association with AS is therefore predominantly attributable to common ERAP1 haplotypes and haplotype combinations.

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Section: Discussionsupporting

confidence: 82%

ERAP1 association with ankylosing spondylitis is attributable to common genotypes rather than rare haplotype combinations

Roberts

Appleton

Cortés

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Therefore, Hap10 and Hap2 of ERAP1 play a central role for patients within the MHC-I-opathy cluster: patients with psoriasis have an increased risk of uveitis [31]. Patients with AS and BD often have uveitis [11,42], and the ERAP1 associations are much stronger in cases that developed uveitis compared with cases with systemic disease alone [2,32]. Although HLA-A29 is also common in some non-European populations, Hap10 and particularly the Hap10-ERAP2 (rs2287987-rs10044354) haplotype are less common in Asian and African individuals compared to European and, as we show, if present may exhibit different functional effects on ERAP1, which may explain why Birdshot primarily affects patients of European descent [18].…”

Section: Discussionmentioning

confidence: 99%

“…Hap10 plays a central role for patients within the MHC-I-opathy cluster: Hap10 is the major risk ERAP1 allotype for patients with Behçet's Disease (BD) and is highly protective against AS (i.e. Hap1/Hap2 are risk haplotypes for AS) [11,12]. Hap10 is associates with BD assuming a recessive model (Birdshot, p meta-recessive = 9.81 × 10 −5 ).…”

Section: Discussionmentioning

confidence: 99%

“…Balancing selection maintains ERAP2 deficiency in one-quarter of the population [9] and drives the polymorphic ERAP1 gene to encode various protein haplotypes (allotypes) [10], few of which paradoxically confer or reduce risk for developing MHC-I-opathies [8]. To date, ERAP allotype studies have been limited to the relatively more common MHC-I-opathies [11][12][13]. In contrast, Birdshot uveitis or Birdshot chorioretinopathy (from here on 'Birdshot') is a severe, extremely rare eye condition (~1-5 cases/500,000) [13,14] that is characterized by enhanced IL-23-IL-17 pathway activation [14][15][16], and occurs exclusively in HLA-A29positive individuals [18].…”

Section: Introductionmentioning

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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“…Moreover, in a recent study, an ERAP1 protein allotype called Hap10 was associated with BD risk in HLA-B*51 carriers following the recessive model [33]. This haplotype carried five non-ancestral alleles, including p.Asp575Asn and p.Arg725Gln, and it was found previously to have lower peptide-trimming activity [29,34].…”

Section: Pathogenesis Via Altered Peptide Presentationmentioning

confidence: 93%

Is Behçet's disease a ‘class 1-opathy’? The role of HLA-B*51 in the pathogenesis of Behçet's disease

Giza

Koftori

Chen

et al. 2017

Clinical and Experimental Immunology

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Summary The association between carriage of the human leucocyte antigen (HLA)-B*51 allele and development of Behçet's disease (BD) has been known since the early 1970s, but the exact mechanisms responsible for its role in pathogenesis remain much-debated. In an effort to explain the disease process, it has been suggested that BD constitutes one of a newly termed group of diseases, the ‘MHC-I-opathies’. Other MHC-I-opathies include ankylosing spondylitis and HLA-B*27-associated spondyloarthropathies and HLA-C*0602-associated skin psoriasis. Recent work analysing the peptidome of HLA-B*51 suggests that altered peptide presentation by HLA-B*51 is vital to the disease process. In this review, we argue that immune receptor interactions with HLA-B*51 or the HLA-B*51-peptide complex could lead to development of inflammation in BD. The evidence for CD8+ T cell involvement is weak, and based on emerging studies it seems more likely that natural killer (NK) or other cell interactions, perhaps mediated by leucocyte immunoglobulin-like receptor (LILR) or killer immunoglobulin-like receptor (KIR) receptors, are culpable in pathogenesis. HLA misfolding leading directly to inflammation is another hypothesis for BD pathogenesis that deserves greater investigation. Ultimately, greater understanding of HLA-B*51's unique role in BD will probably lead to improved development of therapeutic strategies.

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A single endoplasmic reticulum aminopeptidase-1 protein allotype is a strong risk factor for Behçet's disease in HLA-B*51 carriers

Cited by 62 publications

References 17 publications

ERAP1 association with ankylosing spondylitis is attributable to common genotypes rather than rare haplotype combinations

ERAP1 association with ankylosing spondylitis is attributable to common genotypes rather than rare haplotype combinations

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

Is Behçet's disease a ‘class 1-opathy’? The role of HLA-B*51 in the pathogenesis of Behçet's disease

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