Protective effect of an ERAP1 haplotype in ankylosing spondylitis: investigating non-MHC genes in HLA-B27-positive individuals

Bettencourt, Bruno Filipe; Rocha, Fabiana Leal; Alves, Helena; Amorim, Rosa Beatriz; Caetano-Lopes, Joana; Vieira-Sousa, Elsa; Pimentel-Santos, Fernando; Lima, Manuela; Porto, Graça; Branco, Jaime; Fonseca, João Eurico; Bruges-Armas, Jácome

doi:10.1093/rheumatology/ket269

Cited by 34 publications

(23 citation statements)

References 37 publications

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“…Four major haplotypes (named from H1 to H4 in Table 2) are obtained by the combination of the variations of these five SNPs according to data from CEU and also from our population. The H2 and H3 correspond respectively with risk and protection haplotypes in AS [34], [35], however, our data suggest that both haplotypes could be risk factors in BD. Association of ERAP1 with AS is restricted to individuals bearing the HLA-B risk factor for this disease, HLA-B27, [35], [36] whereas in psoriasis the relationship between ERAP1 and HLA-C remains unclear [19], [37].…”

Section: Discussionmentioning

confidence: 55%

Epistatic Interaction of ERAP1 and HLA-B in Behçet Disease: A Replication Study in the Spanish Population

et al. 2014

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Behçet's disease (BD) is a multifactorial disorder associated with the HLA region. Recently, the ERAP1 gene has been proposed as a susceptibility locus with a recessive model and with epistatic interaction with HLA-B51. ERAP1 trims peptides in the endoplasmic reticulum to optimize their length for MHC-I binding. Polymorphisms in this gene have been related with the susceptibility to other immune-mediated diseases associated to HLA class I. Our aim was, the replication in the Spanish population of the association described in the Turkish population between ERAP1 (rs17482078) and BD. Additionally, in order to improve the understanding of this association we analyzed four additional SNPs (rs27044, rs10050860, rs30187 and rs2287987) associated with other diseases related to HLA class I and the haplotype blocks in this gene region. According to our results, frequencies of the homozygous genotypes for the minor alleles of all the SNPs were increased among patients and the OR values were higher in the subgroup of patients with the HLA-B risk factors, although differences were not statistically significant. Moreover, the presence of the same mutation in both chromosomes increased the OR values from 4.51 to 10.72 in individuals carrying the HLA-B risk factors. Therefore, although they were not statistically significant, our data were consistent with an association between ERAP1 and BD as well as with an epistatic interaction between ERAP1 and HLA-B in the Spanish population.

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Section: Discussionmentioning

confidence: 55%

Epistatic Interaction of ERAP1 and HLA-B in Behçet Disease: A Replication Study in the Spanish Population

et al. 2014

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“…Similarly, Bettencourt et al examined the 5 AS-associated variants from the WTCCC study in a collection of 200 HLA-B*27 positive AS patients and 200 HLA-B*27 positive healthy subjects (20). This study replicated the associations of each of these 5 SNPs with AS, identifying the strongest association with the AS risk variant, K528.…”

Section: Genetic Variation Of Erap1 and Susceptibility To Ankylosing mentioning

confidence: 99%

Endoplasmic reticulum-associated amino-peptidase 1 and rheumatic disease

Ombrello

Kastner

Remmers

2015

Current Opinion in Rheumatology

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Purpose of review This article will review the genetic evidence implicating ERAP1, which encodes the endoplasmic reticulum-associated amino-peptidase 1, in susceptibility to rheumatic disease. Recent findings Genetic variants and haplotypes of ERAP1 are associated with ankylosing spondylitis, psoriasis, and Behçet’s disease in people of varying ancestries. In each of these diseases, disease-associated variants of ERAP1 have been shown to interact with disease-associated class I Human Leukocyte Antigen (HLA) alleles to influence disease risk. Functionally, disease-associated missense variants of ERAP1 concertedly alter ERAP1 enzymatic function, both quantitatively and qualitatively, while other disease-associated variants influence ERAP1 expression. Therefore, ERAP1 haplotypes (or allotypes) should be examined as functional units. Biologically, this amounts to an examination of the gene regulation and function of the protein encoded by each allotype. Genetically, the relationship between disease risk and ERAP1 allotypes should be examined to determine whether allotypes or individual variants produce the most parsimonious risk models. Summary Future investigations of ERAP1 should focus on comprehensively characterizing naturally-occurring ERAP1 allotypes, examining the enzymatic function and gene expression of each allotype, and identifying specific allotypes that influence disease susceptibility.

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“…A previous genome-wide association study revealed that ERAP1 polymorphisms are associated with AS at a high level of statistical significance [3], but more recent studies, in different ethnic groups, have produced mixed results [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]. In our previous meta-analysis, we found that the rs27044, rs17482078, rs10050860, rs30187, and rs2287987 polymorphisms of ERAP1 were associated with the development of AS in Europeans [28].…”

Section: Discussionmentioning

confidence: 99%

“…Two studies were excluded because one used the data analyzed in another study and another did not have extractable allele data. Thus, 20 studies met the inclusion criteria (Table 1) [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]27]. However, one of these studies contained data on three groups [13] and two studies had data on two different groups [17].…”

Section: Studies Included In the Meta-analysismentioning

confidence: 99%

“…A genome-wide association study revealed that two single-nucleotide polymorphisms (SNPs) (rs27044, rs30187) of ERAP1 were significantly associated with AS, and demonstrated that rs17482078, rs10050860, and rs2287987 polymorphisms also trended toward association with AS [3]. Although some studies have demonstrated that SNPs of ERAP1 are associated with AS susceptibility, others disagree [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]. It would appear that allelic frequencies often differ substantially between populations, and ethnicity-specific association studies are needed to confirm genetic associations in different populations.…”

Section: Introductionmentioning

confidence: 99%

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Associations between ERAP1 polymorphisms and susceptibility to ankylosing spondylitis: a meta-analysis

Lee

Song

2016

Clin Rheumatol

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The aim of this study was to determine whether 11 polymorphisms of endoplasmic reticulum aminopeptidase 1 (ERAP1) confer susceptibility to ankylosing spondylitis (AS). The authors conducted meta-analyses on associations between ERAP1 polymorphisms and AS susceptibility by using fixed and random effects models. A total of 19 articles were included in this meta-analysis, which comprised a total of 19,902 AS patients and 39,750 controls. The meta-analysis revealed a significant association between AS and the minor alleles of the rs30187 polymorphism in all study subjects (OR = 1.255, 95 % CI = 1.147-1.373, P = 8.0 × 10(-8)). Stratification by ethnicity led to the identification of a significant association between this polymorphism and AS in European patients (OR = 1.283, 95 % CI = 1.237-1.331, P < 1.0 × 10(-9)). Meta-analyses of the results for the rs27044, rs10050860, rs2287987, rs17482078, and rs26653 polymorphisms showed the same pattern that was found for rs30187. Interestingly, the rs27037 polymorphism was significantly associated with AS susceptibility in both European and Asian patients. Meta-analysis showed a significant association between AS and the minor alleles of the rs27980 and rs27582 polymorphisms in the East Asian patients (OR = 0.904, 95 % CI = 0.818-0.999, P = 0.047; OR = 0.871, 95 % CI = 0.772-0.982, P = 0.024, respectively) (Table 2). However, these polymorphisms have not been studied in Europeans. This meta-analysis shows that the ERAP1 polymorphisms are associated with the development of AS in Europeans and East Asians.

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Protective effect of an ERAP1 haplotype in ankylosing spondylitis: investigating non-MHC genes in HLA-B27-positive individuals

Abstract: The identification of a new protection haplotype in ERAP1 and the lack of association of the TNFSF15 region can provide new insights into the understanding of the mechanisms underlying the susceptibility to and protection from AS.

Cited by 34 publications

References 37 publications

Epistatic Interaction of ERAP1 and HLA-B in Behçet Disease: A Replication Study in the Spanish Population

Epistatic Interaction of ERAP1 and HLA-B in Behçet Disease: A Replication Study in the Spanish Population

Endoplasmic reticulum-associated amino-peptidase 1 and rheumatic disease

Associations between ERAP1 polymorphisms and susceptibility to ankylosing spondylitis: a meta-analysis

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