ERAP1 Is Associated with Ankylosing Spondylitis in Han Chinese

Department of Rheumatology, Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou 510630, China.
The Journal of Rheumatology (Impact Factor: 3.19). 11/2010; 38(2):317-21. DOI: 10.3899/jrheum.100013
Source: PubMed


Genetic components play important roles in the incidence and development of ankylosing spondylitis (AS). Aminopeptidase regulator of tumor necrosis factor receptor shedding 1 (ERAP1) was recently found to be associated with AS in North American and British cohorts. We evaluated whether ERAP1 is associated with AS in a Chinese Han population.
A sample of 50 patients and 50 healthy controls was recruited for preliminary screening for informative single-nucleotide polymorphisms (SNP). Then 6 SNP of suggestive significance in the initial screening were followed up in a large sample of 471 patients with AS and 456 ethnically matched controls. Diagnosis of AS followed the 1984 modified New York criteria. Linkage disequilibrium coefficient (D' and r(2)) and haplotypes were estimated by Haploview. Result. Two SNP (rs27434, p = 0.00039, and rs27529, p = 0.0083) in ERAP1 other than that reported previously were found to be significantly associated with AS. Haplotype analysis using 5 SNP within 1 linkage disequilibrium block identified 2 risk haplotypes (GATGT and GACGT) and 1 protective haplotype (GGTGT) for AS.
Our study demonstrated that 2 novel SNP in ERAP1 were associated with AS in the Han Chinese population, suggesting that ERAP1 might confer genetic risk for AS in Han Chinese through the common mechanism shared by different populations, although the AS-associated SNP in ERAP1 might be population-specific.

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    • "These associations have not been subsequently replicated in GWAS studies, likely because this region is now known to be subject to substantial population stratification effects that earlier studies were not able to control for. Nonetheless, GWAS studies have now conclusively demonstrated the association of the IL1R1-IL1R2 locus with AS (International Genetics of Ankylosing Spondylitis et al., 2013; Reveille et al., 2010). Two independent association signals are found at this locus, implicating both genes in AS pathogenesis. "
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    ABSTRACT: Ankylosing spondylitis (AS) is a chronic inflammatory arthritis that affects the spine and sacroiliac joints. It causes significant disability and is associated with a number of other features including peripheral arthritis, anterior uveitis, psoriasis and inflammatory bowel disease (IBD). Significant progress has been made in the genetics of AS have in the last five years, leading to new treatments in trial, and major leaps in understanding of the aetiopathogenesis of the disease.
    Molecular Immunology 07/2013; 57(1). DOI:10.1016/j.molimm.2013.06.013 · 2.97 Impact Factor
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    • "In 2007, the association of ERAP1 (the gene for endoplasmic reticulum aminopeptidase 1 (ERAP-1)) with AS was first identified by the Wellcome Trust Case-Control Consortium and Australo-Anglo-American Spondyloarthritis Consortium (WTCCC/TASC) in European Caucasian population [27]. And then, the association with AS has been found in other Caucasian populations [28, 29] as well as in Chinese population [30]. Our studies demonstrated two novel SNPs (rs27434 and rs27529) in ERAP1 other than that reported previously [14]. "
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    ABSTRACT: Purpose: Ankylosing spondylitis (AS) is a systemic, autoimmune disease resulting in the destruction of the affected joints. Over the past 5 years, several new genes or genetic regions associated with AS have been identified in the Chinese population. This paper aims to discuss the major findings and related potential mechanisms of these studies in our population. Recent findings: In recent years, due to the rapid advances in computational genetics and technology, there has been an increasing list of well-validated genes or genetic regions associated with AS susceptibility. So far, several genes or genetic regions have now been reported in the Han ethnic Chinese population, containing the major histocompatibility complex (MHC), ERAP1, IL-23R, 12q12, 2p15, 5q14.3, and so on. Different hypotheses for disease mechanisms have been investigated on the basis of the functional studies of these genes or genetic regions. Summary: This paper tries to summarize the association of several candidate genes with risk for AS in the Han ethnic Chinese population and aims to identify the novel inflammatory pathways and provide potential strategies for better therapies.
    Clinical and Developmental Immunology 01/2013; 2013(4):419357. DOI:10.1155/2013/419357 · 2.93 Impact Factor
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    ABSTRACT: Autoimmune diseases represent a heterogeneous group of conditions whose incidence is increasing worldwide. This has stimulated studies on their etiopathogenesis, derived from a complex interaction between genetic and environmental factors, aimed at finally improving prevention and treatment of these diseases. In the autoimmune process, immune responses are generated against self antigens presented by Major Histocompatibility Complex (MHC) class I on the cell surface. These peptide/MHC class I complexes are generated and assembled through MHC class I antigen processing and presentation machinery. In the endoplasmic reticulum (ER), aminopeptidases ERAP1 and ERAP2 display distinct trimming activity before antigenic peptides are loaded onto MHC class I molecules. The advent of new tools such as genome-wide association studies (GWAS) has provided evidence for new susceptibility loci and candidate genes playing a role in the autoimmune process for the recognized immune function of their transcripts. Genetic linkage has been discovered with MHC antigens and various autoimmune conditions. Recent GWAS showed the importance of ERAP1 and ERAP2 in several autoimmune diseases, including ankylosing spondylitis, insulin-dependent diabetes mellitus, psoriasis, multiple sclerosis, Crohn's disease. In this review, we first provide a general overview of ERAP1 and ERAP2 genes, their biological functions and their relevancy in autoimmunity. We then discuss the importance of GWAS and the case-control studies that confirm the relevancy of ERAP single-nucleotide polymorphism associations and their linkage with particular MHC class I haplotypes, supporting a putative functional role in the autoimmune process.
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