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Wordsworth BP, Cohen CJ, Davidson C, Vecellio M. Perspectives on the Genetic Associations of Ankylosing Spondylitis. Front Immunol 2021; 12:603726. [PMID: 33746951 PMCID: PMC7977288 DOI: 10.3389/fimmu.2021.603726] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 01/05/2021] [Indexed: 12/11/2022] Open
Abstract
Ankylosing spondylitis (AS) is a common form of inflammatory spinal arthritis with a complex polygenic aetiology. Genome-wide association studies have identified more than 100 loci, including some involved in antigen presentation (HLA-B27, ERAP1, and ERAP2), some in Th17 responses (IL6R, IL23R, TYK2, and STAT3), and others in macrophages and T-cells (IL7R, CSF2, RUNX3, and GPR65). Such observations have already helped identify potential new therapies targeting IL-17 and GM-CSF. Most AS genetic associations are not in protein-coding sequences but lie in intergenic regions where their direct relationship to particular genes is difficult to assess. They most likely reflect functional polymorphisms concerned with cell type-specific regulation of gene expression. Clarifying the nature of these associations should help to understand the pathogenic pathways involved in AS better and suggest potential cellular and molecular targets for drug therapy. However, even identifying the precise mechanisms behind the extremely strong HLA-B27 association with AS has so far proved elusive. Polygenic risk scores (using all the known genetic associations with AS) can be effective for the diagnosis of AS, particularly where there is a relatively high pre-test probability of AS. Genetic prediction of disease outcomes and response to biologics is not currently practicable.
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Affiliation(s)
- B Paul Wordsworth
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford Institute of Musculoskeletal Sciences, Oxford, United Kingdom.,Botnar Research Centre, Nuffield Orthopaedic Centre, Oxford, United Kingdom
| | - Carla J Cohen
- Botnar Research Centre, Nuffield Orthopaedic Centre, Oxford, United Kingdom
| | - Connor Davidson
- Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
| | - Matteo Vecellio
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford Institute of Musculoskeletal Sciences, Oxford, United Kingdom.,Botnar Research Centre, Nuffield Orthopaedic Centre, Oxford, United Kingdom.,Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
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Feng Y, Hong Y, Zhang X, Cao C, Yang X, Lai S, Fan C, Cheng F, Yan M, Li C, Huang W, Chen W, Zhu P, Zeng C. Genetic variants of TREML2 are associated with HLA-B27-positive ankylosing spondylitis. Gene 2018; 668:121-128. [PMID: 29778423 DOI: 10.1016/j.gene.2018.05.057] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Revised: 04/08/2018] [Accepted: 05/16/2018] [Indexed: 01/09/2023]
Abstract
Although ankylosing spondylitis (AS) is a common, highly heritable arthropathy, the precise genetic mechanism underlying the disease remains elusive. Here, we investigate the disease-causing mutations in a large AS family with distinguished complexity, consisting of 23 patients covering four generations and exhibiting a mixed HLA-B27 (+) and (-) status. Linkage analysis with 32 members using three methods and whole-exome sequencing analysis with three HLA-B27 (+) patients, one HLA-B27 (-) patient, and one healthy individual did not identify a mutation common to all of the patients, strongly suggesting the existence of genetic heterogeneity in this large pedigree. However, if only B27-positive patients were analyzed, the linkage analysis located a 22-Mb region harboring the HLA gene cluster in chromosome 6 (LOD = 4.2), and the subsequent exome analysis identified two non-synonymous mutations in the TREML2 and IP6K3 genes. These genes were resequenced among 370 sporadic AS patients and 487 healthy individuals. A significantly higher mutation frequency of TREML2 was observed in AS patients (1.51% versus 0.21%). The results obtained for the AS pedigree and sporadic patients suggest that mutation of TREML2 is a major factor leading to AS for HLA-B27 (+) members in this large family and that TREML2 is also a susceptibility gene promoting the development of ankylosing spondylitis in HLA-B27 (+) individuals.
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Affiliation(s)
- Yuan Feng
- Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shanxi Province, China
| | - Yaqiang Hong
- Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
| | - Xin Zhang
- Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shanxi Province, China
| | - Chunwei Cao
- Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
| | - Xichao Yang
- Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shanxi Province, China
| | - Shujuan Lai
- Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
| | - Chunmei Fan
- Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shanxi Province, China
| | - Feng Cheng
- Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
| | - Mei Yan
- Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shanxi Province, China
| | - Chaohua Li
- Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
| | - Wan Huang
- Department of Cell Biology, Fourth Military Medical University, Xi'an, Shanxi Province, China
| | - Wei Chen
- Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
| | - Ping Zhu
- Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shanxi Province, China.
| | - Changqing Zeng
- Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China; Collaborative Innovation Center for Genetics and Development, Shanghai, China.
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Quantifying the genetic risk for the development of axial spondyloarthropathy: could this become a diagnostic tool? Curr Opin Rheumatol 2018; 30:319-323. [PMID: 29702496 DOI: 10.1097/bor.0000000000000517] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW To assess the utility of recent genetic findings in ankylosing spondylitis (AS) and axial spondyloarthropathy (SpA) in relation to diagnostic testing, prognosis and responses to biologic treatment and the development of new therapies. RECENT FINDINGS AS and other forms of SpA are polygenic with more than 100 genes contributing to disease susceptibility. The role of genes in determining the outcome of the disease and response to treatment is less clear. Here, we review some of the progress that has been made over the past decade in understanding the genetic contribution to these diseases and how this may be used to inform the development of new treatments. In those with a high pretest probability of SpA human leukocyte antigen (HLA)-B27 testing can increase the posttest predictive value to almost 100% in some cases. There are currently no reliable genetic predictors of disease severity or response to treatment. SUMMARY The utility of HLA-B27 as a diagnostic tool when coupled with careful clinical assessment is well established but other genetic markers probably have relatively little to add. In contrast, novel drug targets are likely to be identified from genetic association studies.
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The severity of ankylosing spondylitis and responses to anti-tumour necrosis factor biologics are not influenced by the tumour necrosis factor receptor polymorphism incriminated in multiple sclerosis. Genes Immun 2018. [DOI: 10.1038/s41435-018-0017-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
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El polimorfismo TNF-α-308 determina las manifestaciones clínicas y la respuesta al tratamiento de la espondilitis anquilosante en la etnia china Han. Med Clin (Barc) 2017; 149:517-522. [DOI: 10.1016/j.medcli.2017.04.023] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 04/08/2017] [Accepted: 04/20/2017] [Indexed: 11/21/2022]
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Li Z, Brown MA. Progress of genome-wide association studies of ankylosing spondylitis. Clin Transl Immunology 2017; 6:e163. [PMID: 29333268 PMCID: PMC5750450 DOI: 10.1038/cti.2017.49] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2017] [Revised: 09/30/2017] [Accepted: 09/30/2017] [Indexed: 02/06/2023] Open
Abstract
Ankylosing spondylitis (AS) is an immune-mediated arthritis which primarily affects the spine and sacroiliac joints. Significant progress has been made in discovery of genetic associations with AS by genome-wide association studies (GWAS) over past decade. These findings have uncovered novel pathways involved pathogenesis of the disease and have led to introduction of novel therapeutic treatments for AS. In this Review, we discuss the genetic variations associated with AS identified by GWAS, the major pathways revealed by these AS-associated variations and critical cell types involved in AS development.
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Affiliation(s)
- Zhixiu Li
- Translational Genomics Group, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology at Translational Research Institute, Brisbane, Queensland, Australia
| | - Matthew A Brown
- Translational Genomics Group, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology at Translational Research Institute, Brisbane, Queensland, Australia
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Zhong L, Song H, Wang W, Li J, Ma M. MEFV M694V mutation has a role in susceptibility to ankylosing spondylitis: A meta-analysis. PLoS One 2017; 12:e0182967. [PMID: 28800602 PMCID: PMC5553723 DOI: 10.1371/journal.pone.0182967] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Accepted: 07/27/2017] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVE The aim of the current study was to determine the contributions of several common mutations in the Mediterranean fever (MEFV) gene, namely, E148Q, M680I, M694V and V726A, to ankylosing spondylitis (AS) susceptibility. METHODS Two investigators independently searched the literature regarding the association of MEFV with AS in the PubMed, EMBASE, Web of Science, and Scopus databases. They independently selected eligible articles and then extracted data from the included studies. The associations between MEFV mutations and AS risk were assessed with odds ratios (ORs) and 95% confidence intervals (95% CI). Further analyses were conducted with STATA 12.0 software (Stata Corp.; College Station, Texas, USA). RESULTS Four mutations (E148Q, M680I, M694V and V726A) were genotyped in 869 AS cases and 879 controls from the 8 eligible studies. Of the four mutations, M694V (pooled OR: 3.330, 95% CI: 2.129-5.208) was found to be associated with AS through overall analysis. However, the other mutations demonstrated no relation with AS (pooled ORs: 1.295, 1.258, 1.778; 95% CI: 0.886-1.891, 0.688-2.298 and 0.938-3.371). No significant publication bias was discovered in the meta-analysis. CONCLUSIONS The present study indicates that the MEFV M694V mutation may contribute to the pathogenesis of AS. The associations between the other mutations and AS need to be validated with more relevant and well-designed studies.
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Affiliation(s)
- Linqing Zhong
- Department of Pediatrics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hongmei Song
- Department of Pediatrics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wei Wang
- Department of Pediatrics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ji Li
- Department of Pediatrics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Mingsheng Ma
- Department of Pediatrics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Ghasemi-rad M, Attaya H, Lesha E, Vegh A, Maleki-Miandoab T, Nosair E, Sepehrvand N, Davarian A, Rajebi H, Pakniat A, Fazeli SA, Mohammadi A. Ankylosing spondylitis: A state of the art factual backbone. World J Radiol 2015; 7:236-252. [PMID: 26435775 PMCID: PMC4585948 DOI: 10.4329/wjr.v7.i9.236] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2014] [Revised: 03/04/2015] [Accepted: 06/16/2015] [Indexed: 02/06/2023] Open
Abstract
Ankylosing spondylitis (AS) is a chronic inflammatory disease that affects 1% of the general population. As one of the most severe types of spondyloarthropathy, AS affects the spinal vertebrae and sacroiliac joints, causing debilitating pain and loss of mobility. The goal of this review is to provide an overview of AS, from the pathophysiological changes that occur as the disease progresses, to genetic factors that are involved with its onset. Considering the high prevalence in the population, and the debilitating life changes that occur as a result of the disease, a strong emphasis is placed on the diagnostic imaging methods that are used to detect this condition, as well as several treatment methods that could improve the health of individuals diagnosed with AS.
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Hasi-Zogaj M, Sebold C, Heard P, Carter E, Soileau B, Hill A, Rupert D, Perry B, Atkinson S, O'Donnell L, Gelfond J, Lancaster J, Fox PT, Hale DE, Cody JD. A review of 18p deletions. AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS 2015; 169:251-64. [PMID: 26250845 DOI: 10.1002/ajmg.c.31445] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Since 18p- was first described in 1963, much progress has been made in our understanding of this classic deletion condition. We have been able to establish a fairly complete picture of the phenotype when the deletion breakpoint occurs at the centromere, and we are working to establish the phenotypic effects when each gene on 18p is hemizygous. Our aim is to provide genotype-specific anticipatory guidance and recommendations to families with an 18p- diagnosis. In addition, establishing the molecular underpinnings of the condition will potentially suggest targets for molecular treatments. Thus, the next step is to establish the precise effects of specific gene deletions. As we look forward to deepening our understanding of 18p-, our focus will continue to be on the establishment of robust genotype-phenotype correlations and the penetrance of these phenotypes. We will continue to follow our 18p- cohort closely as they age to determine the presence or absence of some of these diagnoses, including spinocerebellar ataxia (SCA), facioscapulohumeral muscular dystrophy (FSHD), and dystonia. We will also continue to refine the critical regions for other phenotypes as we enroll additional (hopefully informative) participants into the research study and as the mechanisms of the genes in these regions are elucidated. Mouse models will also be developed to further our understanding of the effects of hemizygosity as well as to serve as models for treatment development.
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Brown MA, Xu H. Genetics of axial spondyloarthritis. Rheumatology (Oxford) 2015. [DOI: 10.1016/b978-0-323-09138-1.00116-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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Jung SH, Yim SH, Hu HJ, Lee KH, Lee JH, Sheen DH, Lim MK, Kim SY, Park SW, Kim SH, Han K, Kim TH, Shim SC, Chung YJ. Genome-wide copy number variation analysis identifies deletion variants associated with ankylosing spondylitis. Arthritis Rheumatol 2014; 66:2103-12. [PMID: 24692264 DOI: 10.1002/art.38650] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2013] [Accepted: 03/27/2014] [Indexed: 01/16/2023]
Abstract
OBJECTIVE To identify ankylosing spondylitis (AS)-associated copy number variations (CNVs) in Korean subjects and their synergistic roles in the development of AS. METHODS A genome-wide association study (GWAS) was performed in 309 patients with AS and 309 control subjects, using a copy number variant (CNV) microarray. AS-associated CNV regions were replicated in 2 independent sets (625 patients and 891 control subjects) by quantitative polymerase chain reaction (PCR) and deletion-typing PCR. RESULTS In the CNV GWAS, 227 CNV regions were shown to be significantly associated with the risk of AS. Of the candidate CNV regions, 9 were successfully replicated in the first replication analysis: 1q32.2 (HHAT), 1p34.2 (BMP8A), 2q31.2 (PRKRA), 6p21.32 (HLA-DPB1), 11q22.1 (CNTN5), 13q13.1 (EEF1DP3), 14q24.2 (RGS6), 16p13.3, and 22q11.1 (IL17RA). The 5 deletion-type CNV regions, in 1q32.2, 2q31.2, 6p21.32, 13q13.1, and 16p13.3, were associated with an increased risk of AS, and the other 4 CNV regions were protective. In the second replication analysis, 4 CNV regions in 1q32.2, 2q31.2, 6p21.32, and 16p13.3 were replicated. Among patients with CNV regions in ≥4 risk-increasing loci, the risk was 18.0 times higher than that in patients without any deletions (odds ratio [OR] 17.98, P = 2.3 × 10(-7) ). Among patients with CNV regions in ≥2 protective loci, the risk was 5.2 times lower than that in those without any deletions (OR 0.19, P = 4.0 × 10(-10) ). The additive effects of simultaneous events were shown to be dependent on the frequency of CNV regions. Through deletion-typing PCR and sequencing, the exact sizes and breakpoint sequences were defined in 4 CNV regions. The mechanism of all 3 deletions was shown to be microhomology-based nonhomologous end joining. CONCLUSION The results of this study can help to identify pathogenic mechanisms of AS and can easily be applied in the development of algorithms estimating the risk of AS.
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Keidel S, Chen L, Pointon J, Wordsworth P. ERAP1 and ankylosing spondylitis. Curr Opin Immunol 2013; 25:97-102. [PMID: 23452840 DOI: 10.1016/j.coi.2012.11.002] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2012] [Revised: 11/08/2012] [Accepted: 11/08/2012] [Indexed: 12/21/2022]
Abstract
The strong genetic association of ERAP1 (endoplasmic reticulum aminopeptidase 1) with ankylosing spondylitis (AS), which is restricted to HLA-B27 positive cases, has profound pathogenetic implications. ERAP1 is involved in trimming peptides to optimal length for binding to HLA class 1 molecules, thereby not only affecting the stability and processing of HLA-B27 but also influencing the peptide repertoire presented to the immune system. This could have secondary effects on specific adaptive or autoimmune responses in AS. However, it appears increasingly likely that the pathogenic effect of ERAP1 may be mediated through effects on innate immunity, such as altering the interaction between HLA-B27 and immune receptors such as the killer immunoglobulin-like receptors (KIR) found on a range of innate immune cells or via the endoplasmic reticulum unfolded protein response. ERAP1 variants associated with reduced endopeptidase activity appear to be protective against AS, raising the possibility that ERAP1 inhibition could represent a future treatment strategy.
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Affiliation(s)
- Sarah Keidel
- University of Oxford Institute of Musculoskeletal Sciences, Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Nuffield Orthopaedic Centre, Windmill Road, Oxford OX3 7LD, UK
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Robinson PC, Brown MA. Genetics of ankylosing spondylitis. Mol Immunol 2013; 57:2-11. [PMID: 23916070 DOI: 10.1016/j.molimm.2013.06.013] [Citation(s) in RCA: 92] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2013] [Revised: 06/18/2013] [Accepted: 06/19/2013] [Indexed: 02/08/2023]
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.
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Affiliation(s)
- Philip C Robinson
- University of Queensland Diamantina Institute, Translational Research Institute, 37 Kent Road, Princess Alexandra Hospital, Brisbane, Australia
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Schiotis R, Bartolomé N, Sánchez A, Szczypiorska M, Sanz J, Cuende E, Collantes Estevez E, Martínez A, Tejedor D, Artieda M, Buzoianu A, Mulero J. Both baseline clinical factors and genetic polymorphisms influence the development of severe functional status in ankylosing spondylitis. PLoS One 2012; 7:e43428. [PMID: 22984424 PMCID: PMC3440408 DOI: 10.1371/journal.pone.0043428] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2012] [Accepted: 07/19/2012] [Indexed: 12/17/2022] Open
Abstract
Functional severity in ankylosing spondylitis (AS) patients is variable and difficult to predict early. The aim of our study was to assess whether a combination of baseline clinical factors and genetic markers may predict the development of severe functional status in AS. We performed a cross-sectional association study on AS patients included in the Spanish National Registry of Spondyloarthropathies—REGISPONSER. Bath Ankylosing Spondylitis Functional Index (BASFI) was standardized by adjusting for disease duration since the first symptoms (BASFI/t). We considered as severe functional status the values of BASFI/t in the top of the 60th (p60), 65th (p65), 70th (p70), and 75th (p75) percentile. We selected 384 single nucleotide polymorphisms (SNPs) distributed in 190 genes to be analyzed. The study cohort included 456 patients with mean age 50.8(±10.5) years and with mean disease duration since first symptoms 24.7 (±10.1) years. Older age at disease onset and neck pain at baseline showed statistical significant association with severe BASFI/t. Polymorphisms associated in the allele frequencies test with severe BASFI/t in all classifications were: rs2542151 (p60 [P = .04], p65 [P = .04], p70 [P = .001] and p75 [P = .001]) and rs2254441 (p60 [P = .004], p65 [P = .02], p70 [P = .01] and p75 [P<.001]).. Genotype association, after adjustment for covariates, found an association in three of the four patients' classifications for rs2542151 and in two of the classifications for rs2254441.Forward logistic regression did not identify any model with a good predictive power for severe functional development. In our study we identified clinical factors and 24 polymorphisms associated with development of severe functional status in AS patients. Validation of these results in other cohorts is required.
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Affiliation(s)
- Ruxandra Schiotis
- Department of Pharmacology, “Iuliu Hatieganu” University of Medicine and Pharmacy and SCBI- Rheumatology Department, Cluj-Napoca, Romania
- Department of Rheumatology, University Hospital “Reina Sofía”/IMIBIC, Córdoba, Spain
- * E-mail:
| | - Nerea Bartolomé
- Department of R+D, Progenika Biopharma SA, Derio-Vizcaya, Spain
| | - Alejandra Sánchez
- Department of Rheumatology, “Puerta de Hierro Majadahonda”, University Hospital, Madrid, Spain
| | | | - Jesús Sanz
- Department of Rheumatology, “Puerta de Hierro Majadahonda”, University Hospital, Madrid, Spain
| | - Eduardo Cuende
- Department of Rheumatology, University Hospital “Príncipe de Asturias”, Alcalá de Henares, Madrid, Spain
| | | | | | - Diego Tejedor
- Department of R+D, Progenika Biopharma SA, Derio-Vizcaya, Spain
| | - Marta Artieda
- Department of R+D, Progenika Biopharma SA, Derio-Vizcaya, Spain
| | - Anca Buzoianu
- Department of Pharmacology, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Juan Mulero
- Department of Rheumatology, “Puerta de Hierro Majadahonda”, University Hospital, Madrid, Spain
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MA HJ, YIN QF, HU FP, GUO MH, LIU XD, LIU Y, XU QY. Different clinical features in patients with ankylosing spondylitis from southern and northern China. Int J Rheum Dis 2011; 15:154-62. [DOI: 10.1111/j.1756-185x.2011.01697.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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Pimentel-Santos FM, Ligeiro D, Matos M, Mourão AF, Vieira de Sousa E, Pinto P, Ribeiro A, Santos H, Barcelos A, Godinho F, Cruz M, Fonseca JE, Guedes-Pinto H, Trindade H, Brown MA, Branco JC. ANKH and susceptibility to and severity of ankylosing spondylitis. J Rheumatol 2011; 39:131-4. [PMID: 22089454 DOI: 10.3899/jrheum.110681] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
OBJECTIVE Unconfirmed reports describe association of ankylosing spondylitis (AS) with several candidate genes including ANKH. Cellular export of inorganic pyrophosphate is regulated by the ANK protein, and mutant mice (ank/ank), which have a premature stop codon in the 3' end of the ank gene, develop severe ankylosis. We tested the association between single-nucleotide polymorphisms (SNP) in these genes and susceptibility to AS in a population of patients with AS. We investigated the role of these genes in terms of functional (BASFI) and metrological (BASMI) measures, and the association with radiological severity (mSASSS). METHODS Our study was conducted on 355 patients with AS and 95 ethnically matched healthy controls. AS was defined according to the modified New York criteria. Four SNP in ANKH (rs27356, rs26307, rs25957, and rs28006) were genotyped. Association analysis was performed using Cochrane-Armitage and linear regression tests for dichotomous and quantitative variables. Analyses of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), BASFI, and mSASSS were controlled for sex and disease duration. RESULTS None of the 4 markers showed significant single-locus disease associations (p > 0.05), suggesting that ANKH was not a major determinant of AS susceptibility in our population. No association was observed between these SNP and age at symptom onset, BASDAI, BASFI, BASMI, or mSASSS. CONCLUSION These results confirm data in white Europeans that ANKH is probably not a major determinant of susceptibility to AS. ANKH polymorphisms do not markedly influence AS disease severity, as measured by BASMI and mSASSS.
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Thomas GP. Potential of genome-wide association study data to contribute to better treatments: examples from ankylosing spondylitis. Per Med 2011; 8:599-601. [PMID: 29776203 DOI: 10.2217/pme.11.63] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Affiliation(s)
- Gethin P Thomas
- University of Queensland Diamantina Institute, Princess Alexandra Hospital, Woolloongabba, QLD 4102, Australia.
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Brown MA. Genetics of ankylosing spondylitis. Rheumatology (Oxford) 2011. [DOI: 10.1016/b978-0-323-06551-1.00114-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022] Open
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Akkoc N, Sari I, Akar S, Binicier O, Thomas MG, Weale ME, Birlik M, Savran Y, Onen F, Bradman N, Plaster CA. Increased prevalence of M694V in patients with ankylosing spondylitis: Additional evidence for a link with familial mediterranean fever. ACTA ACUST UNITED AC 2010; 62:3059-63. [DOI: 10.1002/art.27598] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
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Végvári A, Szabó Z, Szántó S, Glant TT, Mikecz K, Szekanecz Z. The genetic background of ankylosing spondylitis. Joint Bone Spine 2010; 76:623-8. [PMID: 19541528 DOI: 10.1016/j.jbspin.2009.02.006] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2008] [Accepted: 02/24/2009] [Indexed: 01/18/2023]
Abstract
It has long been known that the major histocompatibility complex (MHC) is essentially involved in genetic susceptibility to ankylosing spondylitis (AS). The HLA-B27 antigen has been accounted for 20 to 50% of the total genetic risk for this disease. However, susceptibility to AS cannot be fully explained by associations with the MHC. Recent studies including linkage analyses as well as candidate gene and, most recently, genome-wide association studies indicate significant associations of the interleukin-1 gene cluster, interleukin-23 receptor and ARTS1 genes as well as other possible loci with AS. In the murine model of proteoglycan-induced spondylitis, two susceptibility loci termed Pgis1 and Pgis2 were identified. Thus, AS is not a single-gene disease and the involvement of multiple non-MHC genes may account for the individual as well as geographical differences seen in AS.
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Affiliation(s)
- Anikó Végvári
- Department of Rheumatology, Institute of Medicine, University of Debrecen Medical and Health Science Center, 22, Móricz street, Debrecen, H-4032, Hungary
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Brown MA. Progress in spondylarthritis. Progress in studies of the genetics of ankylosing spondylitis. Arthritis Res Ther 2009; 11:254. [PMID: 19886979 PMCID: PMC2787301 DOI: 10.1186/ar2692] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The advent of high-throughput SNP genotyping methods has advanced research into the genetics of common complex genetic diseases such as ankylosing spondylitis (AS) rapidly in recent times. The identification of associations with the genes IL23R and ERAP1 have been robustly replicated, and advances have been made in studies of the major histocompatibility complex genetics of AS, and of KIR gene variants and the disease. The findings are already being translated into increased understanding of the immunological pathways involved in AS, and raising novel potential therapies. The current studies in AS remain underpowered, and no full genomewide association study has yet been reported in AS; such studies are likely to add to the significant advances that have already been made.
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Affiliation(s)
- Matthew A Brown
- Diamantina Institute of Cancer, Immunology and Metabolic Medicine, University of Queensland, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Brisbane 4102, Australia.
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Durmus D, Alayli G, Cengiz K, Yigit S, Canturk F, Bagci H. Clinical significance of MEFV mutations in ankylosing spondylitis. Joint Bone Spine 2009; 76:260-4. [DOI: 10.1016/j.jbspin.2008.09.011] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2008] [Accepted: 09/18/2008] [Indexed: 01/22/2023]
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Spondyloarthritis, Diffuse Idiopathic Skeletal Hyperostosis (DISH) and Chondrocalcinosis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2009. [DOI: 10.1007/978-1-4419-0298-6_3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register]
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Brown MA. Genomewide Screens in Ankylosing Spondylitis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2009; 649:148-58. [DOI: 10.1007/978-1-4419-0298-6_11] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Clinical features of ankylosing spondylitis may correlate with HLA-B27 polymorphism. Rheumatol Int 2008; 29:389-92. [PMID: 18953540 DOI: 10.1007/s00296-008-0743-0] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2008] [Accepted: 10/05/2008] [Indexed: 01/07/2023]
Abstract
The objective of this study is to investigate the relationship between clinical features of ankylosing spondylitis (AS) and HLA-B27 status or its subtypes. Clinical data and blood samples were collected with patients' informed consent. Luminex liquid array combining polymerase chain reaction-sequence specific oligonucleotide probe was used to do the low-resolution HLA-B genotype typing. Polymerase chain reaction-sequence specific primer was applied to do the high resolution HLA-B27 typing. In 98 subjects, 93 were HLA-B27 positive, of which three subtypes were detected: B*2704 (n = 76), B*2705 (n = 12), and B*2715 (n = 5). The onset age for B27 negative and positive group was 28 +/- 7.9 and 21.1 +/- 6.2 years, respectively (chi(2) = -2.047, P = 0.041). The onset age for B*2704, B*2705 and B*2715 group was 20.45 +/- 4.50, 26.67 +/- 9.95 and 17.8 +/- 11.12 years, respectively (chi(2) = 7.888, P = 0.019). No significant difference was found between B27 positive and negative group, or among three B27 subtypes groups for other clinical features. In conclusion, the clinical features of AS may be correlated with HLA-B27 status and its polymorphism.
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Queiro R, Alperi M, Lopez A, Sarasqueta C, Riestra JL, Ballina J. Clinical expression, but not disease outcome, may vary according to age at disease onset in psoriatic spondylitis. Joint Bone Spine 2008; 75:544-7. [PMID: 18456537 DOI: 10.1016/j.jbspin.2007.11.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2007] [Accepted: 11/21/2007] [Indexed: 12/13/2022]
Abstract
OBJECTIVES To investigate whether the clinical expression and disease outcome in psoriatic spondylitis (PsS) may vary according to age at disease onset. METHODS This study included 70 patients from a unique outpatient spondylitis clinic followed on a regular basis with a standard protocol. Patients were diagnosed with PsS according to ESSG criteria plus radiographic sacroiliitis (SI). Outcome parameters included: disease activity, functional evaluation, radiological damage, mobility restriction, and enthesitis score. Patients were divided into those with disease onset before 40 years (young-onset PsS) and those with onset over this age (late-onset PsS). Clinical features and outcome parameters were compared between groups. RESULTS There were 44 men and 26 women. Thirty-nine (M:F ratio 1.8) patients had disease onset before 40 years and 31 (M:F ratio 1.6) over this age. HLA-B27 correlated with PsS susceptibility (34% vs 7%, RR 6.4, p<0.0004), but it was found over-represented in young-onset PsS compared to late-onset cases (51% vs 13%, p=0.001). Young-onset cases tended to have a higher frequency of family history (26% vs 13%), bilateral SI (62% vs 29%, p=0.013), isolated axial pattern (31% vs 13%), and enthesitis (54% vs 29%, p=0.09). In late-onset PsS there was a higher frequency of unilateral SI (71% vs 38%, p=0.013), polyarthritis (45% vs 23%, p=0.022), and silent axial disease (32% vs 10%, p=0.022). Outcome parameters were similar between groups. CONCLUSIONS Clinical picture but not outcome parameters, varies according to age at disease onset in PsS. The correlation between HLA-B27 and young-onset PsS supports the notion that disease susceptibility and disease expression are not driven by the same gene in this entity.
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Affiliation(s)
- Ruben Queiro
- Rheumatology Service, Hospital Universitario Central de Asturias, C/ Celestino Villamil s/n, 33006 Oviedo, Spain.
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Gunal EK, Sarvan FO, Kamali S, Gul A, Inanc M, Carin M, Konice M, Aral O, Ocal L. Low frequency of HLA-B27 in ankylosing spondylitis patients from Turkey. Joint Bone Spine 2008; 75:299-302. [PMID: 18424159 DOI: 10.1016/j.jbspin.2007.06.021] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2007] [Accepted: 06/06/2007] [Indexed: 01/18/2023]
Abstract
OBJECTIVES Ankylosing spondylitis is strongly associated with HLA-B27. However, the strength of the association with HLA-B27 and the clinical features may vary in different parts of the world. The aim of this study is to compare the clinical features of AS and the frequencies of HLA-B27 and its alleles in patients from Turkey with other series. METHODS One hundred and twelve patients (72 male/40 female) fulfilling the modified New York criteria for the classification of AS and 55 (27 male/28 female) healthy controls were typed for HLA-B27 and allele frequencies by sequence specific primer (PCR/SSP) method and assessed for clinical manifestations. RESULTS Male to female ratio was 1.8, mean age at disease onset was 23.5 and 24.1% of patients reported juvenile onset of symptoms. Peripheral arthritis was seen in 52.7% of patients. Family history (p=0.01) and peripheral arthritis (p=0.02) were more frequent in females and spinal involvement in males. HLA-B27 was found to be positive in 70% of patients and associated with younger mean age, uveitis and shorter time elapsed from symptom to diagnosis. The frequency of HLA-B27 alleles associated with SpA was not different between ankylosing spondylitis patients and healthy controls. CONCLUSION Low frequency of HLA-B27 and clinical variations in ankylosing spondylitis may be due to different genetic and/or environmental factors in Turkey.
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Affiliation(s)
- Esen Kasapoglu Gunal
- Maltepe University Medical Faculty, Department of Internal Medicine, Division of Rheumatology, Istanbul, Turkey.
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Novel non-HLA-susceptible regions determined by meta-analysis of four genomewide scans for ankylosing spondylitis. J Genet 2008; 87:75-81. [DOI: 10.1007/s12041-008-0010-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
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Thjodleifsson B, Geirsson AJ, Björnsson S, Bjarnason I. A common genetic background for inflammatory bowel disease and ankylosing spondylitis: a genealogic study in Iceland. ACTA ACUST UNITED AC 2007; 56:2633-9. [PMID: 17665420 DOI: 10.1002/art.22812] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Patients with ankylosing spondylitis (AS) and approximately 50% of their first-degree relatives may have a genetic abnormality that results in subclinical intestinal inflammation. This study was undertaken to examine the familial occurrence and cosegregation of AS and inflammatory bowel disease (IBD) in order to determine whether there is a shared genetic risk factor in families. METHODS The Icelandic genealogy database and population-wide data on all living Icelanders diagnosed as having AS (n = 205) and/or IBD (n = 1,352) were used to estimate the risk ratios of AS for relatives of patients with AS, the risk ratios of IBD for relatives of patients with IBD, and the cross-risk ratios of AS for relatives of patients with IBD or of IBD for relatives of patients with AS. The mean kinship coefficients for each disease were calculated. The control population for disease risk calculations comprised 10,000-100,000 sets of matched Icelandic subjects. RESULTS First-, second-, and third-degree relatives of patients with AS had risk ratios of 94, 25, and 3.5, respectively, indicating an increased risk of developing AS (each P < 0.0005), while first-, second-, and third-degree relatives of patients with IBD had risk ratios for IBD of 4.4, 2.2, and 1.4, respectively (each P < 0.0001). The cross-risk ratios of IBD were 3.0 and 2.1 in first- and second-degree relatives of patients with AS, respectively, and were the same for AS in first- and second-degree relatives of patients with IBD. With the exception of Crohn's disease, the risk of having AS, ulcerative colitis, or IBD in spouses of patients with these diseases did not differ significantly from that in controls. Calculation of the kinship coefficients confirmed these patterns of familial risk. CONCLUSION Patients with AS or IBD in Iceland are significantly more related to each other than are randomly sampled control subjects, in terms of an increased risk of either or both conditions developing in third-degree relatives. These findings suggest that one or more undiscovered genetic variants may underlie the risk of both diseases.
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Lories RJU, Derese I, de Bari C, Luyten FP. Evidence for uncoupling of inflammation and joint remodeling in a mouse model of spondylarthritis. ACTA ACUST UNITED AC 2007; 56:489-97. [PMID: 17265484 DOI: 10.1002/art.22372] [Citation(s) in RCA: 114] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVE To study the relationship between inflammation and remodeling by inhibiting tumor necrosis factor alpha (TNFalpha) in male DBA/1 mice with spontaneous arthritis, a model of spondylarthritis (SpA). METHODS TNFalpha was inhibited using etanercept, a soluble TNF receptor. The efficacy of the dose used (25 micro g/mouse) was confirmed in methylated bovine serum albumin (mBSA)-induced monarthritis, a model of inflammation-driven joint destruction. Male DBA/1 mice with spontaneous arthritis were caged together from the age of 10 weeks onward and were treated twice weekly with etanercept. The incidence and clinical severity of disease were recorded. Mice were killed at age 25 weeks, and histomorphologic analysis was performed. The presence of TNFalpha, NF-kappaB, and Smad signaling was studied using immunohistochemistry. Entheseal endochondral bone formation was modeled using micromass cultures of periosteal cells. RESULTS Etanercept inhibited mouse TNFalpha in vitro and in vivo. Etanercept treatment of mBSA-induced arthritis had a significant effect on the severity of disease. Etanercept did not affect the incidence or severity of spontaneous arthritis. Pathologic analysis revealed no differences between etanercept-treated and phosphate buffered saline-treated mice. TNFalpha-positive cells were observed in the synovium, in vessel-associated cells, in fibrocartilage, and in new cartilage. Activation of Smad signaling was observed in earlier stages of disease than was active NF-kappaB signaling. TNFalpha inhibited chondrogenesis in the micromass model. CONCLUSION Inhibition of TNF did not affect the severity and incidence of joint ankylosis in a mouse model of SpA. Therefore, the process of entheseal ankylosis may be independent of TNF. New tissue formation in SpA could be considered an additional and specific therapeutic target.
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Sims AM, Barnardo M, Herzberg I, Bradbury L, Calin A, Wordsworth BP, Darke C, Brown MA. Non-B27 MHC associations of ankylosing spondylitis. Genes Immun 2006; 8:115-23. [PMID: 17167495 DOI: 10.1038/sj.gene.6364362] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Ankylosing spondylitis (AS) has been associated with human leukocyte antigen (HLA)-B27 for over 30 years; however, the mechanism of action has remained elusive. Although many studies have reported associations between AS and other genes in the major histocompatibility complex (MHC) in AS, no conclusive results have emerged. To investigate the contribution of non-B27 MHC genes to AS, a large cohort of AS families and controls were B27 typed and genotyped across the region. Interrogation of the data identified a region of 270 kb, lying from 31 952 649 to 32 221 738 base pairs from the p-telomere of chromosome 6 and containing 23 genes, which is likely to include genes involved with susceptibility to AS.
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Affiliation(s)
- A-M Sims
- Botnar Research Centre, Nuffield Orthopaedic Centre, Oxford, UK
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Abstract
BACKGROUND In this retrospective study, we report our experience with infliximab for recalcitrant psoriasis. METHODS Twelve patients were treated between September 2001 and April 2005. Infliximab 5 mg/kg was given at 0, 2 and 6 weeks followed by 5 mg/kg at 8-week intervals. When two patients developed resistance to treatment, methotrexate was added at a dose of 5-7.5 mg weekly for all patients. Response to treatment was assessed with physician global assessment with a score of excellent, good, moderate, poor and failure. Ten patients had chronic plaque psoriasis, one had pustular palmoplantar psoriasis and one had acrodermatitis continua of Hallopeau. RESULTS Nine patients, including the patient with acrodermatitis continua, showed an excellent response. Two patients initially showed good response but became resistant to treatment. One patient failed to respond, and treatment was discontinued. With time, six patients with excellent response and two with good response developed side-effects that necessitated stopping treatment. CONCLUSIONS We have found infliximab to be very impressive, both in efficacy and speed of action, in severe psoriasis. Its use, however, is limited, as it requires hospital admission and by the need for concomitant methotrexate. Because of its powerful immunosuppressive action, the possibility of activating tuberculosis and inducing lymphoma remains a concern.
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Affiliation(s)
- K Ahmad
- City of Dublin Skin and Cancer Hospital, and St. Vincent's University Hospital, Dublin, Ireland.
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Adarichev VA, Glant TT. Experimental spondyloarthropathies: Animal models of ankylosing spondylitis. Curr Rheumatol Rep 2006; 8:267-74. [PMID: 16839505 DOI: 10.1007/s11926-006-0007-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Spondyloarthropathies (SpAs), including ankylosing spondylitis, are chronic inflammatory diseases of the axial skeleton. Genomic scans of SpA families revealed the overwhelming complexity of the disease, which appears to be under the control of over 20 chromosome loci, including the major SpA gene HLA-B27 within class I of the major histocompatibility complex (MHC). Animal models confirmed the primary role of MHC in SpA susceptibility and supported the hypothesis that certain enterobacterial infections can trigger SpA. Immunization of mice with proteoglycan aggrecan also can provoke SpA, thus providing the opportunity to study genetic and clinical details of the disease initiation.
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Affiliation(s)
- Vyacheslav A Adarichev
- Rush University Medical Center, Section of Molecular Medicine, Department of Orthopedic Surgery, Chicago, IL 60612, USA.
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Abstract
PURPOSE OF REVIEW Genetic factors provide over 90% of the overall susceptibility to ankylosing spondylitis, with about half of the genetic contribution attributed to HLA-B27 and other major histocompatibility complex genes. Recent studies have focused on non-major histocompatibility complex genes. This review is aimed at summarizing the status of major histocompatibility complex and non-major histocompatibility complex genes in ankylosing spondylitis susceptibility, and suggests areas for future studies. RECENT FINDINGS A recent meta-analysis of published scans of ankylosing spondylitis susceptibility has confirmed sites on chromosomes 3q, 6p (the major histocompatibility complex), 10q, 16q and 19q in ankylosing spondylitis susceptibility. Non-major histocompatibility complex candidate gene analyses have confirmed a role for the IL-1 gene complex. The search for other non-major histocompatibility complex candidate genes, however, has been complicated by inadequate power in most previous studies. Innovations in genetic methodologies will allow thorough genome wide linkage disequilibrium mapping studies in large cohorts of patients that will result in the dissection of the genetic susceptibility to ankylosing spondylitis. SUMMARY Nearly half of the susceptibility to ankylosing spondylitis is provided by major histocompatibility complex genes. Non-major histocompatibility complex genes, most notably the IL-1 gene complex, have been identified and novel technologies promise that a more thorough examination of the rest of the genome will soon elucidate the genetic basis of this disease.
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Affiliation(s)
- John D Reveille
- Division of Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
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Jaakkola E, Herzberg I, Laiho K, Barnardo MCNM, Pointon JJ, Kauppi M, Kaarela K, Tuomilehto-Wolf E, Tuomilehto J, Wordsworth BP, Brown MA. Finnish HLA studies confirm the increased risk conferred by HLA-B27 homozygosity in ankylosing spondylitis. Ann Rheum Dis 2006; 65:775-80. [PMID: 16249228 PMCID: PMC1798178 DOI: 10.1136/ard.2005.041103] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/15/2005] [Indexed: 11/03/2022]
Abstract
OBJECTIVE To determine the influence of HLA-B27 homozygosity and HLA-DRB1 alleles in the susceptibility to, and severity of, ankylosing spondylitis in a Finnish population. METHODS 673 individuals from 261 families with ankylosing spondylitis were genotyped for HLA-DRB1 alleles and HLA-B27 heterozygosity/homozygosity. The frequencies of HLA-B27 homozygotes in probands from these families were compared with the expected number of HLA-B27 homozygotes in controls under Hardy-Weinberg equilibrium (HWE). The effect of HLA-DRB1 alleles was assessed using a logistic regression procedure conditioned on HLA-B27 and case-control analysis. RESULTS HLA-B27 was detected in 93% of cases of ankylosing spondylitis. An overrepresentation of HLA-B27 homozygotes was noted in ankylosing spondylitis (11%) compared with the expected number of HLA-B27 homozygotes under HWE (4%) (odds ratio (OR) = 3.3 (95% confidence interval, 1.6 to 6.8), p = 0.002). HLA-B27 homozygosity was marginally associated with reduced BASDAI (HLA-B27 homozygotes, 4.5 (1.6); HLA-B27 heterozygotes, 5.4 (1.8) (mean (SD)), p = 0.05). Acute anterior uveitis (AAU) was present in significantly more HLA-B27 positive cases (50%) than HLA-B27 negative cases (16%) (OR = 5.4 (1.7 to 17), p<0.004). HLA-B27 positive cases had a lower average age of symptom onset (26.7 (8.0) years) compared with HLA-B27 negative cases (35.7 (11.2) years) (p<0.0001). CONCLUSIONS HLA-B27 homozygosity is associated with a moderately increased risk of ankylosing spondylitis compared with HLA-B27 heterozygosity. HLA-B27 positive cases had an earlier age of onset of ankylosing spondylitis than HLA-B27 negative cases and were more likely to develop AAU. HLA-DRB1 alleles may influence the age of symptom onset of ankylosing spondylitis.
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Affiliation(s)
- E Jaakkola
- Botnar Research Centre, Nuffield Orthopaedic Centre, Oxford, United Kingdom.
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Ferraccioli G, Tolusso B, De Santis M. Pharmacogenetic of antirheumatic treatments: clinical implications. THE PHARMACOGENOMICS JOURNAL 2006; 7:2-9. [PMID: 16702980 DOI: 10.1038/sj.tpj.6500396] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Preliminary pharmacogenetic data suggest that germline genetic informations might be of value in individualizing disease-modifying antirheumatic drugs (DMARDs) therapy in various autoimmune chronic inflammatory diseases. Either DMARDs small molecules (DMARDs-SM) or DMARDs biological therapies (DMARDs-BT) might be selected for their lower toxicity or better efficacy based on single-nucleotide polymorphisms (SNPs) of genes governing the metabolism of drugs, or the response of immune cells to proinflammatory molecules, or the proinflammatory molecular activity of immune cells. Data available for one DMARDs-SM, methotrexate, suggest that a careful assessment of the SNPs of four enzymes involved in the folate metabolism allow one to construct a genetic index of toxicity (toxicogenetic index) that might be employed in daily practice to find the patient's most at risk. Only the full knowledge of the various gene polymorphisms controlling the phenotypic manifestations of the inflammatory-immunological milieu of each rheumatic disease will allow one to obtain the clear definition of a personalized medicine. Few different cytokine gene SNPs seem to be of importance in determining the susceptibility to diseases, or the aggressiveness of diseases. The role of genetics in affecting a possible clinical response to DMARDs-BT targeting specific inflammatory molecules or their receptors still has to be defined. However, the available data suggest that cytokine (and/or receptors) gene SNPs might indeed play a role in determining the biological effects, hence the clinical effectiveness of DMARDs-BT. Crucial to this aim will be the prospective analysis of clinical benefits and safety on the basis of the at baseline stratification of gene SNPs in each chronic inflammatory rheumatic disease before starting any new DMARDs-SM or DMARDs-BT.
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Affiliation(s)
- G Ferraccioli
- Division of Rheumatology, Catholic University of the Sacred Heart-Catholic University of Rome, Rome, Italy.
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Maksymowych WP, Rahman P, Reeve JP, Gladman DD, Peddle L, Inman RD. Association of the IL1 gene cluster with susceptibility to ankylosing spondylitis: an analysis of three Canadian populations. ACTA ACUST UNITED AC 2006; 54:974-85. [PMID: 16508980 DOI: 10.1002/art.21642] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
OBJECTIVE To examine the association between the IL1 gene cluster and susceptibility to ankylosing spondylitis (AS) in 3 independent case-control cohorts. METHODS We analyzed 394 patients and 446 controls from Alberta, Newfoundland, and Toronto, Canada. Samples were genotyped using a panel of 38 single-nucleotide polymorphism (SNP) markers within the IL1 gene cluster. Data from 20 informative and nonredundant SNP markers were analyzed using several association test strategies. First, we used the program WHAP to identify single-marker associations. Second, we used WHAP to analyze "sliding windows" of 3 contiguous markers along the entire extent of the IL1 gene cluster in order to identify haplotypic associations. Third, we used the linkage disequilibrium mapping program DMLE to estimate the posterior probability distribution of a disease locus. RESULTS A total of 14 SNP markers showed significant single-locus disease associations, the most significant being rs3783526 (IL1A) (P = 0.0009 in the Alberta cohort, P = 0.04 in the Newfoundland cohort) and rs1143627 (IL1B) (P = 0.0005 in the Alberta cohort, P = 0.02 in the Newfoundland cohort). Analysis of 3-marker sliding windows revealed significant and consistent associations with all of the haplotypes in the IL1A and IL1B loci in the Alberta cohort and with IL1B in the Newfoundland cohort, especially haplotypes rs1143634/rs1143630/rs3917356 and rs1143630/rs3917356/rs3917354 (P = 0.006-0.0001). With DMLE, a strong peak in the probability distribution was estimated near IL1A in both the Alberta and the Newfoundland populations. CONCLUSION These results indicate that the IL1 locus, or a locus close to IL1, is associated with susceptibility to AS.
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Breban M, Miceli-Richard C, Zinovieva E, Monnet D, Said-Nahal R. The genetics of spondyloarthropathies. Joint Bone Spine 2006; 73:355-62. [PMID: 16650794 DOI: 10.1016/j.jbspin.2005.11.010] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2005] [Accepted: 11/04/2005] [Indexed: 12/21/2022]
Abstract
The spondyloarthropathies constitute a group of inflammatory joint diseases linked by shared characteristics that include a strong common genetic background. Genetic factors include major histocompatibility complex (MHC) genes, among which HLA-B27 contributes 30% of the overall genetic susceptibility to spondyloarthropathies, and non-MHC genes, none of which have been identified to date. Genome screens have identified regions that may contain susceptibility genes for spondyloarthropathies. In particular, a locus on the long arm of chromosome 9 (9q31-34) was identified by two groups working independently from each other. Studies using the candidate gene approach ruled out a role for most of the tested genes, including CARD15/NOD2. However, several independent groups have reported significant associations between ankylosing spondylitis and the IL-1 gene cluster on the long arm of chromosome 2.
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Affiliation(s)
- Maxime Breban
- Département d'immunologie, institut Cochin, Inserm U567/CNRS UMR8104/IFR116, hôpital Cochin, 27, rue du Faubourg-Saint-Jacques, 75014 Paris, France.
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Uppal SS, Abraham M, Chowdhury RI, Kumari R, Pathan EM, Al Rashed A. Ankylosing spondylitis and undifferentiated spondyloarthritis in Kuwait: a comparison between Arabs and South Asians. Clin Rheumatol 2005; 25:219-24. [PMID: 16240074 DOI: 10.1007/s10067-005-1162-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2004] [Revised: 05/13/2005] [Accepted: 05/13/2005] [Indexed: 12/16/2022]
Abstract
The objectives of this study were to describe and compare the clinical characteristics of ankylosing spondylitis (AS) and undifferentiated spondyloarthritis (USpA) in Middle East Arab (MEA) and South Asian (SA) patients diagnosed in our unit. Fifty-eight consecutive patients diagnosed with SpA were studied after classifying them into MEA and SA. They were further classified as per disease diagnosis. Excluding three patients with miscellaneous ethnicity, there were 29 MEA and 26 SA patients. Seventy-two percent of MEA patients were males (vs 92% of SA patients). Of the 29 patients with MEA ethnicity, 17 had AS and 9 had USpA. Of the 26 patients with SA ethnicity, 10 had AS and 14 had USpA. Fifty-nine percent of MEA patients had AS (vs 39% of SA patients). Mean age at onset in AS patients was similar in the two ethnic groups. However, in patients with USpA, mean age at onset was somewhat lower at 21.8 years in the MEA group compared with 29.4 years in the SA group. Family history in first-degree relatives was significantly more common in MEA patients. Weight loss, inflammatory spinal pain, gluteal pain, and enthesopathy were equally common in both ethnic groups. Knee, ankle, and metatarsophalangeal joint involvement was less common in MEA patients. There were no significant differences in the occurrence of syndesmophytes, bamboo spine, and sacroiliitis in the two ethnic groups. HLA-B27 positivity rates in MEA patients were 87% for AS and 67% for USpA compared to 75 and 71%, respectively, in SA patients. It is concluded that some significant new findings have arisen from this study: the majority of MEA patients presented with AS, whereas the majority of SA patients had a picture of USpA. Family history was more common in MEA patients. Peripheral arthritis was less common in MEA patients. Worldwide, this is the first study to show that there are significant differences in the clinical expression of the various SpA in MEA patients compared to SA patients.
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Affiliation(s)
- S S Uppal
- Department of Medicine, Faculty of Medicine, Kuwait University, PO Box 24923, Safat, 13110, Kuwait.
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Lee YH, Rho YH, Choi SJ, Ji JD, Song GG. Ankylosing spondylitis susceptibility loci defined by genome-search meta-analysis. J Hum Genet 2005; 50:453-459. [PMID: 16175319 DOI: 10.1007/s10038-005-0277-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2005] [Accepted: 07/04/2005] [Indexed: 10/25/2022]
Abstract
In genome scans of ankylosing spondylitis (AS), with the exception of the HLA loci, linkage has not been easy to replicate across studies. We applied the genome-search meta-analysis (GSMA) method to genome scans of AS and spondyloarthropathy (SpA) to assess evidence for linkage across studies. Three AS genome scans and one SpA scan including 430 families with 1,048 affected individuals were used. All four original genome scans mainly analyzed Caucasian families. Seven bins had both Psumrnk and Pord<0.05, suggesting these bins most likely contain AS-linked loci; bin 6.2, 6.1, 6.3, 16.3, 19.2, 17.1, and 16.4. The GSMA produced significant genome-wide evidence for linkage on chromosome 6p22.3-6p21.1 (Psumrnk=0.000003), including the HLA locus. In addition to the HLA-B27 locus, strong linkage evidence was found on chromosome 6p25.3-6p22.3 (Psumrnk=0.0013) and 6p21.1-6p15 (Psumrnk=0.043). In the GSMA of four genome scans including one SpA study, the bin 9.4 (9q21.32-9q33.1) was newly found for linkage (Psumrnk=0.043, Pord=0.013). This GSMA added the evidence of the HLA loci as the greatest susceptibility factor to AS and showed evidences of chromosome 6, 16q, 19, 17p, and 9q as non-HLA susceptibility loci.
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Affiliation(s)
- Young Ho Lee
- Division of Rheumatology, Department of Internal Medicine, Medical Center, College of Medicine, Korea University, 126-1 Ka, Anam-Dong, Seongbuk-Ku, Seoul, Korea.
| | - Young Hee Rho
- Division of Rheumatology, Department of Internal Medicine, Medical Center, College of Medicine, Korea University, 126-1 Ka, Anam-Dong, Seongbuk-Ku, Seoul, Korea
| | - Seong Jae Choi
- Division of Rheumatology, Department of Internal Medicine, Medical Center, College of Medicine, Korea University, 126-1 Ka, Anam-Dong, Seongbuk-Ku, Seoul, Korea
| | - Jong Dae Ji
- Division of Rheumatology, Department of Internal Medicine, Medical Center, College of Medicine, Korea University, 126-1 Ka, Anam-Dong, Seongbuk-Ku, Seoul, Korea
| | - Gwan Gyu Song
- Division of Rheumatology, Department of Internal Medicine, Medical Center, College of Medicine, Korea University, 126-1 Ka, Anam-Dong, Seongbuk-Ku, Seoul, Korea
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Végvári A, Szabó Z, Szántó S, Nesterovitch AB, Mikecz K, Glant TT, Adarichev VA. Two Major Interacting Chromosome Loci Control Disease Susceptibility in Murine Model of Spondyloarthropathy. THE JOURNAL OF IMMUNOLOGY 2005; 175:2475-83. [PMID: 16081819 DOI: 10.4049/jimmunol.175.4.2475] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Autoimmune spondylitis was induced in BALB/c mice and their MHC-matched (BALB/c x DBA/2)F1 and F2 hybrids by systemic immunization with cartilage/intervertebral disk proteoglycan (PG). As in human ankylosing spondylitis, the MHC was the major permissive genetic locus in murine PG-induced spondylitis (PGIS). Two major non-MHC chromosome loci with highly significant linkage were found on chromosomes 2 (Pgis2) and 18 (Pgis1) accounting for 40% of the entire F2 trait variance. The dominant spondylitis-susceptibility allele for Pgis2 locus is derived from the BALB/c strain, whereas the Pgis1 recessive allele was present in the disease-resistant DBA/2 strain. The Pgis1 locus significantly affected the disease-controlling Pgis2 locus, inducing as high incidence of spondylitis in F2 hybrids as was found in the spondylitis-susceptible parent BALB/c strain. Additional disease-controlling loci with suggestive linkage were mapped to the chromosomes 12, 15, and 19. Severity of spondylitis in F2 mice positively correlated with serum levels of amyloid A, IL-6, and Pg-specific Abs, and showed negative correlation with Ag-induced T cell proliferation, IFN-gamma, IL-4, and TNF-alpha production. A major locus controlling serum IL-6 was found on chromosome 14 near osteoclast differentiation factor Tnfsf11. Locus on chromosome 11 near the Stat3 and Stat5 genes controlled serum level of the Ig IgG2a isotype. The two major genetic loci Pgis1 and Pgis2 of murine spondylitis were homologous to chromosome regions in human genome, which control ankylosing spondylitis in human patients. Thus, this animal model of experimentally induced spondylitis might facilitate the identification of spondylitis-susceptibility genes in humans.
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Affiliation(s)
- Anikó Végvári
- Section of Molecular Medicine, Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL 60612, USA
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Bárdos T, Szabó Z, Czipri M, Vermes C, Tunyogi-Csapó M, Urban RM, Mikecz K, Glant TT. A longitudinal study on an autoimmune murine model of ankylosing spondylitis. Ann Rheum Dis 2005; 64:981-7. [PMID: 15640265 PMCID: PMC1755557 DOI: 10.1136/ard.2004.029710] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Proteoglycan aggrecan (PG)-induced arthritis (PGIA) is the only systemic autoimmune murine model which affects the axial skeleton, but no studies have been performed characterising the progression of spine involvement. OBJECTIVES To follow pathological events in experimental spondylitis, and underline its clinical, radiographic, and histological similarities to human ankylosing spondylitis (AS); and to determine whether the spondyloarthropathy is a shared phenomenon with PGIA, or an "independent" disease. METHODS Arthritis/spondylitis susceptible BALB/c and resistant DBA/2 mice, and their F1 and F2 hybrids were immunised with cartilage PG, and radiographic and histological studies were performed before onset and weekly during the progression of spondylitis. RESULTS About 70% of the PG immunised BALB/c mice develop spondyloarthropathy (proteoglycan-induced spondylitis (PGISp), and the progression of the disease is very similar to human AS. It begins with inflammation in the sacroiliac joints and with enthesitis, and then progresses upwards, affecting multiple intervertebral disks. In F2 hybrids of arthritis/spondylitis susceptible BALB/c and resistant DBA/2 mice the incidence of arthritis was 43.5%, whereas the incidence of spondylitis was >60%. Some arthritic F2 hybrid mice had no spondylitis, whereas others developed spondylitis in the absence of peripheral arthritis. CONCLUSIONS The PGISp model provides a valuable tool for studying autoimmune reactions in spondylitis, and identifying genetic loci associated with spondyloarthropathy.
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Affiliation(s)
- T Bárdos
- Department of Orthopedic Surgery, Rush University Medical Center, Cohn Research Building, Room 708, 1735 W Harrison Street, Chicago, IL 60612, USA
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Abstract
A great deal of progress has occurred in the past few years in elucidating the causes and designing new treatments for ankylosing spondylitis and other types of spondyloarthritis. In addition to the human leukocyte antigen (HLA)-B27 and other major histocompatibility complex (MHC) genes, chromosomal regions and genes elsewhere in the genome are being implicated both in disease susceptibility and severity. The various ways HLA-B27 may function in causing spondyloarthritis now are better understood to encompass not only antigen presentation but also other mechanisms, possibly all being operative in pathogenesis (misfolding of the HLA-B27 molecule, impaired intracellular killing of bacteria, and HLA-B27 itself serving as an autoantigen). Specific enteric and sexually acquired infections can trigger reactive arthritis, though no specific microbe has been identified in other forms of spondyloarthritis. Intestinal inflammation with impairment of the gut:blood barrier may be operative in driving ankylosing spondylitis and enteropathic arthritis. A number of treatments have been tried in spondyloarthritis, including older agents such as methotrexate and sulfasalazine but also newer drugs such as pamindronate. The recent introduction of tumor necrosis factor (TNF) blockers in the treatment of spondyloarthritis has offered the most hope in not only relieving symptoms and signs of both peripheral arthritis and enthesitis but also spinal disease, which often has been refractory to other agents. Their high cost and considerable side effect profile, however, have necessitated the establishment of guidelines for their use in these diseases in order to target the patient in whom they are likely to have the most benefit.
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Affiliation(s)
- John D Reveille
- Division of Rheumatology, Department of Internal Medicine, The University of Texas-Houston Health Science Center, USA.
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Martin TM, Zhang G, Luo J, Jin L, Doyle TM, Rajska BM, Coffman JE, Smith JR, Becker MD, Mackensen F, Khan MA, Levinson RD, Schumacher HR, Wade NK, Rosenbaum JT, Reveille JD. A locus on chromosome 9p predisposes to a specific disease manifestation, acute anterior uveitis, in ankylosing spondylitis, a genetically complex, multisystem, inflammatory disease. ACTA ACUST UNITED AC 2005; 52:269-74. [PMID: 15641041 DOI: 10.1002/art.20777] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
OBJECTIVE Uveitis or intraocular inflammation is a major cause of visual loss. Acute anterior uveitis (AAU) affects approximately 40% of patients with ankylosing spondylitis (AS) but also affects patients with no evidence of spondylarthritis. We sought to determine whether a unique genetic region could be implicated in a specific manifestation-AAU-of a multisystem, inflammatory, genetically complex disease, AS. METHODS Individuals from families multiplex for AAU were genotyped at 400 markers representing the ABI PRISM linkage map MD-10, and at the HLA-B, DRB1, DQA1, DQB1, and DPB1 alleles. Among the family members with AAU, 76 affected sibpairs were analyzed (6 without concomitant AS, 12 discordant for AS, and 58 concordant for AS). Two-point and multipoint nonparametric linkage analyses were performed, and 1-parameter allele-sharing model logarithm of odds (LOD) scores were determined. RESULTS As previously reported for AS, linkage at the major histocompatibility complex region (chromosome 6p21) was evident, exhibiting the highest multipoint LOD score (4.96 at marker HLA-B). Strong linkage was seen at a region on chromosome 9p21-9p24, with a LOD score of 3.72 at marker D9S157. When compared with a companion cohort of AS families, the linkage at this region was found in association with AAU but not with AS. A third region on chromosome 1q23-1q31 was observed to have suggestive linkage (LOD 2.05 at marker D1S238), which overlaps with a region associated with AS. CONCLUSION This is the first study in which a genetic region for AAU has been identified by genome-wide scan. Even though AS was highly prevalent in this cohort of families, a locus at chromosome 9p21-9p24 was identified that uniquely associates with AAU. Identifying the genetic perturbation at this region may advance our understanding of the mechanisms involved in tissue-specific pathology of complex inflammatory diseases.
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Affiliation(s)
- Tammy M Martin
- Casey Eye Institute, CE-RES, Oregon Health & Science University, 3375 SW Terwilliger Boulevard, Portland, OR 97239, USA.
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Porcher R, Said-Nahal R, D'Agostino MA, Miceli-Richard C, Dougados M, Breban M. Two major spondylarthropathy phenotypes are distinguished by pattern analysis in multiplex families. ACTA ACUST UNITED AC 2005; 53:263-71. [PMID: 15818650 DOI: 10.1002/art.21070] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
OBJECTIVE To examine whether spondylarthropathy (SpA) disease manifestations would combine in any ordered pattern among patients from SpA multiplex families. METHODS SpA patients (n = 540) belonging to 190 multiplex families were thoroughly investigated. Clinical data was collected, systematic pelvic radiographs were taken, and HLA-B27 status was determined. The patterns of SpA manifestations were examined by several methods, including multiple correspondence analysis, nonhierarchical and hierarchical clustering, and discriminant analysis. RESULTS The nonhierarchical cluster analysis allowed us to classify patients, independent of disease duration, into 2 major groups of comparable size. Group A contained a majority of the women, whereas group B predominantly consisted of men. The 2 groups were very similar regarding axial symptoms, radiographic sacroiliitis, and uveitis. Group B was characterized by a younger age at onset and a higher frequency of clinical enthesitis, peripheral arthritis, dactylitis, psoriasis, and inflammatory bowel disease than group A. Patients belonging to those groups exhibited some degree of familial aggregation, thereby supporting their intrinsic validity. CONCLUSION Pattern analysis of SpA manifestations among familial SpA allowed us to recognize 2 main clusters independent of disease duration. Furthermore, there was a trend toward aggregation by cluster among families, suggesting that they are determined by specific genetic factors. These clusters may indeed correspond to different severity patterns.
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Affiliation(s)
- Raphaël Porcher
- INSERM ERM 321, Saint-Louis Hospital, Université Denis Diderot, Paris, France
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Szabó Z, Szántó S, Végvári A, Szekanecz Z, Mikecz K, Glant TT. Genetic control of experimental spondylarthropathy. ACTA ACUST UNITED AC 2005; 52:2452-60. [PMID: 16059927 DOI: 10.1002/art.21193] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
OBJECTIVE To characterize experimentally induced spondylarthropathy (SpA) in arthritis-susceptible inbred mice and in their F(1) and F(2) hybrid generations of susceptible and resistant mouse strains. METHODS SpA was induced in susceptible BALB/c and C3H/HeJCr (C3H) strains of mice, and in their F(1) and F(2) generations derived from intercrosses with arthritis- and/or spondylitis-resistant DBA/2 and DBA/1 parent strains, by systemic immunization with cartilage proteoglycan (PG) aggrecan. The incidence and severity of PG-induced spondylitis (PGIS) were scored histologically, and these scores for spine involvement were correlated with serum antibody and cytokine levels and with in vitro T cell responses to cartilage PG. RESULTS PGIS was induced by systemic immunization with cartilage PG in adjuvant, and approximately 60-70% of susceptible mouse strains and their F(2) hybrids developed spondylitis either with or without arthritis. Adjuvants, particularly those activating the innate immune system and enforcing the Th1 dominance, had significant effects on the outcome and progression of SpA. The DBA/1 strain appeared to carry genes protecting this strain and its F(1) and F(2) hybrids from spondylitis, whereas the DBA/2 strain, although resistant to PGIS, harbored genes permitting PGIS in its hybrid generations. Arthritis- and/or spondylitis-susceptible BALB/c and C3H parent strains and their F(2) hybrids exhibited the highest incidence and severity of spondylitis. CONCLUSION PGIS, a murine model of autoimmune spondylitis, shows similarities to ankylosing spondylitis. Segregation of susceptibility to PG-induced arthritis (PGIA) from that to PGIS in different genetic crosses suggests that PGIA and PGIS are separate diseases. Therefore, this model allows for the elucidation of genetic components involved in the etiology of SpA, independent of those controlling the susceptibility to PGIA.
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Abstract
Spondyloarthritis tends to cluster in families and, to a great extent, is associated with human leukocyte antigen (HLA) B27. In fact, the population frequency of spondyloarthritis in most groups is proportional to that of HLA-B27. But the frequency of HLA-B27 in the population-at-large far exceeds that of spondyloarthritis, suggesting other genetic factors also are operative. Other major histocompatibility complex genes have been implicated, especially HLA-DR, though linkage to HLA-B27 confounds the analysis of this in many studies. Genome-wide scans have implicated regions on chromosomes 2q, 6p, 6q, 10q, 11q, 16q, 17q, and 19q in ankylosing spondylitis, on 4, 6p, and 17q in psoriasis, and on 7q and 16q in inflammatory bowel disease. The search for non-major histocompatibility complex candidate genes has been complicated by inadequate power, because of the small effect they exert on overall disease susceptibility, although recent studies are revealing promising candidates that must be confirmed by other groups.
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Affiliation(s)
- John D Reveille
- Division of Rheumatology, Department of Internal Medicine, The University of Texas Houston Health Science Center at Houston, MSB 5.270, 6431 Fannin, Houston, TX 77030, USA.
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Zhang G, Luo J, Bruckel J, Weisman MA, Schumacher HR, Khan MA, Inman RD, Mahowald M, Maksymowych WP, Martin TM, Yu DTY, Stone M, Rosenbaum JT, Newman P, Lee J, McClain JA, West OC, Jin L, Reveille JD. Genetic studies in familial ankylosing spondylitis susceptibility. ACTA ACUST UNITED AC 2004; 50:2246-54. [PMID: 15248224 DOI: 10.1002/art.20308] [Citation(s) in RCA: 87] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
OBJECTIVE To define the genetic basis of susceptibility to ankylosing spondylitis (AS), especially non-major histocompatibility complex (MHC) genes. METHODS The study group comprised 244 affected sibling pairs from 180 pedigrees of primarily European ancestry. Sibling pairs were concordant for AS by the modified New York criteria and had available sacroiliac radiographs. The subjects were genotyped for 400 markers in ABI PRISM linkage map MD-10 and for 17 additional markers on chromosomes 6p, 6q, and 11q (including HLA-B, DRB1, DQA1, DQB1, and DPB1 alleles). Two-point and multipoint nonparametric linkage (NPL) analyses were conducted using the NPL statistic and 1-parameter allele-sharing model logarithm of odds (LOD) scores, calculated using the Allele-Sharing Model (ASM) computer program. RESULTS Linkage of the MHC region was supported by both 2-point and multipoint analyses, with the strongest peak (45.90 cM) in the MHC at the HLA-DRB1 locus (NPL score 8.720, ASM LOD score 20.49; P = 6.8 x 10(-20) for 2-point analysis). A second region was found to have positive linkage at the q arm of chromosome 6 (D6S441) in 2-point analysis; this was supported by a 39.13-cM region (135.58-174.71 cM) in multipoint analysis, with the smallest P value (4.2 x 10(-3)) at 166.39 cM. A third region was found on chromosome 11q, with the strongest evidence for linkage for D11S4094 at 123 cM (NPL score 2.235, ASM LOD score 1.939) and, on transmission disequilibrium test analysis, D11S4090 at 105.74 cM (P = 6.2 x 10(-5)). Linkage in this area was supported by multipoint analysis, spanning 22.19 cM continuously from 101.68 cM to 123.87 cM, with the strongest peak at 112.33 cM (P = 0.014); this was confirmed by subsequent fine mapping studies. CONCLUSION Thus, this genome-wide scan implicates, in addition to the MHC, regions outside the MHC in AS susceptibility, especially on chromosomes 6q and 11q.
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Affiliation(s)
- Ge Zhang
- Center for Genome Information, University of Cincinnati, Cincinnati, Ohio 45267-0056, USA
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