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1
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Bamias G, Menghini P, Pizarro TT, Cominelli F. Targeting TL1A and DR3: the new frontier of anti-cytokine therapy in IBD. Gut 2025; 74:652-668. [PMID: 39266053 PMCID: PMC11885054 DOI: 10.1136/gutjnl-2024-332504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 08/20/2024] [Indexed: 09/14/2024]
Abstract
TNF-like cytokine 1A (TL1A) and its functional receptor, death-domain receptor 3 (DR3), are members of the TNF and TNFR superfamilies, respectively, with recognised roles in regulating innate and adaptive immune responses; additional existence of a decoy receptor, DcR3, indicates a tightly regulated cytokine system. The significance of TL1A:DR3 signalling in the pathogenesis of inflammatory bowel disease (IBD) is supported by several converging lines of evidence. Herein, we aim to provide a comprehensive understanding of what is currently known regarding the TL1A/DR3 system in the context of IBD. TL1A and DR3 are expressed by cellular subsets with important roles for the initiation and maintenance of intestinal inflammation, serving as potent universal costimulators of effector immune responses, indicating their participation in the pathogenesis of IBD. Recent evidence also supports a homoeostatic role for TL1A:DR3 via regulation of Tregs and innate lymphoid cells. TL1A and DR3 are also expressed by stromal cells and may contribute to inflammation-induced or inflammation-independent intestinal fibrogenesis. Finally, discovery of genetic polymorphisms with functional consequences may allow for patient stratification, including differential responses to TL1A-targeted therapeutics. In conclusion, TL1A:DR3 signalling plays a central and multifaceted role in the immunological pathways that underlie intestinal inflammation, such as that observed in IBD. Such evidence provides the foundation for developing pharmaceutical approaches targeting this ligand-receptor pair in IBD.
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Affiliation(s)
- Giorgos Bamias
- GI Unit, 3rd Academic Department of Internal Medicine, National and Kapodistrian University of Athens, Sotiria Hospital, Athens, Greece
| | - Paola Menghini
- Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
- Digestive Health Research Institute, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
| | - Theresa T Pizarro
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
| | - Fabio Cominelli
- Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
- Digestive Health Research Institute, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
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2
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Abacar K, Macleod T, Direskeneli H, McGonagle D. How underappreciated autoinflammatory (innate immunity) mechanisms dominate disparate autoimmune disorders. Front Immunol 2024; 15:1439371. [PMID: 39372419 PMCID: PMC11449752 DOI: 10.3389/fimmu.2024.1439371] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 09/04/2024] [Indexed: 10/08/2024] Open
Abstract
Historically inflammation against self was considered autoimmune which stems back to the seminal observations by Ehrlich who described serum factors, now known to be autoantibodies produced by B lineage cells that mediate "horror autotoxicus". The 20th century elucidation of B- and T-cell adaptive immune responses cemented the understanding of the key role of adaptive immune responses in mediating pathology against self. However, Mechnikov shared the Nobel Prize for the discovery of phagocytosis, the most rudimentary aspect of innate immunity. Fast forward some 100 years and an immunogenetic understanding of innate immunity led to the categorising of innate immunopathology under the umbrella term 'auto inflammation' and terminology such as "horror autoinflammaticus" to highlight the schism from the classical adaptive immune understanding of autoimmunity. These concepts lead to calls for a two-tiered classification of inflammation against self, but just as innate and adaptive immunity are functionally integrated, so is immunopathology in many settings and the concept of an autoimmune to autoinflammation continuum emerged with overlaps between both. Herein we describe several historically designated disorders of adaptive immunity where innate immunity is key, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD) where the immunopathology phenotype is strongly linked to major histocompatibility complex (MHC) class II associations and responds to drugs that target T-cells. We also consider MHC-I-opathies including psoriasis and Behcet's disease(BD) that are increasingly viewed as archetype CD8 T-cell related disorders. We also briefly review the key role of barrier dysfunction in eczema and ulcerative colitis (UC) where innate tissue permeability barrier dysfunction and microbial dysbiosis contributes to prominent adaptive immune pathological mechanisms. We also highlight the emerging roles of intermediate populations of lymphocytes including gamma delta (γδ) and mucosal-associated invariant T (MAIT) cells that represent a blend of adaptive immune plasticity and innate immune rapid responders that may also determine site specific patterns of inflammation.
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Affiliation(s)
- Kerem Abacar
- Department of Internal Medicine, Division of Rheumatology, Marmara University School of Medicine, Istanbul, Türkiye
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom
| | - Tom Macleod
- Department of Internal Medicine, Division of Rheumatology, Marmara University School of Medicine, Istanbul, Türkiye
| | - Haner Direskeneli
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom
| | - Dennis McGonagle
- Department of Internal Medicine, Division of Rheumatology, Marmara University School of Medicine, Istanbul, Türkiye
- National Institute for Health Research, Leeds Biomedical Research Centre, Leeds Teaching Hospitals, Leeds, United Kingdom
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3
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Sun R, Hedl M, Abraham C. TNFSF15 Promotes Antimicrobial Pathways in Human Macrophages and These Are Modulated by TNFSF15 Disease-Risk Variants. Cell Mol Gastroenterol Hepatol 2020; 11:249-272. [PMID: 32827707 PMCID: PMC7689184 DOI: 10.1016/j.jcmgh.2020.08.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 08/11/2020] [Accepted: 08/12/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS TNFSF15 genetic variants leading to increased TNF superfamily member 15 (TNFSF15) expression confer risk for inflammatory bowel disease (IBD), and TNFSF15 is being explored as a therapeutic target in IBD patients. Although the focus for TNFSF15-mediated inflammatory outcomes has been predominantly on its action on T cells, TNFSF15 also promotes inflammatory outcomes in human macrophages. Given the critical role for macrophages in bacterial clearance, we hypothesized that TNFSF15 promotes antimicrobial pathways in human macrophages and that macrophages from TNFSF15 IBD risk carriers with higher TNFSF15 expression have an advantage in these antimicrobial outcomes. METHODS We analyzed protein expression, signaling, bacterial uptake, and intracellular bacterial clearance in human monocyte-derived macrophages through flow cytometry, enzyme-linked immunosorbent assay, and gentamicin protection. RESULTS Autocrine/paracrine TNFSF15 interactions with death receptor 3 (DR3) were required for optimal levels of pattern-recognition-receptor (PRR)-induced bacterial clearance in human macrophages. TNFSF15 induced pyruvate dehydrogenase kinase 1-dependent bacterial uptake and promoted intracellular bacterial clearance through reactive oxygen species, nitric oxide synthase 2, and autophagy up-regulation. The TNFSF15-initiated TNF receptor-associated factor 2/receptor-interacting protein kinase 1/RIP3 pathway was required for mitogen-activated protein kinase and nuclear factor-κB activation, and, in turn, induction of each of the antimicrobial pathways; the TNFSF15-initiated Fas-associated protein with death domain/mucosa-associated lymphoid tissue lymphoma translocation protein 1/caspase-8 pathway played a less prominent role in antimicrobial functions, despite its key role in TNFSF15-induced cytokine secretion. Complementation of signaling pathways or antimicrobial pathways restored bacterial uptake and clearance in PRR-stimulated macrophages where TNFSF15:DR3 interactions were inhibited. Monocyte-derived macrophages from high TNFSF15-expressing rs6478108 TT IBD risk carriers in the TNFSF15 region showed increased levels of the identified antimicrobial pathways. CONCLUSIONS We identify that autocrine/paracrine TNFSF15 is required for optimal PRR-enhanced antimicrobial pathways in macrophages, define mechanisms regulating TNFSF15-dependent bacterial clearance, and determine how the TNFSF15 IBD risk genotype modulates these outcomes.
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Affiliation(s)
- Rui Sun
- Department of Internal Medicine, Yale University, New Haven, Connecticut
| | - Matija Hedl
- Department of Internal Medicine, Yale University, New Haven, Connecticut
| | - Clara Abraham
- Department of Internal Medicine, Yale University, New Haven, Connecticut.
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4
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Endo K, Kakuta Y, Moroi R, Yamamoto K, Shiga H, Kuroha M, Naito T, Kinouchi Y, Masamune A. TL1A ( TNFSF15) genotype affects the long-term therapeutic outcomes of anti-TNFα antibodies for Crohn's disease patients. JGH OPEN 2020; 4:1108-1113. [PMID: 33319044 PMCID: PMC7731806 DOI: 10.1002/jgh3.12398] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 07/07/2020] [Accepted: 07/16/2020] [Indexed: 02/01/2023]
Abstract
Background and Aim TL1A (TNFSF15) is a major Crohn's disease (CD) susceptibility gene, especially in the East Asian population, and is also known to be associated with some clinical phenotypes, such as stricturing and penetrating behavior. This study aims to investigate the association between TL1A genotype and the long‐term therapeutic outcomes of infliximab and adalimumab in Japanese CD patients. Methods We investigated 119 biologic‐naïve CD patients treated with infliximab or adalimumab. TL1A ‐358C/T (rs6478109) was genotyped as a tag single nucleotide polymorphism (SNP) for CD risk or nonrisk haplotype of TL1A (the ‐358C allele is a risk allele for CD development). We compared the long‐term therapeutic outcomes of anti‐tumor necrosis factor (TNF) antibodies between the TL1A ‐358C/C group and the C/T+T/T group. Results Sixty‐nine cases (58.0%) were homozygous for the risk allele (TL1A ‐358C/C group), and 50 cases (42.0%) were heterozygous for the risk allele or homozygous for the protective allele (TL1A ‐358C/T+T/T group). No significant differences were found in the cumulative retention rates and the relapse‐free survival between the TL1A genotypes. However, the surgery‐free survival was significantly lower in the TL1A ‐358C/C group than in the C/T+T/T group (log‐rank test, P < 0.05). Multivariate analysis showed that TL1A ‐358C/C was identified as an independent risk factor for surgery (hazard ratio, 4.67; 95% confidence interval, 1.39–22.1; P = 0.025). Conclusion An association was found between the TL1A genotype and the therapeutic outcomes of anti‐TNF therapy. Our data indicate that the design of customized therapy with anti‐TNF antibodies using TL1A genomic information could be effective in the future.
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Affiliation(s)
- Katsuya Endo
- Division of Gastroenterology, Department of Internal Medicine Tohoku University Graduate School of Medicine Sendai Japan.,Division of Gastroenterology Tohoku Medical and Pharmaceutical University School of Medicine Sendai Japan
| | - Yoichi Kakuta
- Division of Gastroenterology, Department of Internal Medicine Tohoku University Graduate School of Medicine Sendai Japan
| | - Rintaro Moroi
- Division of Gastroenterology, Department of Internal Medicine Tohoku University Graduate School of Medicine Sendai Japan
| | - Katsutoshi Yamamoto
- Division of Gastroenterology, Department of Internal Medicine Tohoku University Graduate School of Medicine Sendai Japan
| | - Hisashi Shiga
- Division of Gastroenterology, Department of Internal Medicine Tohoku University Graduate School of Medicine Sendai Japan
| | - Masatake Kuroha
- Division of Gastroenterology, Department of Internal Medicine Tohoku University Graduate School of Medicine Sendai Japan
| | - Takeo Naito
- Division of Gastroenterology, Department of Internal Medicine Tohoku University Graduate School of Medicine Sendai Japan
| | - Yoshitaka Kinouchi
- Division of Gastroenterology, Department of Internal Medicine Tohoku University Graduate School of Medicine Sendai Japan
| | - Atsushi Masamune
- Division of Gastroenterology, Department of Internal Medicine Tohoku University Graduate School of Medicine Sendai Japan
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5
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An Integrated Genomic and Transcriptomic Analysis Reveals Candidates of Susceptibility Genes for Crohn's Disease in Japanese Populations. Sci Rep 2020; 10:10236. [PMID: 32581322 PMCID: PMC7314801 DOI: 10.1038/s41598-020-66951-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 06/01/2020] [Indexed: 01/01/2023] Open
Abstract
Expression quantitative trait locus (eQTL) analyses have enabled us to predict the function of disease susceptibility SNPs. However, eQTL for the effector memory T cells (TEM) located in the lamina propria mononuclear cells (LPMCs), which play an important role in Crohn's disease (CD), are not yet available. Thus, we conducted RNA sequencing and eQTL analyses of TEM cells located in the LPMCs from IBD patients (n = 20). Genome-wide association study (GWAS) was performed using genotyping data of 713 Japanese CD patients and 2,063 controls. We compared the results of GWAS and eQTL of TEM, and also performed a transcriptome-wide association study using eQTL from Genotype Tissue Expression project. By eQTL analyses of TEM, correlations of possible candidates were confirmed in 22,632 pairs and 2,463 genes. Among these candidates, 19 SNPs which showed significant correlation with tenascin-XA (TNXA) expression were significantly associated with CD in GWAS. By TWAS, TNFSF15 (FDR = 1.35e-13) in whole blood, ERV3-1 (FDR = 2.18e-2) in lymphocytes, and ZNF713 (FDR = 3.04e-2) in the sigmoid colon was significantly associated with CD. By conducting integration analyses using GWAS and eQTL data, we confirmed multiple gene transcripts are involved in the development of CD.
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Taheri M, Ghandil P, Hashemi SJ, Ghafourian M, Masjedi Zadeh AR, Ghadiri AA. Association study between two polymorphisms of tumor necrosis factor ligand superfamily member 15 (TNFSF15) gene and ulcerative colitis in south-west of Iran. J Cell Biochem 2019; 120:8784-8791. [PMID: 30556168 DOI: 10.1002/jcb.28165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Accepted: 11/08/2018] [Indexed: 01/24/2023]
Abstract
BACKGROUND AND AIMS: Ulcerative colitis (UC) is the most prevalent clinical manifestation of the inflammatory bowel disease (IBD). Several candidate genes have been suggested to be involved in the genetic susceptibility or resistance in the development of UC. Among them, tumor necrosis factor ligand superfamily member 15 (TNFSF15) have been reported in association with IBD in several studies. The aim of this study was to investigate the association of TNFSF15 gene polymorphisms located in the promoter region, including rs6478108 (G/A -9706) and rs3810936 (G/A -15524) in Iranian patients with UC. METHODS: In this way, the two single nucleotide polymorphisms were studied in 115 patients with UC and 115 healthy controls with the same ethnic group from south-west of Iran. The genomic DNA of samples was genotyped using TaqMan Real-time PCR assay. This case-control study was conducted at the Department of Immunology, Jundishapur University of Medical Sciences, Ahvaz, Iran. RESULTS AND CONCLUSION: Our results did not confirm the formerly reported association of the studied polymorphisms with UC disease in comparison with healthy controls, neither with the type of the clinical forms of Colitis in the studied Iranian population. Comparing the genotype frequency of single nucleotide polymorphism (SNP) rs6478108, wild-type homozygous and heterozygote and mutant homozygote were 33%, 55.7%, and 11.3% in cases vs. 34.8%, 50.4%, and 14.8% in the controls (P = 0.6). The genotype frequency of SNP rs3810936 were 20.9%, 40.9%, and 38.2% in the cases compared to 18.3%, 44.3%, and 37.4% in controls, which was not significant ( P = 0.8). As multiple ethnic groups reside in all around the country, further studies using different ethnicities and/or larger sample size are required to clarify the role of these polymorphisms in the genetic susceptibility of UC in Iranian populations.
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Affiliation(s)
- Marzieh Taheri
- Research Center for Infectious Diseases of Digestive System, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,Department of Immunology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Pegah Ghandil
- Cellular and Molecular Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,Department of Medical Genetics, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Seyyed Jalal Hashemi
- Research Center for Infectious Diseases of Digestive System, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mehri Ghafourian
- Department of Immunology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,Infectious and Tropical Disease Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Abdol Rahim Masjedi Zadeh
- Research Center for Infectious Diseases of Digestive System, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Ata Allah Ghadiri
- Research Center for Infectious Diseases of Digestive System, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,Department of Immunology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,Cellular and Molecular Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,Air Pollution and Respiratory Diseases Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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7
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Kadiyska T, Tourtourikov I, Popmihaylova AM, Kadian H, Chavoushian A. Role of TNFSF15 in the intestinal inflammatory response. World J Gastrointest Pathophysiol 2018; 9:73-78. [PMID: 30809418 PMCID: PMC6384511 DOI: 10.4291/wjgp.v9.i4.73] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 10/11/2018] [Accepted: 10/18/2018] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal diseases, specifically Crohn’s disease, ulcerative colitis, diverticular disease, and primary biliary cirrhosis are all characterized by complicated inflammation of the digestive tract. Their pathology is multifactorial, and risk factors encompass both genetic and environmental factors. Recent advances in the genetic component of inflammatory bowel diseases (IBDs) have revealed that the tumor necrosis factor superfamily member 15 (TNFSF15) contains a number of risk alleles associated not only with IBD but also with other diseases such as diverticular disease and primary biliary cirrhosis. These risk alleles in TNFSF15 and the altered expression of its gene product can serve as the common ground between these disorders by explaining at least some of the underlying processes that lead to a dysregulated immune response and subsequent chronic inflammation. Here, we aim to outline how the TNFSF15 gene is involved in the proliferation and cell fate of different populations of T cells and subsequently in the control of both pro- and anti-inflammatory cytokines. Furthermore, we summarize what is currently known of TNFSF15 control region variants, how they are associated with each mentioned disease, and how these variants can explain the autoimmune pathology of said diseases through altered TNFSF15 expression.
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Affiliation(s)
- Tanya Kadiyska
- Department of Medical Chemistry and Biochemistry, Sofia Medical University, Sofia 1431, Bulgaria
- Genetic Medico-Diagnostic Laboratory Genica, Sofia 1612, Bulgaria
| | | | | | - Hilda Kadian
- Bulgarian Association for Inflammatory Bowel Diseases, Sofia 1527, Bulgaria
| | - Ani Chavoushian
- Department of Gastroenterology, Acibadem City Clinic Oncology Center, Sofia 1784, Bulgaria
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8
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Kalita CA, Brown CD, Freiman A, Isherwood J, Wen X, Pique-Regi R, Luca F. High-throughput characterization of genetic effects on DNA-protein binding and gene transcription. Genome Res 2018; 28:1701-1708. [PMID: 30254052 PMCID: PMC6211638 DOI: 10.1101/gr.237354.118] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Accepted: 09/20/2018] [Indexed: 12/29/2022]
Abstract
Many variants associated with complex traits are in noncoding regions and contribute to phenotypes by disrupting regulatory sequences. To characterize these variants, we developed a streamlined protocol for a high-throughput reporter assay, Biallelic Targeted STARR-seq (BiT-STARR-seq), that identifies allele-specific expression (ASE) while accounting for PCR duplicates through unique molecular identifiers. We tested 75,501 oligos (43,500 SNPs) and identified 2720 SNPs with significant ASE (FDR < 10%). To validate disruption of binding as one of the mechanisms underlying ASE, we developed a new high-throughput allele-specific binding assay for NFKB1. We identified 2684 SNPs with allele-specific binding (ASB) (FDR < 10%); 256 of these SNPs also had ASE (OR = 1.97, P-value = 0.0006). Of variants associated with complex traits, 1531 resulted in ASE, and 1662 showed ASB. For example, we characterized that the Crohn's disease risk variant for rs3810936 increases NFKB1 binding and results in altered gene expression.
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Affiliation(s)
- Cynthia A Kalita
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan 48202, USA
| | - Christopher D Brown
- Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Andrew Freiman
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan 48202, USA
| | - Jenna Isherwood
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan 48202, USA
| | - Xiaoquan Wen
- Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA
| | - Roger Pique-Regi
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan 48202, USA.,Department of Obstetrics and Gynecology, Wayne State University, Detroit, Michigan 48202, USA
| | - Francesca Luca
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan 48202, USA.,Department of Obstetrics and Gynecology, Wayne State University, Detroit, Michigan 48202, USA
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9
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Richard AC, Peters JE, Savinykh N, Lee JC, Hawley ET, Meylan F, Siegel RM, Lyons PA, Smith KGC. Reduced monocyte and macrophage TNFSF15/TL1A expression is associated with susceptibility to inflammatory bowel disease. PLoS Genet 2018; 14:e1007458. [PMID: 30199539 PMCID: PMC6130856 DOI: 10.1371/journal.pgen.1007458] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Accepted: 06/01/2018] [Indexed: 12/15/2022] Open
Abstract
Chronic inflammation in inflammatory bowel disease (IBD) results from a breakdown of intestinal immune homeostasis and compromise of the intestinal barrier. Genome-wide association studies have identified over 200 genetic loci associated with risk for IBD, but the functional mechanisms of most of these genetic variants remain unknown. Polymorphisms at the TNFSF15 locus, which encodes the TNF superfamily cytokine commonly known as TL1A, are associated with susceptibility to IBD in multiple ethnic groups. In a wide variety of murine models of inflammation including models of IBD, TNFSF15 promotes immunopathology by signaling through its receptor DR3. Such evidence has led to the hypothesis that expression of this lymphocyte costimulatory cytokine increases risk for IBD. In contrast, here we show that the IBD-risk haplotype at TNFSF15 is associated with decreased expression of the gene by peripheral blood monocytes in both healthy volunteers and IBD patients. This association persists under various stimulation conditions at both the RNA and protein levels and is maintained after macrophage differentiation. Utilizing a "recall-by-genotype" bioresource for allele-specific expression measurements in a functional fine-mapping assay, we localize the polymorphism controlling TNFSF15 expression to the regulatory region upstream of the gene. Through a T cell costimulation assay, we demonstrate that genetically regulated TNFSF15 has functional relevance. These findings indicate that genetically enhanced expression of TNFSF15 in specific cell types may confer protection against the development of IBD.
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Affiliation(s)
- Arianne C. Richard
- Department of Medicine, University of Cambridge School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
- Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, United States of America
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
| | - James E. Peters
- Department of Medicine, University of Cambridge School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
- Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
| | - Natalia Savinykh
- NIHR Cambridge BRC Cell Phenotyping Hub, Department of Medicine, University of Cambridge, Cambridge, United Kingdom
| | - James C. Lee
- Department of Medicine, University of Cambridge School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Eric T. Hawley
- Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, United States of America
| | - Françoise Meylan
- Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, United States of America
| | - Richard M. Siegel
- Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, United States of America
| | - Paul A. Lyons
- Department of Medicine, University of Cambridge School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Kenneth G. C. Smith
- Department of Medicine, University of Cambridge School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
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10
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Wang XM, Tu JC. TNFSF15 is likely a susceptibility gene for systemic lupus erythematosus. Gene 2018; 670:106-113. [PMID: 29803925 DOI: 10.1016/j.gene.2018.05.098] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Revised: 04/27/2018] [Accepted: 05/23/2018] [Indexed: 10/16/2022]
Abstract
We aim to explore the correlation of TNFSF15 genetic polymorphisms with susceptibility to systemic lupus erythematosus (SLE). This study enrolled SLE patients and healthy individuals to detect three single nucleotide polymorphisms (SNPs) of TNFSF15 (rs3810936, rs6478108 and rs4979462) through using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to analyze the possible association of these three SNPs with the risk of SLE and the mRNA level of TNFSF15 was quantified by real-time PCR. The rs3810936 T allele carrier greatly decreased risk of SLE (OR = 0.620, 95% CI = 0.454-0.849, P = 0.003), while the risk of SLE for rs4979462 T allele carrier was significantly increased (OR = 1.66, 95% CI = 1.243-2.218, P < 0.001). The mRNA level of TNFSF15 was obviously higher in SLE patients, and specifically, the patients who carried the CC genotype of TNFSF15 rs3810936 had a higher TNFSF15 mRNA, but the rs4979462 CC genotype carriers appeared to be associated with the decreased TNFSF15 mRNA (all P < 0.05). Besides, the genotypes of rs3810936 and rs4979462 of TNFSF15 were significantly associated with butterfly rash, arthritis, serositis, renal nephritis, hematological disorder, immunological disorder and positive antinuclear antibody (ANA) of SLE patients (all P < 0.05). CCT and CTT haplotypes were risk factors of SLE, but CCC and TTT were protective factors of SLE (all P < 0.05). Logistic regression analysis showed that rs3810936 and rs4979462 of TNFSF15, histories of chilblain and wet living environment were independently associated with the risk of SLE (all P < 0.05).The current results suggested that TNFSF15 (rs3810936 and rs4979462) SNPs may confer susceptibility to SLE risk, which were significantly associated with the clinical phenotypes of SLE.
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Affiliation(s)
- Xian-Mo Wang
- Department of Clinical Laboratory, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei, PR China; The First People's Hospital of Jingzhou, The First Affiliated Hospital of Yangtze University, Jingzhou 434000, Hubei, PR China
| | - Jian-Cheng Tu
- Department of Clinical Laboratory, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei, PR China; The First People's Hospital of Jingzhou, The First Affiliated Hospital of Yangtze University, Jingzhou 434000, Hubei, PR China.
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11
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Kakuta Y, Kimura T, Negoro K, Kuroha M, Shiga H, Endo K, Kinouchi Y, Shimosegawa T. Increased expression of IL12B mRNA transcribed from the risk haplotype for Crohn's disease is a risk factor for disease relapse in Japanese patients. J Gastroenterol 2017; 52:1230-1239. [PMID: 28229296 DOI: 10.1007/s00535-017-1322-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Accepted: 02/10/2017] [Indexed: 02/04/2023]
Abstract
BACKGROUND IL12B is a promising candidate for a susceptibility gene in Crohn's disease (CD). The aim of this study was to perform a candidate gene analysis of IL12B in Japanese CD patients, investigate whether the genotype is associated with disease phenotypes, and determine how the risk allele affects susceptibility to CD. METHODS Three hundred seventy-five patients with CD, 265 patients with ulcerative colitis, and 463 healthy controls were examined. Ten single-nucleotide polymorphisms (SNPs) around IL12B were genotyped. Case-control and subphenotype (including disease course) analyses were performed. The allelic expression ratio of IL12B messenger RNA (mRNA) was examined by a SNaPshot analysis in lipopolysaccharide-stimulated monocytes. RESULTS Four SNPs located upstream of the IL12B gene were significantly associated with CD. A conditional analysis revealed that these associations included two independent signals tagged by IL12B_1 and IL12B_3 (P = 9.42 × 10-6 and 1.49 × 10-4 respectively). IL12B_3 was also associated with earlier relapse in CD (P = 0.0144). The allelic expression ratios of IL12B mRNA transcribed from the risk haplotype to the protective haplotype tagged by IL12B_3 in lipopolysaccharide-stimulated monocytes from ten healthy controls heterozygous for IL12B_3 were significantly higher than that of the respective genomic DNA (P = 0.00923). No SNP was associated with ulcerative colitis. CONCLUSIONS We confirmed the association of SNPs located upstream of IL12B with CD in Japanese patients. The demonstrated allelic expression imbalance supports the idea that the IL12B risk haplotype confers susceptibility not only to CD onset but to also relapse through increased IL12B mRNA expression.
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Affiliation(s)
- Yoichi Kakuta
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, Sendai, 980-8574, Japan.
| | - Tomoya Kimura
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, Sendai, 980-8574, Japan
| | - Kenichi Negoro
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, Sendai, 980-8574, Japan
| | - Masatake Kuroha
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, Sendai, 980-8574, Japan
| | - Hisashi Shiga
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, Sendai, 980-8574, Japan
| | - Katsuya Endo
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, Sendai, 980-8574, Japan
| | - Yoshitaka Kinouchi
- Center for the Advancement of Higher Education, Tohoku University, Sendai, Japan
| | - Tooru Shimosegawa
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, Sendai, 980-8574, Japan
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Hashiramoto A, Konishi Y, Murayama K, Kawasaki H, Yoshida K, Tsumiyama K, Tanaka K, Mizuhara M, Shiotsuki T, Kitamura H, Komai K, Kimura T, Yagita H, Shiozawa K, Shiozawa S. A variant of death-receptor 3 associated with rheumatoid arthritis interferes with apoptosis-induction of T cell. J Biol Chem 2017; 293:1933-1943. [PMID: 29180447 PMCID: PMC5808757 DOI: 10.1074/jbc.m117.798884] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Revised: 11/14/2017] [Indexed: 12/12/2022] Open
Abstract
Rheumatoid arthritis (RA) is a chronic polyarthritis of unknown etiology. To unravel the molecular mechanisms in RA, we performed targeted DNA sequencing analysis of patients with RA. This analysis identified a variant of the death receptor 3 (DR3) gene, a member of the family of apoptosis-inducing Fas genes, which contains four single-nucleotide polymorphisms (SNPs) and a 14-nucleotide deletion within exon 5 and intron 5. We found that the deletion causes the binding of splicing regulatory proteins to DR3 pre-mRNA intron 5, resulting in a portion of intron 5 becoming part of the coding sequence, thereby generating a premature stop codon. We also found that this truncated DR3 protein product lacks the death domain and forms a heterotrimer complex with wildtype DR3 that dominant-negatively inhibits ligand-induced apoptosis in lymphocytes. Myelocytes from transgenic mice expressing the human DR3 variant produced soluble truncated DR3, forming a complex with TNF-like ligand 1A (TL1A), which inhibited apoptosis induction. In summary, our results reveal that a DR3 splice variant that interferes with ligand-induced T cell responses and apoptosis may contribute to RA pathogenesis.
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Affiliation(s)
- Akira Hashiramoto
- From the Department of Biophysics, Kobe University Graduate School of Health Science, Kobe 654-0142
| | - Yoshitake Konishi
- From the Department of Biophysics, Kobe University Graduate School of Health Science, Kobe 654-0142
| | - Koichi Murayama
- From the Department of Biophysics, Kobe University Graduate School of Health Science, Kobe 654-0142
| | - Hiroki Kawasaki
- From the Department of Biophysics, Kobe University Graduate School of Health Science, Kobe 654-0142
| | - Kohsuke Yoshida
- From the Department of Biophysics, Kobe University Graduate School of Health Science, Kobe 654-0142
| | - Ken Tsumiyama
- the Department of Medicine, Rheumatic Diseases Unit, Kyushu University Beppu Hospital, Beppu 874-0838
| | - Kimie Tanaka
- From the Department of Biophysics, Kobe University Graduate School of Health Science, Kobe 654-0142
| | - Masaru Mizuhara
- From the Department of Biophysics, Kobe University Graduate School of Health Science, Kobe 654-0142
| | - Toshio Shiotsuki
- From the Department of Biophysics, Kobe University Graduate School of Health Science, Kobe 654-0142
| | - Hitomi Kitamura
- From the Department of Biophysics, Kobe University Graduate School of Health Science, Kobe 654-0142
| | - Koichiro Komai
- From the Department of Biophysics, Kobe University Graduate School of Health Science, Kobe 654-0142
| | - Tomoatsu Kimura
- the Department of Orthopedic Surgery, Faculty of Medicine, University of Toyama, 3190 Gofuku, 930-0194 Toyama
| | - Hideo Yagita
- the Department of Immunology, Juntendo University School of Medicine, Tokyo 113-8431, and
| | - Kazuko Shiozawa
- the Department of Rheumatology, Hyogo Prefectural Kakogawa Medical Center, Kakogawa 675-8555, Japan
| | - Shunichi Shiozawa
- the Department of Medicine, Rheumatic Diseases Unit, Kyushu University Beppu Hospital, Beppu 874-0838,
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Kmieć Z, Cyman M, Ślebioda TJ. Cells of the innate and adaptive immunity and their interactions in inflammatory bowel disease. Adv Med Sci 2017; 62:1-16. [PMID: 28126697 DOI: 10.1016/j.advms.2016.09.001] [Citation(s) in RCA: 98] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Revised: 09/02/2016] [Accepted: 09/08/2016] [Indexed: 02/06/2023]
Abstract
Inflammatory bowel disease (IBD) is a group of chronic inflammatory conditions of the gastrointestinal tract that includes two major phenotypes, Crohn's disease and ulcerative colitis that are characterized by different clinical features and different course of the immune response. The exact aetiology of IBD still remains unknown, although it is thought that the diseases result from an excessive immune response directed against microbial or environmentally derived antigens which can be triggered by the disruption of the intestinal epithelial barrier integrity. In this review we present immune mechanisms and interactions between cells of the immune system and tissue environment that contribute to the development and progression of IBD in humans. Since dysregulation of the intestinal immune response is a hallmark of chronic inflammatory conditions, we characterize cells of the innate and adaptive immunity involved in the pathogenesis of IBD and their cross-talks. We describe various subclasses of recently discovered innate lymphoid cells, as well as dendritic cells, macrophages and T cells, including Th17, Th22 and T regulatory cells, present in the intestinal lamina propria and cytokine-mediated regulation of the immune response in IBD, highlighting the role of IL-22 and IL-17A/IL-23 axis. Insights into novel therapeutic modalities targeting certain elements of the immune pathways important for the pathogenesis of IBD have been also shortly presented.
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Richard AC, Peters JE, Lee JC, Vahedi G, Schäffer AA, Siegel RM, Lyons PA, Smith KGC. Targeted genomic analysis reveals widespread autoimmune disease association with regulatory variants in the TNF superfamily cytokine signalling network. Genome Med 2016; 8:76. [PMID: 27435189 PMCID: PMC4952362 DOI: 10.1186/s13073-016-0329-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Accepted: 06/21/2016] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Tumour necrosis factor (TNF) superfamily cytokines and their receptors regulate diverse immune system functions through a common set of signalling pathways. Genetic variants in and expression of individual TNF superfamily cytokines, receptors and signalling proteins have been associated with autoimmune and inflammatory diseases, but their interconnected biology has been largely unexplored. METHODS We took a hypothesis-driven approach using available genome-wide datasets to identify genetic variants regulating gene expression in the TNF superfamily cytokine signalling network and the association of these variants with autoimmune and autoinflammatory disease. Using paired gene expression and genetic data, we identified genetic variants associated with gene expression, expression quantitative trait loci (eQTLs), in four peripheral blood cell subsets. We then examined whether eQTLs were dependent on gene expression level or the presence of active enhancer chromatin marks. Using these eQTLs as genetic markers of the TNF superfamily signalling network, we performed targeted gene set association analysis in eight autoimmune and autoinflammatory disease genome-wide association studies. RESULTS Comparison of TNF superfamily network gene expression and regulatory variants across four leucocyte subsets revealed patterns that differed between cell types. eQTLs for genes in this network were not dependent on absolute gene expression levels and were not enriched for chromatin marks of active enhancers. By examining autoimmune disease risk variants among our eQTLs, we found that risk alleles can be associated with either increased or decreased expression of co-stimulatory TNF superfamily cytokines, receptors or downstream signalling molecules. Gene set disease association analysis revealed that eQTLs for genes in the TNF superfamily pathway were associated with six of the eight autoimmune and autoinflammatory diseases examined, demonstrating associations beyond single genome-wide significant hits. CONCLUSIONS This systematic analysis of the influence of regulatory genetic variants in the TNF superfamily network reveals widespread and diverse roles for these cytokines in susceptibility to a number of immune-mediated diseases.
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Affiliation(s)
- Arianne C. Richard
- />Department of Medicine and Cambridge Institute for Medical Research, The University of Cambridge, Box 139, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY UK
- />Autoimmunity Branch, National Institute for Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892 USA
| | - James E. Peters
- />Department of Medicine and Cambridge Institute for Medical Research, The University of Cambridge, Box 139, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY UK
| | - James C. Lee
- />Department of Medicine and Cambridge Institute for Medical Research, The University of Cambridge, Box 139, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY UK
| | - Golnaz Vahedi
- />Department of Genetics, Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104 USA
| | - Alejandro A. Schäffer
- />Computational Biology Branch, National Center for Biotechnology Information, National Institutes of Health, Bethesda, MD 20894 USA
| | - Richard M. Siegel
- />Autoimmunity Branch, National Institute for Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892 USA
| | - Paul A. Lyons
- />Department of Medicine and Cambridge Institute for Medical Research, The University of Cambridge, Box 139, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY UK
| | - Kenneth G. C. Smith
- />Department of Medicine and Cambridge Institute for Medical Research, The University of Cambridge, Box 139, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY UK
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Abstract
BACKGROUND A dysregulated mucosal immune response to the intestinal environment in a genetically susceptible host is hypothesized to be critical to the pathogenesis of Crohn's disease (CD). Therefore, we examined CD-susceptibility genes involved in the immune response through a genome-wide association study and consecutive genotyping of human leukocyte antigens (HLAs) and killer cell immunoglobulin-like receptors. METHODS An initial genome-wide association study was performed with 275 CD patients and 2369 controls from a Korean population. To validate the loci identified in the genome-wide association study, replication genotyping was performed in a different cohort of 242 CD patients and 1066 controls. Finally, high-resolution genotyping of HLA and killer cell immunoglobulin-like receptor was performed. RESULTS Four susceptibility loci, a promoter region in tumor necrosis factor (ligand) superfamily member (TNFSF15) and 3 independent regions in HLAs, showed significant associations with CD. Among them, rs114985235 in the intergenic region between HLA-B and HLA-C showed the strongest association, with an increased risk of CD (P = 8.71 × 10; odds ratio, 2.25). HLA typing in this region showed HLA-C*01 to be responsible for the association of CD among 43 HLA-B and HLA-C genotypes identified in the Korean population. However, the interaction of HLA-C with killer cell immunoglobulin-like receptor had little effect on the development of CD. CONCLUSIONS We newly identified HLA-C*01 as a prominent CD-susceptibility HLA allotype in the Korean population. In addition, these results confirm that genetic variations in immune response genes, such as HLAs and TNFSF15, are important host factors for the pathogenesis of CD.
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Differential Levels of Tl1a Affect the Expansion and Function of Regulatory T Cells in Modulating Murine Colitis. Inflamm Bowel Dis 2016; 22:548-59. [PMID: 26818423 PMCID: PMC4752386 DOI: 10.1097/mib.0000000000000653] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Expression of TL1A (tumor necrosis factor-like ligand 1A) is increased in patients with inflammatory bowel disease (IBD). Mice with elevated T-cell expression of Tl1a (L-Tg) have increased regulatory T cells, yet develop worsened colitis and intestinal fibrosis. The aim of this study was to investigate the role of Tl1a in the differentiation and function of Tregs and their effects in modulating murine colitis. METHODS Tl1a overexpressing L-Tg, Foxp3-mRFP (FIR)-LTg, and DR3KO-LTg mice were used for the study. In the L-Tg mice, Tl1a expressing cells can be identified by green fluorescent protein (GFP). RESULTS We report that Foxp3 expression in the L-Tg mice is variable based on high or low level of Tl1a expression, referred to herein as GFPhigh and GFPlow T cells. Treg-specific suppressive molecules were highly expressed on the GFPlow Foxp3 Tregs and were significantly reduced on Tregs expressing high Tl1a. In vitro suppression function was significantly enhanced in the GFPlow compared with the GFPhigh Tregs. RAG mice cotransferred with either GFPlow or wild-type Tregs were protected from colitis. Furthermore, GFPlow Tregs lost the suppression function in the absence of DR3 (Death receptor 3). CONCLUSIONS Tregs expressing low levels of Tl1a ameliorate murine colitis and promote the maintenance of Treg suppressor function in a DR3-dependent manner, partly due to a heightened regulatory program. These data reveal novel roles for differential levels of Tl1a in regulating T cell-mediated immune responses that have implications in understanding the pathogenesis of IBD.
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Tougaard P, Zervides KA, Skov S, Hansen AK, Pedersen AE. Biologics beyond TNF-αinhibitors and the effect of targeting the homologues TL1A-DR3 pathway in chronic inflammatory disorders. Immunopharmacol Immunotoxicol 2016; 38:29-38. [DOI: 10.3109/08923973.2015.1130721] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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18
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Siakavellas SI, Bamias G. Tumor Necrosis Factor-like Cytokine TL1A and Its Receptors DR3 and DcR3: Important New Factors in Mucosal Homeostasis and Inflammation. Inflamm Bowel Dis 2015; 21:2441-2452. [PMID: 26099067 DOI: 10.1097/mib.0000000000000492] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Tumor necrosis factor (TNF)-like cytokine 1A (TL1A) is a member of the TNF superfamily of proteins (TNFSF15), which signals through association with death domain receptor 3 (DR3). Decoy receptor 3 (DcR3) competes with DR3 for TL1A binding and inhibits functional signaling. These proteins are significantly upregulated in inflamed intestinal tissues, and their pathogenetic importance for inflammatory bowel disease (IBD) is suggested by accumulating evidence. TL1A/DR3 induce costimulatory signals to activated lymphocytes, including the gut-specific populations of CD4+CD161+ and CD4+CCR9+ cells, affecting all major effector pathways and inducing the mucosal upregulation of Th1, Th2, and Th17 factors. They may also participate in mucosal homeostasis and defense against pathogens through their effects on the development and function of the recently described innate lymphoid cells. T-regulatory lymphocytes highly express DR3, and they respond to TL1A stimulation also. Mechanistic studies by transgenic expression of TL1A, deletion of TL1A or DR3, and therapeutic blockade by anti-TL1A antibodies all support the critical involvement of the corresponding pathways in the pathogenesis of chronic mucosal inflammation. Wide genome association studies have identified IBD-specific polymorphisms in TNFSF15 gene, which have functional implications and serve as poor prognostic factors. Recently, TL1A blockade in mice was presented as a unique pharmacological treatment for the reversal of established intestinal fibrosis. Finally, TL1A/DR3 signaling seems to critically participate in extraintestinal inflammatory conditions that are frequently associated with IBD as part of the gut-joint-skin-eye axis. These converging lines of evidence make TL1A/DR3 a suitable model for personalized approaches to IBD therapy.
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Affiliation(s)
- Spyros I Siakavellas
- Laikon Hospital, Academic Department of Gastroenterology, Kapodistrian University of Athens, Athens, Greece
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19
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Richard AC, Ferdinand JR, Meylan F, Hayes ET, Gabay O, Siegel RM. The TNF-family cytokine TL1A: from lymphocyte costimulator to disease co-conspirator. J Leukoc Biol 2015; 98:333-45. [PMID: 26188076 PMCID: PMC4763597 DOI: 10.1189/jlb.3ri0315-095r] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2015] [Revised: 06/10/2015] [Accepted: 06/19/2015] [Indexed: 12/12/2022] Open
Abstract
Originally described in 2002 as a T cell-costimulatory cytokine, the tumor necrosis factor family member TNF-like factor 1A (TL1A), encoded by the TNFSF15 gene, has since been found to affect multiple cell lineages through its receptor, death receptor 3 (DR3, encoded by TNFRSF25) with distinct cell-type effects. Genetic deficiency or blockade of TL1A-DR3 has defined a number of disease states that depend on this cytokine-receptor pair, whereas excess TL1A leads to allergic gastrointestinal inflammation through stimulation of group 2 innate lymphoid cells. Noncoding variants in the TL1A locus are associated with susceptibility to inflammatory bowel disease and leprosy, predicting that the level of TL1A expression may influence host defense and the development of autoimmune and inflammatory diseases.
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Affiliation(s)
- Arianne C Richard
- *Immunoregulation Section, Autoimmunity Branch, NIAMS, National Institutes of Health, Bethesda, Maryland, USA; Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge, Cambridge, United Kingdom; Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - John R Ferdinand
- *Immunoregulation Section, Autoimmunity Branch, NIAMS, National Institutes of Health, Bethesda, Maryland, USA; Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge, Cambridge, United Kingdom; Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Françoise Meylan
- *Immunoregulation Section, Autoimmunity Branch, NIAMS, National Institutes of Health, Bethesda, Maryland, USA; Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge, Cambridge, United Kingdom; Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Erika T Hayes
- *Immunoregulation Section, Autoimmunity Branch, NIAMS, National Institutes of Health, Bethesda, Maryland, USA; Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge, Cambridge, United Kingdom; Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Odile Gabay
- *Immunoregulation Section, Autoimmunity Branch, NIAMS, National Institutes of Health, Bethesda, Maryland, USA; Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge, Cambridge, United Kingdom; Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Richard M Siegel
- *Immunoregulation Section, Autoimmunity Branch, NIAMS, National Institutes of Health, Bethesda, Maryland, USA; Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge, Cambridge, United Kingdom; Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
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20
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Aiba Y, Yamazaki K, Nishida N, Kawashima M, Hitomi Y, Nakamura H, Komori A, Fuyuno Y, Takahashi A, Kawaguchi T, Takazoe M, Suzuki Y, Motoya S, Matsui T, Esaki M, Matsumoto T, Kubo M, Tokunaga K, Nakamura M. Disease susceptibility genes shared by primary biliary cirrhosis and Crohn's disease in the Japanese population. J Hum Genet 2015; 60:525-31. [PMID: 26084578 DOI: 10.1038/jhg.2015.59] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Revised: 05/01/2015] [Accepted: 05/01/2015] [Indexed: 01/08/2023]
Abstract
We previously identified TNFSF15 as the most significant susceptibility gene at non-HLA loci for both primary biliary cirrhosis (PBC) and Crohn's diseases (CD) in the Japanese population. The aim of this study is to identify further disease susceptibility genes shared by PBC and CD. We selected 15 and 33 genetic variants that were significantly associated with PBC and CD, respectively, based on previously reported genome-wide association studies of the Japanese population. Next, an association study was independently performed for these genetic variants in CD (1312 CD patients and 3331 healthy controls) and PBC (1279 PBC patients and 1015 healthy controls) cohorts. Two CD susceptibility genes, ICOSLG rs2838519 and IL12B rs6556412, were also nominally associated with susceptibility to PBC (P=3.85 × 10(-2) and P=8.40 × 10(-3), respectively). Three PBC susceptibility genes, CXCR5 rs6421571, STAT4 rs7574865 and NFKB1 rs230534, were nominally associated with susceptibility to CD (P=2.82 × 10(-2), P=3.88 × 10(-2) and P=2.04 × 10(-2), respectively). The effect of ICOSLG and CXCR5 variants were concordant but the effect of STAT4, NFKB1 and IL12B variants were discordant for PBC and CD. TNFSF15 and ICOSLG-CXCR5 might constitute a shared pathogenic pathway in the development of PBC and CD in the Japanese population, whereas IL12B-STAT4-NFKB1 might constitute an opposite pathogenic pathway, reflecting the different balance between Th1 and Th17 in the two diseases.
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Affiliation(s)
- Yoshihiro Aiba
- Clinical Research Center, National Hospital Organization, Nagasaki Medical Center, Omura, Japan
| | - Keiko Yamazaki
- Laboratory for Genotyping Development, Center for Integrative Medical Science, Institute of Physical and Chemical Research (RIKEN), Yokohama, Japan
| | - Nao Nishida
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
| | - Minae Kawashima
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Japan Science and Technology Agency (JST), Tokyo, Japan
| | - Yuki Hitomi
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hitomi Nakamura
- Clinical Research Center, National Hospital Organization, Nagasaki Medical Center, Omura, Japan
| | - Atsumasa Komori
- Clinical Research Center, National Hospital Organization, Nagasaki Medical Center, Omura, Japan.,Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Yuta Fuyuno
- Laboratory for Genotyping Development, Center for Integrative Medical Science, Institute of Physical and Chemical Research (RIKEN), Yokohama, Japan.,Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Atsushi Takahashi
- Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan
| | - Takaaki Kawaguchi
- Department of Medicine, Division of Gastroenterology, Tokyo Yamate Medical Center, Tokyo, Japan
| | - Masakazu Takazoe
- Department of Medicine, Division of Gastroenterology, Tokyo Yamate Medical Center, Tokyo, Japan
| | - Yasuo Suzuki
- Department of Internal Medicine, Faculty of Medicine, Toho University, Chiba, Japan
| | - Satoshi Motoya
- Department of Gastroenterology, Sapporo Kosei Hospital, Sapporo, Japan
| | - Toshiyuki Matsui
- Laboratory for Genotyping Development, Center for Integrative Medical Science, Institute of Physical and Chemical Research (RIKEN), Yokohama, Japan.,Department of Gastroenterology, Fukuoka University Chikushi Hospital, Fukuoka, Japan
| | - Motohiro Esaki
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takayuki Matsumoto
- Division of Gastroenterology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan
| | - Michiaki Kubo
- Laboratory for Genotyping Development, Center for Integrative Medical Science, Institute of Physical and Chemical Research (RIKEN), Yokohama, Japan
| | - Katsushi Tokunaga
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Minoru Nakamura
- Clinical Research Center, National Hospital Organization, Nagasaki Medical Center, Omura, Japan.,Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.,Headquarters of PBC Research in the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ) and gp210 working in Research Program of Intractable Hepatoboliary Disease Study Group supported by the Ministry of Health, Labour, and Welfare of Japan, Clinical Research Center, National Hospital Organization Nagasaki Medical Center, Nagasaki, Japan
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21
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Czogalla B, Schmitteckert S, Houghton LA, Sayuk GS, Camilleri M, Olivo-Diaz A, Spiller R, Wouters MM, Boeckxstaens G, Bermejo JL, Niesler B. A meta-analysis of immunogenetic Case-Control Association Studies in irritable bowel syndrome. Neurogastroenterol Motil 2015; 27:717-27. [PMID: 25824902 DOI: 10.1111/nmo.12548] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2014] [Accepted: 02/18/2015] [Indexed: 12/17/2022]
Abstract
BACKGROUND To date, genetic-association studies of single nucleotide polymorphisms (SNP) in selected candidate genes with the symptom phenotype of irritable bowel syndrome (IBS) have typically involved hundreds to 2000 patients. SNPs in immune-related genes, such as cytokine and cytokine receptor encoding genes, have been reported to associate with IBS risk. METHODS We conducted two independent case-control studies on 16 SNPs in IL1R1, IL4, IL6, IL8, IL10, IL23R, TNFA, and TNFSF15, one from the UK (194 patients and 92 healthy volunteers) and one from the USA (137 patients and 96 healthy volunteers). The main aim was to examine the relationship between inherited immunological diversity and IBS risk in a meta-analysis which included 12 additional, earlier studies. The meta-analysis comprised a total of 2894 patients (839 IBS-C, 1073 IBS-D, 502 IBS-M), and 3138 healthy volunteers with self-reported Caucasian ancestry. KEY RESULTS The association of SNP rs4263839 (TNFSF15) was investigated in four studies and confirmed in the meta-analysis: IBS (OR 1.19, 95% CI 1.08-1.31), and IBS-C (OR 1.24, 95% CI 1.08-1.42). No additional SNPs residing in immunogenes associated with IBS symptom phenotypes. CONCLUSIONS & INFERENCES Our meta-analysis could not confirm a major role of most investigated SNPs, but a moderate association between rs4263839 TNFSF15 and IBS, in particular IBS-C. The analysis emphasizes the importance of definition and phenotype homogeneity, adequate study size and representativeness of the patient and control collective.
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Affiliation(s)
- B Czogalla
- Institute of Human Genetics, Department of Human Molecular Genetics, University of Heidelberg, Heidelberg, Germany
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Hitomi Y, Kawashima M, Aiba Y, Nishida N, Matsuhashi M, Okazaki H, Nakamura M, Tokunaga K. Human primary biliary cirrhosis-susceptible allele of rs4979462 enhances TNFSF15 expression by binding NF-1. Hum Genet 2015; 134:737-47. [PMID: 25899471 DOI: 10.1007/s00439-015-1556-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2015] [Accepted: 04/12/2015] [Indexed: 01/12/2023]
Abstract
A genome-wide association study (GWAS) identified tumor necrosis factor superfamily member 15 (TNFSF15) as the strongest associated gene with susceptibility to primary biliary cirrhosis (PBC) outside the HLA loci in the Japanese population. However, causal functional variants of the TNFSF15 locus and the molecular mechanism underlying disease susceptibility have not been clarified. Here, to identify the functional causal variants of the TNFSF15 locus, integrated analysis comprising in silico analysis, a case-control association study and in vitro functional analysis was performed. Initially, 32 functional candidate single-nucleotide polymorphisms (SNPs) in the expression regulatory motifs, the coding region, or the untranslated regions (UTRs) of the TNFSF15 locus were selected by in silico analysis. By the case-control association studies using PBC patients (n = 1279) and healthy controls (n = 1091) in the Japanese population, rs4979462 [P = 1.85 × 10(-14) (our previous study)], rs56211063 (P = 2.21 × 10(-14)), and rs55768522 (r(2) = 1 with rs4979462) were likely candidates for causal variants. Among these SNPs, rs4979462 was identified as the causal variant by in vitro functional analysis using luciferase assay and electrophoretic mobility shift assay (EMSA). Super-shift assay clarified that PBC-susceptible allele of rs4979462 generated a novel NF-1 binding site. Moreover, higher endogenous TNFSF15 protein and mRNA expression levels were observed in individuals with the PBC-susceptible allele of rs4979462. This study identified the causal variant for PBC susceptibility in the TNFSF15 locus and clarified its underlying molecular mechanism. TNFSF15 and NF-1 are considered to be potential targets for the treatment of PBC.
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Affiliation(s)
- Yuki Hitomi
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan,
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Chua KH, Lian LH, Khor WC, Lee WS, Hilmi I, Goh KL, Kee BP. Association between genetic polymorphisms in interferon regulatory factor 5 (IRF5) gene and Malaysian patients with Crohn's disease. J Dig Dis 2015; 16:205-216. [PMID: 25564941 DOI: 10.1111/1751-2980.12229] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE The study aimed to investigate the association between the interferon regulatory factor 5 (IRF5) gene polymorphisms and the onset of Crohn's disease (CD) in a Malaysian cohort. METHODS Genomic DNA was extracted from blood samples collected from 91 CD patients and 100 healthy individuals via a conventional phenol-chloroform extraction method. Screening of the four target single nucleotide polymorphisms (SNPs), including rs3807306, rs4728142, rs10954213 and rs11770589 was carried out in a real-time polymerase chain reaction (PCR) thermal cycler using TaqMan genotyping assay. The genetic data obtained was subsequently subjected to statistical analysis to relate the SNPs to the onset of CD in the Malaysian population. The genotyping assay and data were further validated selectively by conventional PCR amplification of the SNP sites and DNA sequencing. RESULTS The rs3807306 G allele was a risk factor for CD (OR 2.3630, P = 0.00004), whereas the homozygous T genotype was protective against the disease (OR 0.2038, P = 0.00004). The heterozygous A/G genotype of rs10954213 was significantly associated with CD (OR 4.319, P = 0.0377). On the other hand, the homozygous A and heterozygous A/G genotypes of the rs11770589 were significant in the controls (OR 0.4242, P = 0.0166) and patients (OR 2.000, P = 0.0179), respectively. In the ethnic-stratification analysis, the rs11770589 homozygous A genotype was protective in Indians (OR 0.1551, P = 0.0112). CONCLUSION IRF5 gene polymorphisms may play a role in the development of CD in the Malaysian population.
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Affiliation(s)
- Kek Heng Chua
- Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
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Ballester V, Guo X, Vendrell R, Haritunians T, Klomhaus AM, Li D, McGovern DPB, Rotter JI, Torres EA, Taylor KD. Association of NOD2 and IL23R with inflammatory bowel disease in Puerto Rico. PLoS One 2014; 9:e108204. [PMID: 25259511 PMCID: PMC4178120 DOI: 10.1371/journal.pone.0108204] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2014] [Accepted: 08/18/2014] [Indexed: 12/19/2022] Open
Abstract
The Puerto Rico population may be modeled as an admixed population with contributions from three continents: Sub-Saharan Africa, Ancient America, and Europe. Extending the study of the genetics of inflammatory bowel disease (IBD) to an admixed population such as Puerto Rico has the potential to shed light on IBD genes identified in studies of European populations, find new genes contributing to IBD susceptibility, and provide basic information on IBD for the care of US patients of Puerto Rican and Latino descent. In order to study the association between immune-related genes and Crohn’s disease (CD) and ulcerative colitis (UC) in Puerto Rico, we genotyped 1159 Puerto Rican cases, controls, and family members with the ImmunoChip. We also genotyped 832 subjects from the Human Genome Diversity Panel to provide data for estimation of global and local continental ancestry. Association of SNPs was tested by logistic regression corrected for global continental descent and family structure. We observed the association between Crohn’s disease and NOD2 (rs17313265, 0.28 in CD, 0.19 in controls, OR 1.5, p = 9×10−6) and IL23R (rs11209026, 0.026 in CD, 0.0.071 in controls, OR 0.4, p = 3.8×10−4). The haplotype structure of both regions resembled that reported for European populations and “local” continental ancestry of the IL23R gene was almost entirely of European descent. We also observed suggestive evidence for the association of the BAZ1A promoter SNP with CD (rs1200332, 0.45 in CD, 0.35 in controls, OR 1.5, p = 2×10−6). Our estimate of continental ancestry surrounding this SNP suggested an origin in Ancient America for this putative susceptibility region. Our observations underscored the great difference between global continental ancestry and local continental ancestry at the level of the individual gene, particularly for immune-related loci.
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Affiliation(s)
- Veroushka Ballester
- Department of Medicine, Division of Gastroenterology, School of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico
| | - Xiuqing Guo
- Institute of Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor/UCLA Medical Center, Torrance, California, United States of America
| | - Roberto Vendrell
- Department of Medicine, Division of Gastroenterology, School of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico
| | - Talin Haritunians
- Medical Genetics Institute & Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California, United States of America
| | - Alexandra M. Klomhaus
- Institute of Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor/UCLA Medical Center, Torrance, California, United States of America
| | - Dalin Li
- Medical Genetics Institute & Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California, United States of America
| | - Dermot P. B. McGovern
- Medical Genetics Institute & Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California, United States of America
| | - Jerome I. Rotter
- Institute of Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor/UCLA Medical Center, Torrance, California, United States of America
| | - Esther A. Torres
- Department of Medicine, Division of Gastroenterology, School of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico
| | - Kent D. Taylor
- Institute of Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor/UCLA Medical Center, Torrance, California, United States of America
- * E-mail:
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Zhang Z, Yu D, Lu J, Zhai K, Cao L, Rao J, Liu Y, Zhang X, Guo Y. Functional genetic variants of TNFSF15 and their association with gastric adenocarcinoma: a case-control study. PLoS One 2014; 9:e108321. [PMID: 25251497 PMCID: PMC4176965 DOI: 10.1371/journal.pone.0108321] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2014] [Accepted: 08/19/2014] [Indexed: 01/26/2023] Open
Abstract
The purpose of this study was to identify functional genetic variants in the promoter of tumor necrosis factor superfamily member 15 (TNFSF15) and evaluate their effects on the risk of developing gastric adenocarcinoma. Forty DNA samples from healthy volunteers were sequenced to identify single nucleotide polymorphisms (SNPs) in the TNFSF15 promoter. Two TNFSF15 SNPs (−358T>C and −638A>G) were identified by direct sequencing. Next, genotypes and haplotypes of 470 gastric adenocarcinoma patients and 470 cancer-free controls were analyzed. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression. Serologic tests for Helicobacter pylori infection were measured by enzyme-linked immuno-sorbent assay (ELISA). Subjects carrying the TNFSF15 −358CC genotype were at an elevated risk for developing gastric adenocarcinoma, compared with those with the −358TT genotype (OR 1.42, 95% CI, 1.10 to 2.03). H. pylori infection was a risk factor for developing gastric adenocarcinoma (OR 2.31, 95% CI, 1.76 to 3.04). In the H. pylori infected group, subjects with TNFSF15 −358CC genotype were at higher risks for gastric adenocarcinoma compared with those carrying −358TT genotype (OR: 2.01, 95%CI: 1.65 to 4.25), indicating that H. pylori infection further influenced gastric adenocarcinoma susceptibility. The −358 T>C polymorphism eliminates a nuclear factor Y (NF-Y) binding site and the −358C containing haplotypes showed significantly decreased luciferase expression compared with −358T containing haplotypes. Collectively these findings indicate that functional genetic variants in TNFSF15 may play a role in increasing susceptibility to gastric adenocarcinoma.
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Affiliation(s)
- Zhi Zhang
- Department of Chemotherapy and Radiotherapy, Tangshan Gongren Hospital, Tangshan, China
- Institute of Molecular Genetics, College of Life Science, Hebei United University, Tangshan, China
| | - Dianke Yu
- Department of Etiology of Carcinogenesis, Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jie Lu
- Beijing Key Laboratory for Pediatric Otolaryngology, Head and Neck Science, Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, Beijing, China
| | - Kan Zhai
- Department of Etiology of Carcinogenesis, Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lei Cao
- Institute of Molecular Genetics, College of Life Science, Hebei United University, Tangshan, China
| | - Juan Rao
- Institute of Molecular Genetics, College of Life Science, Hebei United University, Tangshan, China
| | - Yingwen Liu
- Institute of Molecular Genetics, College of Life Science, Hebei United University, Tangshan, China
| | - Xuemei Zhang
- Institute of Molecular Genetics, College of Life Science, Hebei United University, Tangshan, China
- * E-mail: (YG); (XZ)
| | - Yongli Guo
- Beijing Key Laboratory for Pediatric Otolaryngology, Head and Neck Science, Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, Beijing, China
- * E-mail: (YG); (XZ)
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Abstract
TNFRSF25 is an understudied broad-acting T cell costimulator with high homology to TNFR1, however, the overall role of this receptor in T cell immunobiology is unclear. Ligation of TNFRSF25 by its monogamous ligand, TNFSF15 (TL1A), leads to recruitment of TNFR-associated factor 2 and TNFR-associated death domain in primary T cells with downstream activation of both NFκB as well as the PI3K/Akt axis. These signaling pathways are dependent upon coordinated engagement of the T cell receptor and interleukin-2 receptor and leads to the constitutive proliferation of CD4+FoxP3+ regulatory T cells (Treg) as a result of tonic exposure to self-antigen. Concurrent activation of CD4+ or CD8+ conventional T cell clones is dependent upon the availability of cognate foreign antigen. Here, we provide a review of both the literature and our work on this receptor and propose that the overall function of TL1A signaling to TNFRSF25 in T cells is to provide simultaneous costimulation of foreign-antigen-specific effector T cells and pre-existing Treg in order to focus the clonality of effector immunity to pathogen-derived antigens and reduce the risk of bystander inflammation toward self- or endogenous microbial antigens.
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Ślebioda TJ, Kmieć Z. Tumour necrosis factor superfamily members in the pathogenesis of inflammatory bowel disease. Mediators Inflamm 2014; 2014:325129. [PMID: 25045210 PMCID: PMC4087264 DOI: 10.1155/2014/325129] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Accepted: 05/29/2014] [Indexed: 12/13/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the gastrointestinal tract of unclear aetiology of which two major forms are Crohn's disease (CD) and ulcerative colitis (UC). CD and UC are immunologically distinct, although they both result from hyperactivation of proinflammatory pathways in intestines and disruption of intestinal epithelial barrier. Members of the tumour necrosis factor superfamily (TNFSF) are molecules of broad spectrum of activity, including direct disruption of intestinal epithelial barrier integrity and costimulation of proinflammatory functions of lymphocytes. Tumour necrosis factor (TNF) has a well-established pathological role in IBD which also serves as a target in IBD treatment. In this review we discuss the role of TNF and other TNFSF members, notably, TL1A, FasL, LIGHT, TRAIL, and TWEAK, in the pathogenesis of IBD.
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Affiliation(s)
- Tomasz J. Ślebioda
- Department of Histology, Medical University of Gdańsk, Dębinki 1, 80-211 Gdańsk, Poland
| | - Zbigniew Kmieć
- Department of Histology, Medical University of Gdańsk, Dębinki 1, 80-211 Gdańsk, Poland
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Nakamura M. Analysis of disease-pathways by susceptibility genes in primary biliary cirrhosis. Inflamm Regen 2014. [DOI: 10.2492/inflammregen.34.078] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
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The role of TL1A and DR3 in autoimmune and inflammatory diseases. Mediators Inflamm 2013; 2013:258164. [PMID: 24453414 PMCID: PMC3880748 DOI: 10.1155/2013/258164] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2013] [Accepted: 12/02/2013] [Indexed: 02/07/2023] Open
Abstract
TNF-like ligand 1A (TL1A), which binds its cognate receptor DR3 and the decoy receptor DcR3, is an identified member of the TNF superfamily. TL1A exerts pleiotropic effects on cell proliferation, activation, and differentiation of immune cells, including helper T cells and regulatory T cells. TL1A and its two receptors expression is increased in both serum and inflamed tissues in autoimmune diseases such as inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and ankylosing spondylitis (AS). Polymorphisms of the TNFSF15 gene that encodes TL1A are associated with the pathogenesis of irritable bowel syndrome, leprosy, and autoimmune diseases, including IBD, AS, and primary biliary cirrhosis (PBC). In mice, blocking of TL1A-DR3 interaction by either antagonistic antibodies or deletion of the DR3 gene attenuates the severity of multiple autoimmune diseases, whereas sustained TL1A expression on T cells or dendritic cells induces IL-13-dependent small intestinal inflammation. This suggests that modulation of TL1A-DR3 interaction may be a potential therapeutic target in several autoimmune diseases, including IBD, RA, AS, and PBC.
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Hu J, Peter I. Evidence of expression variation and allelic imbalance in Crohn's disease susceptibility genes NOD2 and ATG16L1 in human dendritic cells. Gene 2013; 527:496-502. [PMID: 23850724 DOI: 10.1016/j.gene.2013.06.066] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2012] [Revised: 06/17/2013] [Accepted: 06/20/2013] [Indexed: 01/08/2023]
Abstract
Human dendritic cells (DCs) play an important role in induction and progression of Crohn's disease (CD). Accumulating evidence suggests that viral infection is required to trigger CD pathogenesis in genetically predisposed individuals. NOD2 and ATG16L1 are among the major CD susceptibility genes implicated in impaired immune response to bacterial infection. In this study, we investigated gene expression and allelic imbalance (AI) of NOD2 and ATG16L1 using common variants in human monocyte-derived DCs. Significant AI was observed in ~40% and ~70% of NOD2 and ATG16L1 heterozygotes, respectively (p<0.05). AI of NOD2 was inversely associated with its expression level (p=0.015). No correlation was detected between gene expression and AI for ATG16L1. When infected with Newcastle Disease Virus (NDV), NOD2 expression in DCs was induced about four-fold (p<0.001), whereas ATG16L1 expression was not affected (p=0.88). In addition, NDV infection tended to lower the variance in AI among DC populations for the NOD2 gene (p=0.05), but not the ATG16L1 gene (p=0.32). Findings of a simulation study, aimed to verify whether the observed variation in gene expression and AI is a result of sample-to-sample variability or experimental measurement error, suggested that NOD2 AI is likely to result from a deterministic event at a single cell level. Overall, our results present initial evidence that AI of the NOD2 and ATG16L1 genes exists in populations of human DCs. In addition, our findings suggest that viral infection may regulate NOD2 expression.
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Affiliation(s)
- Jianzhong Hu
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1 Gustave L Levy Place, New York, NY, USA.
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TL1A/TNFSF15 directly induces proinflammatory cytokines, including TNFα, from CD3+CD161+ T cells to exacerbate gut inflammation. Mucosal Immunol 2013; 6:886-99. [PMID: 23250276 DOI: 10.1038/mi.2012.124] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2012] [Accepted: 11/13/2012] [Indexed: 02/04/2023]
Abstract
Tumor necrosis factor (TNF)-like cytokine 1A (TL1A)/TNF superfamily member 15 (TNFSF15) is a proinflammatory cytokine and TNFα superfamily member that is linked preclinically and clinically to inflammatory bowel disease (IBD). By homology and function, TNFα is its closest family member. In this study, we investigated the mechanism of TL1A-induced inflammation in CD4+ T cells and compared it with the TNFα pathway. We found that TL1A induces proinflammatory cytokines, including TNFα, from isolated human CD4+CD161+ T cells, whereas these cells were resistant to TNFα treatment. Anti-TNFα failed to block TL1A-induced cytokine production, indicating that the effects of TL1A are direct. Lastly, CD161 and TL1A expression were significantly and selectively increased in gut tissue biopsies, but not in the peripheral blood, from IBD patients. Thus, TLIA not only functions upstream of TNFα, driving its expression from CD161+ T cells, but is also independent of TNFα. These findings may have therapeutic IBD implications.
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D'Amato M. Genes and functional GI disorders: from casual to causal relationship. Neurogastroenterol Motil 2013; 25:638-49. [PMID: 23826979 DOI: 10.1111/nmo.12173] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2013] [Accepted: 05/24/2013] [Indexed: 12/20/2022]
Abstract
BACKGROUND The functional gastrointestinal disorders (FGID), and in particular irritable bowel syndrome (IBS), pose a considerable burden on health care and society, and negatively impact quality of life. These are common conditions of unknown etiology, and symptom-based criteria are currently the sole nosological tools for their clinical classification. Major insight into FGID pathophysiology is therefore needed and, in recent years, increasing hope has been put on genetic research for the identification of causative pathways. This is more advanced in IBS compared with other FGID, but it has still provided often indecipherable results and no unequivocal evidence of a pathogenetic role for any particular gene. Although thousands of genetic variants have been undoubtedly linked to human disease in hundreds of genome-wide association studies (GWAS), no similar effort has yet even been attempted in FGID. If meaningful, robust, and reproducible results are to be obtained for IBS and other FGID, we must shift gear and adopt these powerful hypothesis-free approaches through concerted actions and allocation of adequate resources. Provided these are in place, the major challenge will be, inevitably, the choice of the target phenotype(s) beyond a descriptive symptom-based classification. PURPOSE In view of these much awaited developments, salient results and difficulties inherent to IBS gene discovery are briefly summarized here.
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Affiliation(s)
- Mauro D'Amato
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
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Swan C, Duroudier NP, Campbell E, Zaitoun A, Hastings M, Dukes GE, Cox J, Kelly FM, Wilde J, Lennon MG, Neal KR, Whorwell PJ, Hall IP, Spiller RC. Identifying and testing candidate genetic polymorphisms in the irritable bowel syndrome (IBS): association with TNFSF15 and TNFα. Gut 2013; 62:985-94. [PMID: 22684480 DOI: 10.1136/gutjnl-2011-301213] [Citation(s) in RCA: 130] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES The postinfectious irritable bowel syndrome (PI-IBS) suggests that impaired resolution of inflammation could cause IBS symptoms. The authors hypothesised that polymorphisms in genes whose expression were altered by gastroenteritis might be linked to IBS with diarrhoea (IBS-D) which closely resembles PI-IBS. DESIGN Part 1: 25 healthy volunteers (HVs), 21 patients 6 months after Campylobacter jejuni infection, 37 IBS-D and 19 IBS with constipation (IBS-C) underwent rectal biopsy for gene expression analysis and peripheral blood mononuclear cell cytokine production assessment. Part 2: Polymorphisms in genes whose expression was altered in Part 1 were assessed in 179 HV, 179 IBS-D, 122 IBS-C and 41 PI-IBS. RESULTS Part 1: Mucosal expression of seven genes was altered in IBS: CCL11, CCL13, Calpain 8 and TNFSF15 increased while NR1D1, GPR161 and GABRE decreased with similar patterns after infection with C jejuni. Part 2: The authors assessed 21 known single nucleotide polymorphisms (SNPs) in these seven genes and one SNP in each of the TNFα and IL-10 genes. Three out of five TNFSF15 SNPs (rs6478108, rs6478109 and rs7848647) showed reduced minor allele frequency (MAF) (0.28, 0.27 and 0.27) in subjects with IBS-D compared with HV (0.38, 0.36 and 0.37; p=0.007, 0.015 and 0.007, respectively) confirming others recent findings. The authors also replicated the previously reported association of the TNFα SNP rs1800629 with PI-IBS which showed an increase in the MAF at 0.30 versus 0.19 for HV (p=0.04). CONCLUSION IBS-D and PI-IBS patients are associated with TNFSF15 and TNFα genetic polymorphisms which also predispose to Crohn's disease suggesting possible common underlying pathogenesis.
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Affiliation(s)
- Caroline Swan
- Division of Therapeutics and Molecular Medicine, University of Nottingham, Nottingham, UK
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Gonsky R, Deem RL, Targan SR. Multiple activating and repressive cis-promoter regions regulate TNFSF15 expression in human primary mononuclear cells. Cytokine 2013; 63:36-42. [PMID: 23642711 DOI: 10.1016/j.cyto.2013.04.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2012] [Revised: 03/15/2013] [Accepted: 04/01/2013] [Indexed: 12/13/2022]
Abstract
TL1A/TNFSF15 has been associated with IBD (inflammatory bowel disease) in GWAS (genome-wide association study) and plays a role mediating mucosal inflammation in IBD. Higher TL1A expression is associated with disease severity in both patients and mouse models. Although TL1A has been studied extensively for IBD-associated SNPs, the cis/trans-regulatory regions are poorly defined. Herein we identify response elements regulating TNFSF15 in primary human myeloid cells. Peripheral mononuclear cells transfected with TNFSF15 promoter constructs displayed 30-fold enhanced promoter activity in a minimal -74 bp region. Transactivation was mediated partly by AP-1, since mutation of the AP-1 site resulting in loss of promoter activity. Monocytes transfected with c-Jun siRNA or treated with TAT-TI-JIP (JNK Inhibitor VII TAT-TI-JIP) demonstrated reduced TL1A mRNA and protein levels. Surprisingly, constructs larger than -74 bp did not increase promoter expression (expression of -1275 bp construct was 25% of -74 bp activity), suggesting the presence of both activating and repressing TL1A promoter elements. In fact, mutation of the -210 bp NFκB site enhanced promoter activity (60-fold) suggesting a repressive role for this site. DNA-protein binding to the TL1A AP-1 and NFκB elements was inhibited by excess consensus or TL1A oligonucleotides and binding and confirmed by chromatin immuno-precipitation analysis. Yet, despite the fact that the -210 bp NFκB site acts as a suppressor element, overall mRNA and protein expression were inhibited in monocytes treated with MG132 (NFκB/proteasome inhibitor) or SN50 (NFκB-p50 blocking peptide), suggesting that NFκB acts as both an activator and silencer of TL1A expression. These data suggest that modulation of TL1A expression involves a complex interplay between positive and negative signals, binding to distinct regulatory regions.
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Affiliation(s)
- Rivkah Gonsky
- F. Widjaja Inflammatory Bowel & Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Richard L Deem
- F. Widjaja Inflammatory Bowel & Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Stephan R Targan
- F. Widjaja Inflammatory Bowel & Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States.
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Abstract
BACKGROUND A large-scale meta-analysis of a series of European genome-wide association studies revealed 71 susceptibility loci for Crohn's disease (CD). However, it is not clear whether these susceptibility loci are also shared with Japanese populations. METHODS We genotyped 71 single-nucleotide polymorphisms (SNPs) comprising 1311 CD cases and 6585 controls of Japanese descent, and their associations with CD were evaluated using the Cochran-Armitage trend test. In addition, genotype-phenotype analyses were conducted on the SNPs showing associations with Japanese CD based on the Montreal classification. RESULTS Twenty-seven SNPs showed at least nominal association (P < 0.05) and 11 of them remained significant even after Bonferroni correction (P < 0.0007). Despite high statistical power, we could not find any association in 17 loci. Moreover, SNPs in 9 loci were rare or absent in the Japanese population. Genetic variations involved in the innate immune system (NOD2, ATG16L1, and IRGM) showed no association with CD susceptibility in the Japanese population. Genotype-phenotype analyses showed that rs3810936, a marker of TNFSF15, correlated with severe CD phenotypes. CONCLUSIONS Our study suggests that there is a differential genetic background of CD susceptibility between Japanese and European populations.
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Nakamura M, Nishida N, Kawashima M, Aiba Y, Tanaka A, Yasunami M, Nakamura H, Komori A, Nakamuta M, Zeniya M, Hashimoto E, Ohira H, Yamamoto K, Onji M, Kaneko S, Honda M, Yamagiwa S, Nakao K, Ichida T, Takikawa H, Seike M, Umemura T, Ueno Y, Sakisaka S, Kikuchi K, Ebinuma H, Yamashiki N, Tamura S, Sugawara Y, Mori A, Yagi S, Shirabe K, Taketomi A, Arai K, Monoe K, Ichikawa T, Taniai M, Miyake Y, Kumagi T, Abe M, Yoshizawa K, Joshita S, Shimoda S, Honda K, Takahashi H, Hirano K, Takeyama Y, Harada K, Migita K, Ito M, Yatsuhashi H, Fukushima N, Ota H, Komatsu T, Saoshiro T, Ishida J, Kouno H, Kouno H, Yagura M, Kobayashi M, Muro T, Masaki N, Hirata K, Watanabe Y, Nakamura Y, Shimada M, Hirashima N, Komeda T, Sugi K, Koga M, Ario K, Takesaki E, Maehara Y, Uemoto S, Kokudo N, Tsubouchi H, Mizokami M, Nakanuma Y, Tokunaga K, Ishibashi H. Genome-wide association study identifies TNFSF15 and POU2AF1 as susceptibility loci for primary biliary cirrhosis in the Japanese population. Am J Hum Genet 2012; 91:721-728. [PMID: 23000144 PMCID: PMC3484650 DOI: 10.1016/j.ajhg.2012.08.010] [Citation(s) in RCA: 202] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2012] [Revised: 06/03/2012] [Accepted: 08/08/2012] [Indexed: 01/12/2023] Open
Abstract
For the identification of susceptibility loci for primary biliary cirrhosis (PBC), a genome-wide association study (GWAS) was performed in 963 Japanese individuals (487 PBC cases and 476 healthy controls) and in a subsequent replication study that included 1,402 other Japanese individuals (787 cases and 615 controls). In addition to the most significant susceptibility region, human leukocyte antigen (HLA), we identified two significant susceptibility loci, TNFSF15 (rs4979462) and POU2AF1 (rs4938534) (combined odds ratio [OR] = 1.56, p = 2.84 × 10(-14) for rs4979462, and combined OR = 1.39, p = 2.38 × 10(-8) for rs4938534). Among 21 non-HLA susceptibility loci for PBC identified in GWASs of individuals of European descent, three loci (IL7R, IKZF3, and CD80) showed significant associations (combined p = 3.66 × 10(-8), 3.66 × 10(-9), and 3.04 × 10(-9), respectively) and STAT4 and NFKB1 loci showed suggestive association with PBC (combined p = 1.11 × 10(-6) and 1.42 × 10(-7), respectively) in the Japanese population. These observations indicated the existence of ethnic differences in genetic susceptibility loci to PBC and the importance of TNF signaling and B cell differentiation for the development of PBC in individuals of European descent and Japanese individuals.
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Affiliation(s)
- Minoru Nakamura
- Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, and Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, Nagasaki 856-8562, Japan.
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Abstract
The development of genome-wide association scanning (GWAS) has revolutionized the search for genetic loci associated with complex diseases. Crohn's disease (CD), together with ulcerative colitis, has been a principal beneficiary of this technology with a recent meta-analysis from the International IBD Genetics Consortium increasing the number of confirmed CD susceptibility loci to 71. When one considers that prior to the development of GWAS only three susceptibility loci had been identified, the degree of progress becomes obvious. In this article we will summarize the principal discoveries that have been made in CD genetics and explain how these have contributed to our improved understanding of disease pathogenesis.
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Affiliation(s)
- James C Lee
- Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Cambridge, UK
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A hospital-based study of clinical and genetic features of Crohn's disease. J Formos Med Assoc 2011; 110:600-6. [PMID: 21930071 DOI: 10.1016/j.jfma.2011.07.009] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2010] [Revised: 06/17/2010] [Accepted: 10/12/2010] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND/PURPOSE The aim of this study was to gain a better understanding of the current incidence of Crohn's disease (CD) in Taiwan and examine its clinical/genetic characteristics because there has been a trend toward increased diagnosis in the Asia-Pacific area. The genetic background seen in CD cases in Taiwan seems to be different from that in Western countries. METHODS By reviewing the database in the National Taiwan University Hospital, CD patients were identified by clinical, endoscopic, and imaging findings. The clinical characteristics were recorded and analyzed. DNA was extracted from the peripheral blood of patients after obtaining informed consent. Polymerase chain reaction was performed with specific primers followed by direct sequencing to determine the single-nucleotide polymorphisms ATG16L1, CCR6, IL12B, IL23R, LRRK2, TNFSF2, and TNFSF15 CD-associated genes. RESULTS Clinical data from 110 CD patients were examined from 1988 to 2008, with a mean follow-up period of 4.5 years. There was a marked increase in new CD diagnosis, especially after 2004. Among the 110 patients, 71 men and 39 women, the age at diagnosis was 30.5±17.8 years (mean±standard deviation). Stenosis occurred in 33.6% (37 of 110) and 40.9% (45 of 110) of patients who underwent surgery. The mortality rate was 2.7%, all because of sepsis. Genetic analysis of 39 patients showed that ATG16L1 and TNFSF15 were associated with susceptibility to CD in Taiwan. CONCLUSION Recently, the incidence of CD diagnosis in Taiwan has markedly increased. ATG16L1 and TNFSF15 are associated with CD in Taiwan.
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Abstract
OBJECTIVE : Our objective is to assess the effect of genetic and environmental factors on Crohn's disease location. DESIGN : We identified 628 patients with Crohn's disease within the Washington University database (April 2005 through February 2010) that had complete information on 31 Crohn's disease-associated genotypes and clinical information on disease location (L1 to L4), smoking, sex, race, and age at diagnosis. For statistical reasons, the 3 major NOD2 alleles (rs2066844, rs2066845, and rs2066847) were grouped together. Logistic regression incorporating all of the genotypes and clinical covariates, including smoking, was performed with stepwise variable selection and by best subset selection. RESULTS : Stepwise variable selection selected 3 major covariates, composite NOD2 genotype, smoking, and TNFSF15 genotype, which are also the 3 covariates selected by the best subset method. Whereas the NOD2 genotype and smoking are positively associated with ileal (L1 + L3) disease, the TNFSF15 genotype is positively associated with isolated colonic (L2) disease. LIMITATIONS : The ability to detect disease site associations in this single-center study may be limited by the population size, low allelic frequency, and/or low odds ratio of certain Crohn's disease risk alleles. CONCLUSION : These results indicate that NOD2 genotype, smoking status, and TNFSF15 genotype should be included as covariates in assessing the effect of genetic and environmental factors on Crohn's disease site location.
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Affiliation(s)
- Hongyan Chen
- Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, USA
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40
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Abstract
TL1A (also known as TNFSF15) is a tumor necrosis factor (TNF) family member expressed by monocytes, macrophages, dendritic cells (DCs), synovial fibroblasts, and endothelial cells in response to stimulation by cytokines, immune complexes, and microorganisms. Its cell surface receptor, DR3 (also known as TNFSF25, WSL-1, TRAMP, and LARD), is mainly expressed by T cells.
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Affiliation(s)
- H Hsu
- Department of Inflammation, Amgen Inc., Thousand Oaks, California, USA.
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41
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Cho JH, Brant SR. Recent insights into the genetics of inflammatory bowel disease. Gastroenterology 2011; 140:1704-12. [PMID: 21530736 PMCID: PMC4947143 DOI: 10.1053/j.gastro.2011.02.046] [Citation(s) in RCA: 296] [Impact Index Per Article: 21.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2010] [Revised: 02/04/2011] [Accepted: 02/14/2011] [Indexed: 02/06/2023]
Abstract
Inflammatory bowel diseases (IBDs) are complex, multifactorial disorders that comprise Crohn's disease (CD) and ulcerative colitis (UC). Genome-wide association studies have identified approximately 100 loci that are significantly associated with IBD. These loci implicate a diverse array of genes and pathophysiologic mechanisms, including microbe recognition, lymphocyte activation, cytokine signaling, and intestinal epithelial defense. Consistent with epidemiologic predictions, many IBD-associated loci demonstrate genome-wide significant associations to both CD and UC, notably, genes whose products function in the interleukin-23 pathway, and transcription factors, including NK2 transcription factor related, locus 3 (NKX2-3), SMAD3, STAT3, ZMIZ1, and c-REL. Although CD and UC are both associated with genomic regions that implicate products of genes involved in leukocyte trafficking, there is evidence for association patterns that are distinct between CD and UC. CD-predominant associations include NOD2 and genes that regulate autophagy. In UC, the predominant association signal is on chromosome 6p21, in the major histocompatibility complex region, near HLA class II genes. UC-predominant loci have also implicated genes mediating epithelial defense function. There is a striking overlap of loci between diseases, which could provide comparative insight into mechanisms of disease pathogenesis. Genes that encode factors that function in the interleukin-23 pathway have been associated with a number of chronic inflammatory diseases, notably psoriasis and ankylosing spondylitis. Distinct genetic associations indicate that the colitis associated with primary sclerosing cholangitis is pathophysiologically distinct from UC that is not associated with primary sclerosing cholangitis. As many as 14 susceptibility loci are shared between IBD and celiac disease, indicating significant overlap in pathophysiology. Future genetic studies will be directed toward identifying uncommon variations with potentially greater statistical effects, defining population differences, and more completely accounting for familial transmission of disease.
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Affiliation(s)
- Judy H. Cho
- Departments of Medicine and Genetics, Yale University, New Haven, Connecticut
| | - Steven R. Brant
- Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, School of Medicine, Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland
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Shih DQ, Michelsen KS, Barrett RJ, Biener-Ramanujan E, Gonsky R, Zhang X, Targan SR. Insights into TL1A and IBD pathogenesis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2011; 691:279-88. [PMID: 21153332 DOI: 10.1007/978-1-4419-6612-4_29] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- David Q Shih
- Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Suite D4063, Los Angeles, CA 90048, USA.
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Arai T, Kakuta Y, Kinouchi Y, Kimura T, Negoro K, Aihara H, Endo K, Shiga H, Kanazawa Y, Kuroha M, Moroi R, Nagasawa H, Shimodaira Y, Takahashi S, Shimosegawa T. Increased expression of NKX2.3 mRNA transcribed from the risk haplotype for ulcerative colitis in the involved colonic mucosa. Hum Immunol 2011; 72:587-91. [PMID: 21514341 DOI: 10.1016/j.humimm.2011.03.023] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2010] [Revised: 03/23/2011] [Accepted: 03/31/2011] [Indexed: 12/16/2022]
Abstract
NKX2.3 is a promising candidate for susceptibility genes to inflammatory bowel disease (IBD). The aim of this study was to perform a candidate gene analysis of NKX2.3 in Japanese IBD and to examine how the risk allele (haplotype) affects susceptibility to IBD using allelic expression ratios of NKX2.3 mRNA in the involved colonic mucosa. A total of 344 patients with Crohn's disease (CD), 253 patients with ulcerative colitis (UC), and 243 healthy controls (HCs) were genotyped for 3 tag-single nucleotide polymorphisms (SNPs; rs10883365, rs888208, and rs11596008) around NKX2.3. The allelic expression ratio of NKX2.3-mRNA was examined by TaqMan assay using rs888208 as an allelic (haplotypic) marker. Two SNPs (rs10883365 and rs888208) were significantly associated with UC (p = 7.79 × 10(-4), odds ratio [OR] = 1.54 [95% confidence interval (95% CI) 1.20-1.99], p = 7.70 × 10(-3), OR = 1.41 [95% CI 1.10-1.81], respectively) and 1 SNP (rs10883365) was associated with CD (p = 0.0366, OR = 1.29 [95% CI 1.02-1.63]). Haplotype B formed by the 3 SNPs demonstrated a significant association with UC (p = 6.11 × 10(-4), OR = 1.56 [95% CI 1.21-2.00]). Subgroup analyses indicated that rs10883365 was significantly associated mainly with colonic CD (p = 1.99 × 10(-3), OR = 1.91 [95% CI 1.27-2.88], vs HCs). The allelic expression ratios of NKX2.3 mRNA transcribed from haplotype B (risk haplotype) to haplotype A (the nonrisk haplotype) in the involved mucosa from 10 IBD patients were significantly higher than the allelic ratio of respective genomic DNA (p = 0.00195). We confirmed the association of SNP rs10883365 located in the 5' flanking region of NKX2-3 with Japanese UC and colonic CD and determined the risk haplotype (haplotype B) for UC. The demonstrated allelic expression imbalance supports the idea that the risk haplotype of NKX2.3 confers susceptibility to UC through increasing expression of NKX2.3 mRNA in the colonic mucosa.
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Affiliation(s)
- Takashi Arai
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
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Li MX, Gui HS, Kwan JSH, Sham PC. GATES: a rapid and powerful gene-based association test using extended Simes procedure. Am J Hum Genet 2011; 88:283-93. [PMID: 21397060 DOI: 10.1016/j.ajhg.2011.01.019] [Citation(s) in RCA: 309] [Impact Index Per Article: 22.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2010] [Revised: 01/26/2011] [Accepted: 01/31/2011] [Indexed: 01/01/2023] Open
Abstract
The gene has been proposed as an attractive unit of analysis for association studies, but a simple yet valid, powerful, and sufficiently fast method of evaluating the statistical significance of all genes in large, genome-wide datasets has been lacking. Here we propose the use of an extended Simes test that integrates functional information and association evidence to combine the p values of the single nucleotide polymorphisms within a gene to obtain an overall p value for the association of the entire gene. Our computer simulations demonstrate that this test is more powerful than the SNP-based test, offers effective control of the type 1 error rate regardless of gene size and linkage-disequilibrium pattern among markers, and does not need permutation or simulation to evaluate empirical significance. Its statistical power in simulated data is at least comparable, and often superior, to that of several alternative gene-based tests. When applied to real genome-wide association study (GWAS) datasets on Crohn disease, the test detected more significant genes than SNP-based tests and alternative gene-based tests. The proposed test, implemented in an open-source package, has the potential to identify additional novel disease-susceptibility genes for complex diseases from large GWAS datasets.
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Affiliation(s)
- Miao-Xin Li
- Department of Psychiatry and State Key Laboratory for Cognitive and Brain Sciences, the University of Hong Kong, Pokfulam, Hong Kong
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Rai E, Wakeland EK. Genetic predisposition to autoimmunity--what have we learned? Semin Immunol 2011; 23:67-83. [PMID: 21288738 DOI: 10.1016/j.smim.2011.01.015] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2010] [Accepted: 01/10/2011] [Indexed: 12/20/2022]
Abstract
Rapid advances in genetic technologies have led to the identification of more than 85 loci that contribute to susceptibility to autoimmune diseases. These susceptibility genes are distributed throughout the innate and adaptive immune systems, indicating that dysregulations in both immune systems participate in the development of autoimmunity. A significant subset of these susceptibility genes are shared between multiple autoimmune diseases. However, the dysregulation of specific pathways, such as the pathogen recognition receptors of the innate immune system and the TNF supergene family, are significantly involved in some autoimmune diseases. Although these findings dramatically increase the details available concerning the nature of genetic predisposition to autoimmunity, a mechanistic understanding of the processes involved has not been achieved. Future studies must focus on correlating phenotypes with specific genotypes to improve our understanding of the immune processes that are dysregulated during the development of autoimmunity.
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Affiliation(s)
- Ekta Rai
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75229, USA
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Endo K, Kinouchi Y, Kakuta Y, Ueki N, Takahashi S, Shimosegawa T. Involvement of NF-kappa B pathway in TL1A gene expression induced by lipopolysaccharide. Cytokine 2010; 49:215-20. [DOI: 10.1016/j.cyto.2009.09.006] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2009] [Revised: 08/20/2009] [Accepted: 09/11/2009] [Indexed: 11/28/2022]
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Zinovieva E, Bourgain C, Kadi A, Letourneur F, Izac B, Said-Nahal R, Lebrun N, Cagnard N, Vigier A, Jacques S, Miceli-Richard C, Garchon HJ, Heath S, Charon C, Bacq D, Boland A, Zelenika D, Chiocchia G, Breban M. Comprehensive linkage and association analyses identify haplotype, near to the TNFSF15 gene, significantly associated with spondyloarthritis. PLoS Genet 2009; 5:e1000528. [PMID: 19543369 PMCID: PMC2689651 DOI: 10.1371/journal.pgen.1000528] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2008] [Accepted: 05/19/2009] [Indexed: 12/03/2022] Open
Abstract
Spondyloarthritis (SpA) is a chronic inflammatory disorder with a strong genetic predisposition dominated by the role of HLA-B27. However, the contribution of other genes to the disease susceptibility has been clearly demonstrated. We previously reported significant evidence of linkage of SpA to chromosome 9q31–34. The current study aimed to characterize this locus, named SPA2. First, we performed a fine linkage mapping of SPA2 (24 cM) with 28 microsatellite markers in 149 multiplex families, which allowed us to reduce the area of investigation to an 18 cM (13 Mb) locus delimited by the markers D9S279 and D9S112. Second, we constructed a linkage disequilibrium (LD) map of this region with 1,536 tag single-nucleotide polymorphisms (SNPs) in 136 families (263 patients). The association was assessed using a transmission disequilibrium test. One tag SNP, rs4979459, yielded a significant P-value (4.9×10−5). Third, we performed an extension association study with rs4979459 and 30 surrounding SNPs in LD with it, in 287 families (668 patients), and in a sample of 139 cases and 163 controls. Strong association was observed in both familial and case/control datasets for several SNPs. In the replication study, carried with 8 SNPs in an independent sample of 232 cases and 149 controls, one SNP, rs6478105, yielded a nominal P-value<3×10−2. Pooled case/control study (371 cases and 312 controls) as well as combined analysis of extension and replication data showed very significant association (P<5×10−4) for 6 of the 8 latter markers (rs7849556, rs10817669, rs10759734, rs6478105, rs10982396, and rs10733612). Finally, haplotype association investigations identified a strongly associated haplotype (P<8.8×10−5) consisting of these 6 SNPs and located in the direct vicinity of the TNFSF15 gene. In conclusion, we have identified within the SPA2 locus a haplotype strongly associated with predisposition to SpA which is located near to TNFSF15, one of the major candidate genes in this region. Spondyloarthritis (SpA) is a common variety of articular inflammatory disorder characterized by axial and/or peripheral arthritis, frequently associated with extra-articular manifestations such as psoriasis, uveitis, and inflammatory bowel diseases (ulcerative colitis or Crohn's disease (CD)). SpA is a complex disorder with high heritability. The MHC class I HLA-B27 allele is a very strong risk factor for its development, but other genetic factors located outside the MHC also play a role in disease susceptibility. By a previous whole-genome linkage investigation, we have demonstrated that a region located on the chromosome 9q31–34 was involved in SpA susceptibility. The present study aimed to further characterize this locus. Using a stepwise linkage and association approach, we identified a haplotype spanning 6 single-nucleotide polymorphisms strongly associated with SpA and located in a genomic region paralogous to the MHC, near to the TNFSF15 gene. Interestingly, polymorphisms of this gene have previously been shown to be associated with CD. This original finding offers a new research track for the understanding of SpA pathophysiology, which is still poorly understood, as well as new hope for diagnostic and therapeutic innovation.
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Affiliation(s)
- Elena Zinovieva
- Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France
- INSERM U567, Paris, France
| | - Catherine Bourgain
- INSERM U535, Université Paris Sud – Paul Brousse Hospital, Villejuif, France
| | - Amir Kadi
- Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France
- INSERM U567, Paris, France
| | - Franck Letourneur
- Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France
- INSERM U567, Paris, France
| | - Brigitte Izac
- Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France
- INSERM U567, Paris, France
| | - Roula Said-Nahal
- Rheumatology Division, Ambroise Paré Hospital (AP-HP), and Versailles Saint Quentin en Yvelines University, Boulogne-Billancourt, France
| | - Nicolas Lebrun
- Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France
- INSERM U567, Paris, France
| | - Nicolas Cagnard
- Bioinformatics Platform, Faculty of Medicine Paris Descartes, Necker Hospital, Paris, France
| | - Agathe Vigier
- Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France
- INSERM U567, Paris, France
| | - Sébastien Jacques
- Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France
- INSERM U567, Paris, France
| | | | - Henri-Jean Garchon
- Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France
- INSERM U567, Paris, France
| | - Simon Heath
- National Genotyping Center (CNG), Evry, France
| | | | | | - Anne Boland
- National Genotyping Center (CNG), Evry, France
| | | | - Gilles Chiocchia
- Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France
- INSERM U567, Paris, France
- Rheumatology Division, Ambroise Paré Hospital (AP-HP), and Versailles Saint Quentin en Yvelines University, Boulogne-Billancourt, France
| | - Maxime Breban
- Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France
- INSERM U567, Paris, France
- Rheumatology Division, Ambroise Paré Hospital (AP-HP), and Versailles Saint Quentin en Yvelines University, Boulogne-Billancourt, France
- * E-mail:
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