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Kozlowska J, Humphryes-Kirilov N, Pavlovets A, Connolly M, Kuncheva Z, Horner J, Manso AS, Murray C, Fox JC, McCarthy A. Unveiling new genetic insights in rheumatoid arthritis for drug discovery through Taxonomy3 analysis. Sci Rep 2024; 14:14153. [PMID: 38898196 PMCID: PMC11186831 DOI: 10.1038/s41598-024-64970-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 06/14/2024] [Indexed: 06/21/2024] Open
Abstract
Genetic support for a drug target has been shown to increase the probability of success in drug development, with the potential to reduce attrition in the pharmaceutical industry alongside discovering novel therapeutic targets. It is therefore important to maximise the detection of genetic associations that affect disease susceptibility. Conventional statistical methods such as genome-wide association studies (GWAS) only identify some of the genetic contribution to disease, so novel analytical approaches are required to extract additional insights. C4X Discovery has developed Taxonomy3, a unique method for analysing genetic datasets based on mathematics that is novel in drug discovery. When applied to a previously published rheumatoid arthritis GWAS dataset, Taxonomy3 identified many additional novel genetic signals associated with this autoimmune disease. Follow-up studies using tool compounds support the utility of the method in identifying novel biology and tractable drug targets with genetic support for further investigation.
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Affiliation(s)
- Justyna Kozlowska
- C4X Discovery Ltd, Manchester One, 53 Portland Street, Manchester, M1 3LD, UK.
| | | | - Anastasia Pavlovets
- C4X Discovery Ltd, Manchester One, 53 Portland Street, Manchester, M1 3LD, UK
| | - Martin Connolly
- C4X Discovery Ltd, Manchester One, 53 Portland Street, Manchester, M1 3LD, UK
| | - Zhana Kuncheva
- C4X Discovery Ltd, Manchester One, 53 Portland Street, Manchester, M1 3LD, UK
| | - Jonathan Horner
- C4X Discovery Ltd, Manchester One, 53 Portland Street, Manchester, M1 3LD, UK
| | - Ana Sousa Manso
- C4X Discovery Ltd, Manchester One, 53 Portland Street, Manchester, M1 3LD, UK
| | - Clare Murray
- C4X Discovery Ltd, Manchester One, 53 Portland Street, Manchester, M1 3LD, UK
| | - J Craig Fox
- C4X Discovery Ltd, Manchester One, 53 Portland Street, Manchester, M1 3LD, UK
| | - Alun McCarthy
- C4X Discovery Ltd, Manchester One, 53 Portland Street, Manchester, M1 3LD, UK
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Johnson WT, McBride DA, Kerr MD, Nguyen A, Zoccheddu M, Bollmann M, Wei X, Jones RM, Wang W, Svensson MN, Bottini N, Shah NJ. Immunomodulatory Nanoparticles for Modulating Arthritis Flares. ACS NANO 2024; 18:1892-1906. [PMID: 38016062 PMCID: PMC11755865 DOI: 10.1021/acsnano.3c05298] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2023]
Abstract
Disease-modifying drugs have improved the treatment for autoimmune joint disorders, such as rheumatoid arthritis, but inflammatory flares are a common experience. This work reports the development and application of flare-modulating poly(lactic-co-glycolic acid)-poly(ethylene glycol)-maleimide (PLGA-PEG-MAL)-based nanoparticles conjugated with joint-relevant peptide antigens, aggrecan70-84 and type 2 bovine collagen256-270. Peptide-conjugated PLGA-PEG-MAL nanoparticles encapsulated calcitriol, which acted as an immunoregulatory agent, and were termed calcitriol-loaded nanoparticles (CLNP). CLNP had a ∼200 nm hydrodynamic diameter with a low polydispersity index. In vitro, CLNP induced phenotypic changes in bone marrow derived dendritic cells (DC), reducing the expression of costimulatory and major histocompatibility complex class II molecules, and proinflammatory cytokines. Bulk RNA sequencing of DC showed that CLNP enhanced expression of Ctla4, a gene associated with downregulation of immune responses. In vivo, CLNP accumulated in the proximal lymph nodes after intramuscular injection. Administration of CLNP was not associated with changes in peripheral blood cell numbers or cytokine levels. In the collagen-induced arthritis and SKG mouse models of autoimmune joint disorders, CLNP reduced clinical scores, prevented bone erosion, and preserved cartilage proteoglycan, as assessed by high-resolution microcomputed tomography and histomorphometry analysis. The disease protective effects were associated with increased CTLA-4 expression in joint-localized DC and CD4+ T cells but without generalized suppression of T cell-dependent immune response. The results support the potential of CLNP as modulators of disease flares in autoimmune arthropathies.
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Affiliation(s)
- Wade T. Johnson
- Department of Nano and Chemical Engineering, University of California, San Diego, La Jolla, CA 92093, USA
| | - David A. McBride
- Department of Nano and Chemical Engineering, University of California, San Diego, La Jolla, CA 92093, USA
| | - Matthew D. Kerr
- Department of Nano and Chemical Engineering, University of California, San Diego, La Jolla, CA 92093, USA
| | - Anders Nguyen
- Department of Rheumatology and Inflammation Research, University of Gothenburg 41346, Sweden
- SciLifeLab, University of Gothenburg, 41346, Sweden
| | - Martina Zoccheddu
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Miriam Bollmann
- Department of Rheumatology and Inflammation Research, University of Gothenburg 41346, Sweden
- SciLifeLab, University of Gothenburg, 41346, Sweden
| | - Xiaofu Wei
- Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA
| | - Ryan M. Jones
- Department of Nano and Chemical Engineering, University of California, San Diego, La Jolla, CA 92093, USA
| | - Wei Wang
- Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Mattias N.D. Svensson
- Department of Rheumatology and Inflammation Research, University of Gothenburg 41346, Sweden
- SciLifeLab, University of Gothenburg, 41346, Sweden
| | - Nunzio Bottini
- Kao Autoimmunity Institute and Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Nisarg J. Shah
- Department of Nano and Chemical Engineering, University of California, San Diego, La Jolla, CA 92093, USA
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Cai L, He C, Liu Y, Sun Y, He L, Baranova A. Inflammation and immunity connect hypertension with adverse COVID-19 outcomes. Front Genet 2022; 13:933148. [PMID: 36160003 PMCID: PMC9493274 DOI: 10.3389/fgene.2022.933148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Accepted: 07/08/2022] [Indexed: 11/23/2022] Open
Abstract
Objectives: To explore the connection of hypertension and severe COVID-19 outcomes. Methods: A total of 68 observational studies recording mortality and/or general severity of COVID-19 were pooled for meta-analyses of the relationship of severe COVID-19 outcomes with hypertension as well as systolic and diastolic blood pressure. Genome-wide cross-trait meta-analysis (GWCTM) was performed to explore the genes linking between hypertension and COVID-19 severity. Results: The results of meta-analysis with the random effect model indicated that pooled risk ratios of hypertension on mortality and severity of COVID-19 were 1.80 [95% confidence interval (CI) 1.54-2.1] and 1.78 (95% confidence interval 1.56-2.04), respectively, although the apparent heterogeneity of the included studies was detected. In subgroup analysis, cohorts of severe and mild patients of COVID-19 assessed in Europe had a significant pooled weighted mean difference of 6.61 mmHg (95% CI 3.66-9.55) with no heterogeneity found (p = 0.26). The genes in the shared signature of hypertension and the COVID-19 severity were mostly expressed in lungs. Analysis of molecular networks commonly affected both by hypertension and by severe COVID-19 highlighted CCR1/CCR5 and IL10RB signaling, as well as Th1 and Th2 activation pathways, and also a potential for a shared regulation with multiple sclerosis. Conclusion: Hypertension is significantly associated with the severe course of COVID-19. Genetic variants within inflammation- and immunity-related genes may affect their expression in lungs and confer liability to both elevated blood pressure and to severe COVID-19.
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Affiliation(s)
- Lei Cai
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Collaborative Innovation Center for Genetics and Development, Shanghai Mental Health Center, Shanghai Jiaotong University, Shanghai, China
| | - Chuan He
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Collaborative Innovation Center for Genetics and Development, Shanghai Mental Health Center, Shanghai Jiaotong University, Shanghai, China
| | - Yonglin Liu
- Sanya Women and Children’s Hospital managed by Shanghai Children’s Medical Center, Sanya, China
| | - Yanlan Sun
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Collaborative Innovation Center for Genetics and Development, Shanghai Mental Health Center, Shanghai Jiaotong University, Shanghai, China
| | - Lin He
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Collaborative Innovation Center for Genetics and Development, Shanghai Mental Health Center, Shanghai Jiaotong University, Shanghai, China
- Shanghai Center for Women and Children’s Health, Shanghai, China
| | - Ancha Baranova
- School of Systems Biology, George Mason University, Fairfax, VA, United States
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Placebo effect in the treatment of non-small cell lung cancer: a meta-analysis. JOURNAL OF BIO-X RESEARCH 2022. [DOI: 10.1097/jbr.0000000000000123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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Ortíz-Fernández L, Martín J, Alarcón-Riquelme ME. A Summary on the Genetics of Systemic Lupus Erythematosus, Rheumatoid Arthritis, Systemic Sclerosis, and Sjögren's Syndrome. Clin Rev Allergy Immunol 2022; 64:392-411. [PMID: 35749015 DOI: 10.1007/s12016-022-08951-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/31/2022] [Indexed: 11/03/2022]
Abstract
Systemic lupus erythematosus, systemic sclerosis, rheumatoid arthritis, and Sjögren's syndrome are four major autoimmune rheumatic diseases characterized by the presence of autoantibodies, caused by a dysregulation of the immune system that leads to a wide variety of clinical manifestations. These conditions present complex etiologies strongly influenced by multiple environmental and genetic factors. The human leukocyte antigen (HLA) region was the first locus identified to be associated and still represents the strongest susceptibility factor for each of these conditions, particularly the HLA class II genes, including DQA1, DQB1, and DRB1, but class I genes have also been associated. Over the last two decades, the genetic component of these disorders has been extensively investigated and hundreds of non-HLA risk genetic variants have been uncovered. Furthermore, it is widely accepted that autoimmune rheumatic diseases share molecular disease pathways, such as the interferon (IFN) type I pathways, which are reflected in a common genetic background. Some examples of well-known pleiotropic loci for autoimmune rheumatic diseases are the HLA region, DNASEL13, TNIP1, and IRF5, among others. The identification of the causal molecular mechanisms behind the genetic associations is still a challenge. However, recent advances have been achieved through mouse models and functional studies of the loci. Here, we provide an updated overview of the genetic architecture underlying these four autoimmune rheumatic diseases, with a special focus on the HLA region.
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Affiliation(s)
- Lourdes Ortíz-Fernández
- Institute of Parasitology and Biomedicine López-Neyra, CSIC, Parque Tecnológico de La Salud, 18016, Granada, Spain
| | - Javier Martín
- Institute of Parasitology and Biomedicine López-Neyra, CSIC, Parque Tecnológico de La Salud, 18016, Granada, Spain
| | - Marta E Alarcón-Riquelme
- GENYO. Center for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, Av de la Ilustración 114, Parque Tecnológico de La Salud, 18016, Granada, Spain. .,Institute for Environmental Medicine, Karolinska Institutet, 171 77, Solna, Sweden.
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Lashgari M, Keshavarz Shahbaz S, Javadi A, Sahmani M, Khalaji M, Maali A, Foroughi F. Survey of the association between polymorphisms of CTLA-4 exon 1 49 A/G genes with rheumatoid arthritis in Iran. J Immunoassay Immunochem 2022; 43:480-492. [PMID: 35607764 DOI: 10.1080/15321819.2022.2076109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), which suppresses T cell proliferation, is a promising candidate for the susceptibility genes to rheumatic arthritis diseases (RA). This study aims to examine the association between the polymorphisms of the CTLA-4 exon 1(+ 49) genes with RA in the Qazvin city of Iran population. The polymerase chain reaction of genomic DNA-restriction fragment length polymorphism (PCR-RFLP) was applied to genotype the CTLA-4 exon 1(+ 49) polymorphisms in 105 RA patients and 90 control subjects. Laboratory diagnostic tests were also measured for RA and control groups. Our results did not demonstrate a significant difference in allele and genotype frequencies of the CTLA-4 exon 1(+ 49) between RA patients and the control group (p < .0001). There was no significant difference in age at onset, CRP, RF value in patients with RA according to the CTLA-4 polymorphisms; just anti-CCP showed a significant difference. Our data declared that polymorphisms of CTLA-4 exon 1(+ 49) genes are not correlated with RA susceptibility and its clinical and paraclinical manifestations.
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Affiliation(s)
- Mahin Lashgari
- Metabolic Disease Research Center, Research Institute for Prevention of non-Communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Sanaz Keshavarz Shahbaz
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Amir Javadi
- Department of Community Medicine, Qazvin University of Medical Sciences, Qazvin, Iran.,Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Mehdi Sahmani
- Department of Biochemistry & Genetics, School of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Maryam Khalaji
- Department of Biochemistry & Genetics, School of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Amirhosein Maali
- Department of Medical Biotechnology, School of Allied Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Farshad Foroughi
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran.,Department of Immunology, School of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
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7
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Immunosuppression in Rheumatologic and Auto-immune Disease. Handb Exp Pharmacol 2021; 272:181-208. [PMID: 34734308 DOI: 10.1007/164_2021_551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Many rheumatologic diseases are thought to originate in dysregulation of the immune system; lupus nephritis, for example, involves humoral immunity, while autoinflammatory diseases such as familial Mediterranean fever are caused by defects in innate immunity. Of note, this dysregulation may involve both upregulation of immune system components and aspects of immunodeficiency. Treatment of rheumatologic diseases thus requires a familiarity with a variety of immunosuppressive medications and their effects on immune system function.In many rheumatologic conditions, due to an incompletely elucidated mechanism of disease, immunosuppression is relatively broad in contrast to agents used, for example, in treatment of transplant rejection. Multiple immunosuppressive drugs may also be used in succession or in combination. As such, an understanding of the mechanisms and targets of immunosuppressive drugs is essential to appreciating their utility and potential adverse effects. Because of the overlap between therapies used in rheumatologic as well as other inflammatory disorders, some of these medications are discussed in other disease processes (e.g., Immunosuppression for inflammatory bowel disease) or in greater detail in other chapters of this textbook (corticosteroids, mTOR inhibitors, antiproliferative agents).
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Louthrenoo W, Kasitanon N, Wongthanee A, Kuwata S, Takeuchi F. CTLA-4 polymorphisms in Thai patients with rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis. Int J Rheum Dis 2021; 24:1378-1385. [PMID: 34533895 DOI: 10.1111/1756-185x.14219] [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: 06/11/2021] [Revised: 09/06/2021] [Accepted: 09/08/2021] [Indexed: 11/30/2022]
Abstract
AIMS Studies on polymorphisms of the cytotoxic T lymphocytes associated antigen-4 (CTLA-4) genes in rheumatic disease patients are limited in Southeast Asia. This pilot study aimed to determine CTLA-4 polymorphisms in Thai patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc), and correlate them with serology. METHOD One-hundred RA, 70 SLE and 50 SSc patients, and 99 healthy controls (HCs) were included in this study. Polymorphisms of the CTLA-4 gene at +49A/G, -318C/T, -1661A/G and -1722T/C loci were determined by polymerase chain reaction restriction fragment length polymorphism methods. Patient serum samples were determined as follows: RA (rheumatoid factor [RF] and anticyclic citrullinated peptide [anti-CCP]), SLE (antinuclear antibodies [ANA], anti-double-stranded DNA [anti-dsDNA], anti-Smith [anti-Sm], anti-ribonucleoprotein [anti-RNP], and anti-Sjögren's syndrome antigen A [SSA]), and SSc (ANA, anti-RNP, anti-SSA, anti-topoisomerase-1 [anti-Scl70], and anti-centromere antibodies [ACA]). RESULTS Among the 4 loci studied (+49A/G, -318C/T, -1661A/G and -1722T/C) only the A allele frequency at the +49A/G was significantly higher in the RA patients than their HCs (47.25% vs 35.86%, P = .029, odds ratio [OR] 1.60; 95% CI 1.04-2.47). It also was significantly higher in the subgroup of RA patients with positive RF and anti-CCP than their HCs (47.50% vs 35.86%, P = .020, OR 1.62; 95% CI 1.06-2.47 and 48.89% vs 35.86%, P = .012, OR 1.71; 95% CI 1.11-2.64, respectively). No polymorphisms at these 4 loci were observed in SLE or SSc patients. CONCLUSION The A allele at +49A/G locus of the CTLA-4 gene was associated with RA in Thais.
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Affiliation(s)
- Worawit Louthrenoo
- Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Nuntana Kasitanon
- Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Antika Wongthanee
- Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Shoji Kuwata
- Kidney and Dialysis Center, Goi Hospital, Goi, Japan
| | - Fujio Takeuchi
- School of Pharmacological Sciences, University of Shizuoka, Shizuoka, Japan
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Zhou C, Gao S, Yuan X, Shu Z, Li S, Sun X, Xiao J, Liu H. Association between CTLA-4 gene polymorphism and risk of rheumatoid arthritis: a meta-analysis. Aging (Albany NY) 2021; 13:19397-19414. [PMID: 34339393 PMCID: PMC8386564 DOI: 10.18632/aging.203349] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 06/19/2021] [Indexed: 01/11/2023]
Abstract
Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) gene polymorphisms may be involved in the risk of Rheumatoid arthritis (RA). However, evidence for the association remains controversial. Therefore, we performed a meta-analysis to confirm the relationship between CTLA-4 gene polymorphisms and RA. The pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of association. Stratified analysis was conducted by ethnicity. In total, 66 case-control studies including 21681 cases and 23457 controls were obtained. For rs3087243 polymorphism, significant association was detected in Asians (A vs. G: OR=0.77, 95%CI=0.65-0.90, P=0.001; AA vs. GG: OR=0.67, 95%CI=0.48-0.94, P=0.02) and Caucasians (A vs. G: OR=0.89, 95%CI=0.86-0.93, P<0.00001; AA vs. GG: OR=0.81, 95%CI=0.75-0.88, P<0.00001). For rs231775 polymorphism, significant association was observed in the overall (G vs. A: OR =1.16, 95%CI=1.08-1.25, P<0.0001; GG vs. AA: OR=1.29, 95%CI=1.12-1.50, P=0.0006), and in Asians (G vs. A: OR=1.27, 95%CI=1.10-1.47, P=0.001; GG vs. AA: OR=1.58, 95%CI=1.24-2.01, P=0.0002), but not in Caucasians. However, there was no association between rs5742909 polymorphism and RA. This meta-analysis confirmed that rs3087243 and rs231775 polymorphism were associated with the risk of RA in both overall population and ethnic-specific analysis, but there was no association between rs5742909 polymorphism and RA risk.
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Affiliation(s)
- Chuankun Zhou
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Shutao Gao
- Department of Spine Surgery, The First Affiliate Hospital of Xinjiang Medical University, Urumqi 830054, Xinjiang, China
| | - Xi Yuan
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Zixing Shu
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Song Li
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Xuying Sun
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Jun Xiao
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Hui Liu
- Department of Orthopedics Trauma and Microsurgery, Zhongnan Hospital, Wuhan University, Wuhan 430000, Hubei, China
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Yu L, Shao M, Zhou T, Xie H, Wang F, Kong J, Xu S, Shuai Z, Pan F. Association of CTLA-4 (+49 A/G) polymorphism with susceptibility to autoimmune diseases: A meta-analysis with trial sequential analysis. Int Immunopharmacol 2021; 96:107617. [PMID: 33866246 DOI: 10.1016/j.intimp.2021.107617] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 03/13/2021] [Accepted: 03/24/2021] [Indexed: 10/21/2022]
Abstract
OBJECTIVES In recent years, more and more studies have been focusing on the association between Cytotoxic T lymphocyte antigen-4 (CTLA-4) (+49 A/G) gene polymorphism and autoimmune diseases. However, the results of previous studies are still controversial. The meta-analysis is aiming at determining the association in CTLA-4 (+49 A/G) gene rs231775 polymorphism and ankylosing spondylitis (AS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE). METHODS We searched PubMed, Web of Science, Chinese National Knowledge Infrastructure (CNKI) and Chinese Biomedical Database (CBM) up to November 2020, use random or fixed-effect models to perform meta-analysis to compare alleles and other genetic models, including homozygous, heterozygous, recessive and dominant models. The odds ratio (OR) with a 95% confidence interval (95% CI) was used to assess the correlation between CTLA-4 (+49 A/G) gene polymorphism and the genetic affectability of AS, RA, and SLE. Meanwhile, we used sequential trial analysis (TSA) to analyze the reliability of the results. Finally, we searched the relevant data of genome-wide association studies (GWAS) to further verify the accuracy of the experimental results. RESULTS 47 studies with 11,893 cases and 12,032 healthy controls were included. The rs231775 G allele was relevant to high risk of autoimmune disease over all people (P < 0.05). The G allele of rs231775 was significantly related to RA susceptibility (P < 0.05), but not with AS or SLE. Subgroup analysis by ethnicity indicated that rs231775 G allele was closely related to RA in Caucasian populations and Mongolian populations (P < 0.05). A strong connection within rs231775 G allele and AS affectability was uncovered in Caucasian populations (P < 0.05). The analysis of the TSA shows that the meta-analysis can draw the conclusion. CONCLUSION CTLA-4 (+49 A/G) gene rs231775 G allele increases the risk of autoimmune diseases in Caucasian populations. And it also increases the risk of RA in Caucasian and Mongolian populations. More sample size and more elaborately designed studies are needed to elucidate the relationship in CTLA-4 (+49 A/G) gene rs231775 G allele and autoimmune diseases, especially AS, SLE.
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Affiliation(s)
- Lingxiang Yu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Ming Shao
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Tingting Zhou
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Huimin Xie
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Feier Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Jiangping Kong
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Shenqian Xu
- Department of Rheumatism and Immunity, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Zongwen Shuai
- Department of Rheumatism and Immunity, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Faming Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China.
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11
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Liu W, Yang Z, Chen Y, Yang H, Wan X, Zhou X, Liu R, Zhang Y. The Association Between CTLA-4, CD80/86, and CD28 Gene Polymorphisms and Rheumatoid Arthritis: An Original Study and Meta-Analysis. Front Med (Lausanne) 2021; 8:598076. [PMID: 33604347 PMCID: PMC7884472 DOI: 10.3389/fmed.2021.598076] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 01/12/2021] [Indexed: 12/26/2022] Open
Abstract
Background: Rheumatoid arthritis (RA) is related to several pivotal susceptibility genes, including cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and costimulatory molecule (CD80/CD86) genes. Although the connection between polymorphisms of CTLA-4 and CD86 genes in different populations of RA have been studied extensively, the results are controversial. Objective: To clarify the correlation in the Chinese Han population between CTLA-4, CD80/86, and CD28 gene polymorphisms, and RA susceptibility. Methods: A case-control study (574 RA patients and 804 controls) was conducted to determine the correlation between CTLA-4 rs231775 and rs16840252 gene polymorphisms, CD86 rs17281995 gene polymorphisms, and the risk of RA for the Chinese Han population. Furthermore, an additional meta-analysis, including three single nucleotide polymorphisms (SNPs) (CTLA-4 rs231775, CTLA-4 rs3087243, and CTLA-4 rs5742909) from 32 citations, including 43 studies, 24,703 cases and 23,825 controls was performed to elucidate the relationship between known SNPs in the CTLA-4 genes and RA for more robust conclusions. Results: The results showed that CTLA-4 rs231775 gene polymorphism decreased the RA risk (GA vs. AA, OR = 0.77, P = 0.025), whereas CTLA-4 rs16840252 and CD86 rs17281995 gene polymorphisms were not related to RA susceptibility. Stratification analyses by RF, ACPA, CRP, ESR, DAS28, and functional class identified significant associations for CTLA-4 rs231775 and rs16840252 gene polymorphisms in the RF-positive and RF-negative groups. A meta-analysis of the literature on CTLA-4 gene polymorphisms and RA risk revealed that the risk of RA was decreased by CTLA-4 rs231775 gene polymorphisms. Conclusions: The CTLA-4 rs231775 gene polymorphism decreased the risk of RA, whereas CTLA-4 rs16840252 and CD86 rs17281995 gene polymorphisms were not related to RA risk. A meta-analysis indicated that CTLA-4 rs231775 and rs3087243 gene polymorphisms decreased the risk of RA. To support these analytical results, additional clinical cases should be investigated in further studies.
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Affiliation(s)
- Weixi Liu
- Department of Orthopaedics, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou, China
| | - Zhicheng Yang
- Department of Orthopaedics, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou, China
| | - Yan Chen
- Department of Orthopaedics, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou, China
| | - Haoyu Yang
- Department of Orthopaedics, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou, China
| | - Xiaoxian Wan
- Department of Orthopaedics, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou, China
| | - Xindie Zhou
- Department of Orthopaedics, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou, China
| | - Ruiping Liu
- Department of Orthopaedics, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou, China
| | - Yunkun Zhang
- Department of Orthopaedics, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou, China
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12
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Mohammadzadeh A. Co-inhibitory receptors, transcription factors and tolerance. Int Immunopharmacol 2020; 84:106572. [DOI: 10.1016/j.intimp.2020.106572] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 04/20/2020] [Accepted: 05/04/2020] [Indexed: 12/23/2022]
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13
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Schnell A, Bod L, Madi A, Kuchroo VK. The yin and yang of co-inhibitory receptors: toward anti-tumor immunity without autoimmunity. Cell Res 2020; 30:285-299. [PMID: 31974523 PMCID: PMC7118128 DOI: 10.1038/s41422-020-0277-x] [Citation(s) in RCA: 147] [Impact Index Per Article: 29.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 01/06/2020] [Indexed: 12/31/2022] Open
Abstract
Co-inhibitory receptors are important regulators of T-cell function that define the balance between tolerance and autoimmunity. The immune regulatory function of co-inhibitory receptors, including CTLA-4, PD-1, TIM-3, TIGIT, and LAG-3, was first discovered in the setting of autoimmune disease models, in which their blockade or deficiency resulted in induction or exacerbation of the disease. Later on, co-inhibitory receptors on lymphocytes have also been found to influence outcomes in tumor and chronic viral infection settings. These receptors suppress T-cell function in the tumor microenvironment (TME), thereby making the T cells dysfunctional. Based on this observation, blockade of co-inhibitory receptors (also known as checkpoint molecules) has emerged as a successful treatment option for a number of human cancers. However, severe autoimmune-like side effects limit the use of therapeutics that block individual or combinations of co-inhibitory receptors for cancer treatment. In this review we provide an overview of the role of co-inhibitory receptors in autoimmunity and anti-tumor immunity. We then discuss current approaches and future directions to leverage our knowledge of co-inhibitory receptors to target them in tumor immunity without inducing autoimmunity.
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Affiliation(s)
- Alexandra Schnell
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, 02115, USA
| | - Lloyd Bod
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, 02115, USA
| | - Asaf Madi
- Department of Pathology, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv-Yafo, Israel
| | - Vijay K Kuchroo
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, 02115, USA.
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
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Hosseini A, Gharibi T, Marofi F, Babaloo Z, Baradaran B. CTLA-4: From mechanism to autoimmune therapy. Int Immunopharmacol 2020; 80:106221. [PMID: 32007707 DOI: 10.1016/j.intimp.2020.106221] [Citation(s) in RCA: 168] [Impact Index Per Article: 33.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Revised: 01/15/2020] [Accepted: 01/15/2020] [Indexed: 12/16/2022]
Abstract
CD28 and CTLA-4 are both important stimulatory receptors for the regulation of T cell activation. Because receptors share common ligands, B7.1 and B7.2, the expression and biological function of CTLA-4 is important for the negative regulation of T cell responses. Therefore, elimination of CTLA-4 can result in the breakdown of immune tolerance and the development of several diseases such as autoimmunity. Inhibitory signals of CTLA-4 suppress T cell responses and protect against autoimmune diseases in many ways. In this review, we summarize the structure, expression and signaling pathway of CTLA-4. We also highlight how CTLA-4 defends against potentially self-reactive T cells. Finally, we discuss how the CTLA-4 regulates a number of autoimmune diseases that indicate manipulation of this inhibitory molecule is a promise as a strategy for the immunotherapy of autoimmune diseases.
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Affiliation(s)
- Arezoo Hosseini
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Tohid Gharibi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Faroogh Marofi
- Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zohreh Babaloo
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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15
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Grywalska E, Smarz-Widelska I, Mertowski S, Gosik K, Mielnik M, Podgajna M, Abramiuk M, Drop B, Roliński J, Załuska W. CTLA-4 Expression Inversely Correlates with Kidney Function and Serum Immunoglobulin Concentration in Patients with Primary Glomerulonephritides. Arch Immunol Ther Exp (Warsz) 2019; 67:335-349. [PMID: 31177287 PMCID: PMC6732130 DOI: 10.1007/s00005-019-00548-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2019] [Accepted: 05/21/2019] [Indexed: 12/01/2022]
Abstract
Major causes of chronic kidney disease are primary proliferative and nonproliferative glomerulonephritides (PGN and NPGN). However, the pathogenesis of PGN and NPGN is still not fully understood. Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is a T-cell membrane receptor that plays a key role in T-cell inhibition. Despite its role in autoimmunological diseases, little is known about the involvement of CTLA-4 in the pathogenesis of PGN and NPGN. The objective of this study was to determine the role of CTLA-4 in the pathogenesis of PGN and NPGN by evaluating the frequencies of T and B lymphocytes expressing CTLA-4 and the serum concentration of the sCTLA-4 isoform in patients with PGN and NPGN in relation to clinical parameters. The study included peripheral blood (PB) samples from 40 PGN and NPGN patients and 20 healthy age- and sex-matched volunteers (control group). The viable PB lymphocytes were labeled with fluorochrome-conjugated monoclonal anti-CTLA-4 antibodies and analyzed using flow cytometry. The serum concentration of sCTLA-4 was measured using ELISA. The frequencies and absolute counts of CD4+/CTLA-4+ T lymphocytes, CD8+/CTLA-4+ T lymphocytes and CD19+/CTLA-4+ B lymphocytes and the serum sCTLA-4 concentration were lower in PGN and NPGN patients that in the control group. Reduced sCTLA-4 expression was associated with a lower concentration of serum immunoglobulins. Our results indicate that deregulation of CTLA-4 expression may result in continuous activation of T cells and contribute to the pathogenesis of PGN and NPGN.
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Affiliation(s)
- Ewelina Grywalska
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, Chodzki 4a, 20-093, Lublin, Poland.
| | - Iwona Smarz-Widelska
- Department of Nephrology, Cardinal Stefan Wyszynski Provincial Hospital in Lublin, Lublin, Poland
| | - Sebastian Mertowski
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, Chodzki 4a, 20-093, Lublin, Poland
| | - Krzysztof Gosik
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, Chodzki 4a, 20-093, Lublin, Poland
| | - Michał Mielnik
- Department of Hematooncology and Bone Marrow Transplantation, Medical University of Lublin, Lublin, Poland
| | - Martyna Podgajna
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, Chodzki 4a, 20-093, Lublin, Poland
| | - Monika Abramiuk
- The First Department of Gynecologic Oncology and Gynecology, Medical University of Lublin, Lublin, Poland
| | - Bartłomiej Drop
- Department of Informatics and Medical Statistics, Medical University of Lublin, Lublin, Poland
| | - Jacek Roliński
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, Chodzki 4a, 20-093, Lublin, Poland
| | - Wojciech Załuska
- Department of Nephrology, Medical University of Lublin, Lublin, Poland
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The preliminary efficacy evaluation of the CTLA-4-Ig treatment against Lupus nephritis through in-silico analyses. J Theor Biol 2019; 471:74-81. [DOI: 10.1016/j.jtbi.2019.03.017] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Accepted: 03/22/2019] [Indexed: 01/04/2023]
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17
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Cytotoxic T- Lymphocyte Antigen-4 (CTLA4) Gene Expression and Urinary CTLA4 Levels in Idiopathic Nephrotic Syndrome. Indian J Pediatr 2019; 86:26-31. [PMID: 29968132 DOI: 10.1007/s12098-018-2734-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2018] [Accepted: 06/08/2018] [Indexed: 11/27/2022]
Abstract
OBJECTIVES To detect Cytotoxic T- Lymphocyte Antigen-4 (CTLA4) single nucleotide polymorphisms (SNPs) at +49A/G (rs231775) and -318C/T (rs5742909) positions in children with idiopathic nephrotic syndrome (INS) and also assay urinary soluble CTLA4 (sCTLA4) levels in children with minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS) and steroid sensitive nephrotic syndrome (SSNS) in remission. METHODS The study included 59 patients of INS (MCD-23, FSGS-15 and SSNS in remission-21) and 35 healthy controls. The CTLA4 SNPs profiling was done in peripheral blood mononuclear cells and urinary sCTLA4 level was assayed by ELISA kit. RESULTS Although frequency of homozygous +49 GG (rs4553808) genotype (26.3% vs. 11.4%; p = 0.231) and G allele (52.6% vs. 40%; p = 0.216) were found to be higher in INS as compared to controls, the differences were statistically non-significant. Genotypes GG, AG, AA and alleles A and G frequencies were comparable among MCD, FSGS and controls. SNP at -318 C/T (rs5742909) did not show homozygous TT genotype both in INS as well as controls. Median urinary sCTLA4/creatinine level was significantly higher in MCD as compared to FSGS (p = 0.027), SSNS in remission (p = 0.001) and controls (p = 0.003). CONCLUSIONS The positive associations of +49 GG genotype and G allele in patients with nephrotic syndrome were not observed. The frequencies did not differ significantly among MCD, FSGS and controls. Urinary sCTLA4 level was significantly increased in MCD; suggesting its possible role in the pathogenesis of disease.
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18
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Yao L, Liu B, Jiang L, Zhou L, Liu X. Association of cytotoxic T-lymphocyte antigen 4 gene with immune thrombocytopenia in Chinese Han children. ACTA ACUST UNITED AC 2018; 24:123-128. [PMID: 30319055 DOI: 10.1080/10245332.2018.1530179] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
OBJECTIVES To investigate the association of cytotoxic T lymphocyte-associated antigen 4 (CTLA4) with immune thrombocytopenia (ITP). METHODS A case-control association analysis of 277 Chinese Han children was performed. The tagging variants rs11571315 and rs3087243 in the CTLA4 gene were detected using polymerase chain reaction-restriction fragment length polymorphism method. The expression quantitative trait loci (eQTL) analysis and quantitative real-time polymerase chain reaction were performed to determine the relationship of CTLA4 with ITP. RESULTS Neither SNP was significantly different between case and control groups in either the genotypic or allelic distribution. The eQTL analysis results indicated that in the spleen, the rs3087243 was significant with the expression of CTLA4. The rs11571315 has similar results. Interestingly, the transcript level of CTLA4 was found to significantly decrease in patients with ITP. DISCUSSION The autoimmune and gene etiology is implicated in the pathogen of ITP. The CTLA4 is important for negative regulation of T-cell activation, and CTLA-4 gene has been identified as a risk factor for some autoimmune diseases. However, association studies of ITP and CTLA4 gene have obtained conflicting results. This is the first study to systematically investigate the association of CTLA4 with ITP in Chinese Han children. CONCLUSIONS The CTLA4 gene is suggested to correlate with ITP through its abnormal expression level instead of gene site mutation.
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Affiliation(s)
- Liqiong Yao
- a The Clinical Laboratory , The First Clinical Medical College of Lanzhou University , Lanzhou , People's Republic of China
| | - Bei Liu
- b The Hematology Department , The First Clinical Medical College of Lanzhou University , Lanzhou , People's Republic of China
| | - Li Jiang
- c The Pediatric Department , The First Clinical Medical College of Lanzhou University , Lanzhou , People's Republic of China
| | - Lanxia Zhou
- d The Central Laboratory , The First Clinical Medical College of Lanzhou University , Lanzhou , People's Republic of China
| | - Xiaoju Liu
- e The Gerontology Department , The First Clinical Medical College of Lanzhou university , Lanzhou , People's Republic of China
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19
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Onofrio LI, Zacca ER, Ferrero P, Acosta C, Mussano E, Onetti L, Cadile I, Gazzoni MV, Jurado R, Boari JT, Ramello MC, Montes CL, Gruppi A, Acosta Rodríguez EV. Inhibitory Receptor Expression on T Cells as a Marker of Disease Activity and Target to Regulate Effector Cellular Responses in Rheumatoid Arthritis. Arthritis Rheumatol 2018; 70:1429-1439. [PMID: 29648684 PMCID: PMC6115289 DOI: 10.1002/art.40521] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Accepted: 04/02/2018] [Indexed: 01/03/2023]
Abstract
OBJECTIVE Inhibitory receptors are essential for the regulation of effector immune responses and may play critical roles in autoimmune diseases. We evaluated whether inhibitory receptor expression on T cells from patients with rheumatoid arthritis (RA) were correlated with immune activation, disease activity, and response to treatment, as well as whether inhibitory receptor-mediated pathways were functional. METHODS Using flow cytometry, we performed extensive phenotypic and functional evaluation of CD4+ and CD8+ T cells from the blood and synovial fluid (SF) of RA patients ex vivo and after culture. The relationship of each parameter with the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) and response to treatment was examined. RESULTS In RA patients with low levels of T cell activation, inhibitory receptor expression showed an inverse relationship with the DAS28-ESR. The frequency of T cells expressing multiple inhibitory receptors was reduced in untreated RA patients but returned to normal levels in treated patients. RA patients who responded to treatment showed an augmented frequency of inhibitory receptor-expressing T cells that correlated with reduced inflammatory cytokine production in comparison to nonresponders. Higher frequencies of effector and memory T cells that expressed multiple inhibitory receptors were seen in SF than in peripheral blood. Notably, inhibitory pathways were operative in blood and synovial T cells from all RA patients, although cells from nonresponder patients were less sensitive to inhibition. CONCLUSION Inhibitory receptor expression on T cells from RA patients is inversely correlated with effector T cell function and disease activity and may predict response to treatment. Furthermore, different inhibitory pathways are functional and cooperatively suppress synovial T cells, providing a rationale for new treatment strategies to regulate acute local inflammation.
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Affiliation(s)
- Luisina I Onofrio
- Hospital Nacional de Clínicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Estefania R Zacca
- Hospital Nacional de Clínicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Paola Ferrero
- Hospital Nacional de Clínicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Cristina Acosta
- Hospital Nacional de Clínicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Eduardo Mussano
- Hospital Nacional de Clínicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Laura Onetti
- Hospital Nacional de Clínicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Isaac Cadile
- Hospital Nacional de Clínicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - M Victoria Gazzoni
- Hospital Nacional de Clínicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Raúl Jurado
- Hospital Nacional de Clínicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Jimena Tosello Boari
- Universidad Nacional de Córdoba and Consejo Nacional de Investigaciones Científicas y Técnicas, Córdoba, Argentina
| | - Maria C Ramello
- Universidad Nacional de Córdoba and Consejo Nacional de Investigaciones Científicas y Técnicas, Córdoba, Argentina
| | - Carolina L Montes
- Universidad Nacional de Córdoba and Consejo Nacional de Investigaciones Científicas y Técnicas, Córdoba, Argentina
| | - Adriana Gruppi
- Universidad Nacional de Córdoba and Consejo Nacional de Investigaciones Científicas y Técnicas, Córdoba, Argentina
| | - Eva V Acosta Rodríguez
- Universidad Nacional de Córdoba and Consejo Nacional de Investigaciones Científicas y Técnicas, Córdoba, Argentina
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Aghchelli A, Yazdani Y, Bazzazi H, Aghaei M. Association Assessment of Peptidylarginine Deiminase Type 4 (PADI4) rs1748033 polymorphism and susceptibility to rheumatoid arthritis in Gorgan, Northeast of Iran. JOURNAL OF CLINICAL AND BASIC RESEARCH 2018. [DOI: 10.29252/jcbr.2.2.11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
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21
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Su J, Li Y, Su G, Wang J, Qiu T, Ma R, Zhao L. Genetic association of CTLA4 gene with polycystic ovary syndrome in the Chinese Han population. Medicine (Baltimore) 2018; 97:e11422. [PMID: 30024513 PMCID: PMC6086533 DOI: 10.1097/md.0000000000011422] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
The autoimmune and gene etiology are implicated in the pathogenesis of polycystic ovary syndrome (PCOS). The cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) is important for negative regulation of T-cell activation, and CTLA4 gene has been identified as a risk factor for some autoimmune diseases. However, none studies have been performed about the association between PCOS and the CTLA4 gene before. Here, we aimed to investigate the association of CTLA4 with PCOS in the Chinese Han population though a case-control association analysis of 606 individuals. The tagging variants rs733618 and rs231775 in the CTLA4 gene were detected using polymerase chain reaction-denaturing gradient gel electrophoresis method. Further analysis found the rs733618 was significantly different between case and control groups in either genotypic or allelic distribution (P = .01 and .009, respectively) while rs231775 not. Moreover, rs733618 was significantly associated with higher body mass index in the dominant model (P = .003) and with higher waist/hip ratio in the recessive model (P = .02). Interestingly, rs733618 was only found to have significant association with homeostatic model assessment for insulin resistance (HOMA-IR) in both dominant and recessive model (P = .009 and .0065, respectively). This is the first study to investigate the association of CTLA4 gene with PCOS. The CTLA4 gene is suggested to correlated with PCOS, and influence PCOS through regulating obesity and the HOMA-IR in a novel way.
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Affiliation(s)
- Jing Su
- Department of Gynecology, The First Affiliated Hospital of Xinjiang Medical University
| | - Yan Li
- Department of Gynecology, The First Affiliated Hospital of Xinjiang Medical University
| | - Guanglong Su
- Department of Clinical Laboratory, Maternal and Child Health Hospital of Urumqi, Urumqi Xinjiang, China
| | - Jing Wang
- Department of Gynecology, The First Affiliated Hospital of Xinjiang Medical University
| | - Ting Qiu
- Department of Gynecology, The First Affiliated Hospital of Xinjiang Medical University
| | - Rong Ma
- Department of Gynecology, The First Affiliated Hospital of Xinjiang Medical University
| | - Lei Zhao
- Department of Gynecology, The First Affiliated Hospital of Xinjiang Medical University
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Fan Q, Zhang J, Cui Y, Wang C, Xie Y, Wang Q, Wu L. The synergic effects of CTLA-4/Foxp3-related genotypes and chromosomal aberrations on the risk of recurrent spontaneous abortion among a Chinese Han population. J Hum Genet 2018; 63:579-587. [PMID: 29476189 PMCID: PMC5915418 DOI: 10.1038/s10038-018-0414-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Revised: 01/04/2018] [Accepted: 01/05/2018] [Indexed: 11/22/2022]
Abstract
The current study was aimed to investigate the association of CLTA-4/Foxp3 polymorphisms and chromosomal abnormalities with recurrent spontaneous abortion (RSA) risk in a Chinese Han population. Altogether, 1284 RSA women and 1046 women with normal pregnancy were incorporated in this study. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was implemented to genotype the single-nucleotide polymorphisms (SNPs) located within CTLA4 and Foxp3. Moreover, the cytogenetic diagnosis was performed in line with the standards of G banding karyotype. As a consequence, rs231775 and rs3087243 of CTLA4, as well as rs2232365 and rs2232368 of Foxp3, all appeared to modify the risk of RSA. Besides, significant differences were found between the ratio of structural abnormality and that of numerical abnormality (P < 0.038), and chromosome abnormality was associated with higher miscarriage frequency (>3) than normal karyotypes. Of note, the synergic effects of the genotypes and chromosomal abnormality all tallied with the sub-multiplication model (ORchromosome × ORSNP > ORchromosome+SNP), while rs2232365 GG and chromosomal aberration impacted the RSA risk in a super-multiplicative way that ORchromosome × ORSNP < ORchromosome+SNP. In conclusion, susceptibility to RSA was subject to the synthetic regulation of chromosomal aberrations and genetic mutations within CLTA-4 and Foxp3, suggesting that the conduction of karyotype analysis and genetic detection for RSA patients could effectively guide effective RSA counseling and sound child rearing.
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Affiliation(s)
- Qin'e Fan
- Department of Obstetrics and Gynecology, Taihe Hospital, Hubei University of Medicine, Shiyan City, Hubei Province, China
| | - Juanjuan Zhang
- Department of Obstetrics and Gynecology, Taihe Hospital, Hubei University of Medicine, Shiyan City, Hubei Province, China
| | - Yu Cui
- Department of Obstetrics and Gynecology, Taihe Hospital, Hubei University of Medicine, Shiyan City, Hubei Province, China
| | - Chaoyun Wang
- Department of Obstetrics and Gynecology, Taihe Hospital, Hubei University of Medicine, Shiyan City, Hubei Province, China
| | - Yongjun Xie
- Department of Obstetrics and Gynecology, Taihe Hospital, Hubei University of Medicine, Shiyan City, Hubei Province, China
| | - Qiurong Wang
- Department of Otolaryngology, Taihe Hospital, Hubei University of Medicine, Shiyan City, Hubei Province, China
| | - Libing Wu
- Reproductive Medicine Centre, Taihe Hospital, Hubei University of Medicine, Shiyan City, Hubei Province, China.
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Dahmani CA, Benzaoui A, Amroun H, Mecabih F, Sediki FZ, Zemani-Fodil F, Fodil M, Boughrara W, Mecheti B, Attal N, Mehtar N, Petit-Teixeira E, Boudjema A. Association of the HLA-B27 antigen and the CTLA4 gene CT60/rs3087243 polymorphism with ankylosing spondylitis in Algerian population: A case-control study. Int J Immunogenet 2018; 45:109-117. [PMID: 29675891 DOI: 10.1111/iji.12369] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Revised: 01/30/2018] [Accepted: 03/22/2018] [Indexed: 12/14/2022]
Abstract
Ankylosing spondylitis (AS) is a complex inflammatory disease that represents a major health problem both in Algeria and worldwide. Several lines of evidence support that genetic risk factors play a role in AS etiology and the CTLA4 gene has attracted a considerable attention. In this study, we were interested in evaluating the HLA-B27 frequency and in exploring the CTLA4 gene in a sample of the North African population. The dataset of the current study is composed of 81 patients with AS and 123 healthy controls. All samples were genotyped by TaqMan® allelic discrimination assay. The genetic risk of the HLA-B27 specificity and the CTLA4/CT60 polymorphism were assessed by odds ratios (OR) with 95% confidence intervals (CI). High spondylitis risk was detected for HLA-B27 allele (OR= 14.62, p = 10-6 ) in addition to a significant association of the CT60*G allele (OR= 1.89, p = .002). After gender and age stratifications, the association of the CT60*G allele was still significant in females sample (OR= 2.10, p = .001) and when age up to 30 years (OR = 2.21, p = .008). Interestingly, the CT60*G allele revealed an increased spondylitis risk in the B27 negative group (OR= 2.81, p = .006). The present work showed in West Algerian population that the HLA-B27 antigen and the variation in the CTLA4 3'UTR region played an important role in the ankylosing spondylitis susceptibility. The heterogeneity of this disease is deduced by genetic difference found between B27+ and B27- groups.
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Affiliation(s)
- C A Dahmani
- Laboratoire de Génétique Moléculaire et Cellulaire (LGMC), Université des Sciences et de la Technologie d'Oran-Mohamed Boudiaf (USTO-MB), Oran, Algeria
| | - A Benzaoui
- Service de Rhumatologie, Centre Hospitalo-Universitaire (CHU) d'Oran, Oran, Algeria
| | - H Amroun
- Laboratoire d'Immunogénétique et de Transplantation, Département d'Immunologie, Institut Pasteur d'Algérie à, Alger, Algeria
| | - F Mecabih
- Laboratoire d'Immunogénétique et de Transplantation, Département d'Immunologie, Institut Pasteur d'Algérie à, Alger, Algeria
| | - F Z Sediki
- Laboratoire de Génétique Moléculaire et Cellulaire (LGMC), Université des Sciences et de la Technologie d'Oran-Mohamed Boudiaf (USTO-MB), Oran, Algeria
| | - F Zemani-Fodil
- Laboratoire de Génétique Moléculaire et Cellulaire (LGMC), Université des Sciences et de la Technologie d'Oran-Mohamed Boudiaf (USTO-MB), Oran, Algeria
| | - M Fodil
- Laboratoire de Génétique Moléculaire et Cellulaire (LGMC), Université des Sciences et de la Technologie d'Oran-Mohamed Boudiaf (USTO-MB), Oran, Algeria
| | - W Boughrara
- Laboratoire de Génétique Moléculaire et Cellulaire (LGMC), Université des Sciences et de la Technologie d'Oran-Mohamed Boudiaf (USTO-MB), Oran, Algeria
| | - B Mecheti
- Laboratoire d'Immunogénétique et de Transplantation, Département d'Immunologie, Institut Pasteur d'Algérie à, Alger, Algeria
| | - N Attal
- Laboratoire d'Immunogénétique et de Transplantation, Département d'Immunologie, Institut Pasteur d'Algérie à, Alger, Algeria
| | - N Mehtar
- Laboratoire de Génétique Moléculaire et Cellulaire (LGMC), Université des Sciences et de la Technologie d'Oran-Mohamed Boudiaf (USTO-MB), Oran, Algeria
| | - E Petit-Teixeira
- Laboratoire Européen de la Polyarthrite Rhumatoide, Université d'Evry-Val D'Essonne, Evry, France
| | - A Boudjema
- Laboratoire de Génétique Moléculaire et Cellulaire (LGMC), Université des Sciences et de la Technologie d'Oran-Mohamed Boudiaf (USTO-MB), Oran, Algeria
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López-Mejías R, Castañeda S, Genre F, Remuzgo-Martínez S, Carmona FD, Llorca J, Blanco R, Martín J, González-Gay MA. Genetics of immunoglobulin-A vasculitis (Henoch-Schönlein purpura): An updated review. Autoimmun Rev 2018; 17:301-315. [DOI: 10.1016/j.autrev.2017.11.024] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2017] [Accepted: 11/16/2017] [Indexed: 12/12/2022]
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Abstract
Ligase IV and XRCC4 genes, important molecules in the nonhomologous end-joining pathway for repairing DNA double-strand breaks, may play crucial roles in carcinogenesis. To detect their effects on the risk of human glioma, their gene expression differences between 110 human glioma tissues and 50 healthy brain tissues were determined using quantitative real-time PCR. Furthermore, two tagging single nucleotide polymorphisms (SNPs) in ligase IV and four SNPs in XRCC4 genes were genotyped in 317 glioma patients and 352 healthy controls. The association of glioma and ligase IV/XRCC4 was evaluated using methods for SNP, haplotype, and gene-gene interaction analysis. Compared with those in normal brain tissues, the relative gene expression levels of ligase IV and XRCC4 were significantly downregulated in glioma tissue (P=0.0017 and 0.0006, respectively). Single SNP analysis indicated that only rs10131 in ligase IV remained significantly associated with glioma (P=0.0036) after 10 000 permutation tests. Haplotype analysis showed that the haplotype profiles of ligase IV and XRCC4 were significantly different between glioma patients and healthy controls (P=0.004 and 3.13E-6, respectively). Finally, the gene-gene interaction analysis suggested that the three-locus model (rs1805388, rs10131, and rs2075685) was the best model for ligase IV and XRCC4 to have interaction effects on the risk of glioma. In conclusion, both ligase IV and XRCC4 may act in concert to modulate the development of glioma.
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Arshad M, Bhatti A, John P, Jalil F, Williams RO. Association of rs182429 variant in TAGAP with rheumatoid arthritis in Pakistani population. Meta Gene 2017. [DOI: 10.1016/j.mgene.2017.08.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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Arshad M, Bhatti A, John P, Jalil F, Borghese F, Kawalkowska JZ, Williams RO, Clanchy FIL. T cell activation Rho GTPase activating protein (TAGAP) is upregulated in clinical and experimental arthritis. Cytokine 2017; 104:130-135. [PMID: 29017772 DOI: 10.1016/j.cyto.2017.10.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Revised: 09/11/2017] [Accepted: 10/02/2017] [Indexed: 12/15/2022]
Abstract
Genome-wide association studies have identified various susceptibility variants and loci associated with incidence of rheumatoid arthritis (RA) in different populations. One of these is T cell activation Rho GTPase activating protein (TAGAP). The present study sought to measure the expression of TAGAP in RA patients, CD4+ T cells subsets from healthy humans and in mice with collagen-induced arthritis. Peripheral blood mononuclear cells (PBMC) from RA patients and tissues of arthritic mice at different stages of the disease were used for the evaluation of TAGAP mRNA expression. Increased TAGAP expression was observed in RA patients compared to healthy controls, and there were differences in the expression level of TAGAP in the tissues of mice with experimental arthritis. Gene expression in CD4+ T cells from healthy humans was greatest 4 h after activation and protein expression was greatest after 24 h. The expression of TAGAP was not correlated with CD4+ lymphocyte subsets which were enriched for functionally defined subsets (Th17, Treg, Th1), further indicating its utility as an indicator of lymphocyte activation. These findings indicate that increased TAGAP expression is a distinguishing feature of inflammatory disease and further highlight the role of TAGAP in RA susceptibility.
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Affiliation(s)
- Maria Arshad
- Atta-ur-Rahman School of Applied Biosciences, National University of Sciences & Technology, Islamabad, Pakistan
| | - Attya Bhatti
- Atta-ur-Rahman School of Applied Biosciences, National University of Sciences & Technology, Islamabad, Pakistan
| | - Peter John
- Atta-ur-Rahman School of Applied Biosciences, National University of Sciences & Technology, Islamabad, Pakistan
| | - Fazal Jalil
- Department of Biotechnology, Abdul Wali Khan University Mardan, Pakistan
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Danila MI, Laufer VA, Reynolds RJ, Yan Q, Liu N, Gregersen PK, Lee A, Kern M, Langefeld CD, Arnett DK, Bridges SL. Dense Genotyping of Immune-Related Regions Identifies Loci for Rheumatoid Arthritis Risk and Damage in African Americans. Mol Med 2017; 23:177-187. [PMID: 28681901 DOI: 10.2119/molmed.2017.00081] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Accepted: 06/19/2017] [Indexed: 12/29/2022] Open
Abstract
Over 100 risk loci for rheumatoid arthritis (RA) have been identified in individuals of European and Asian descent, but the genetic basis for RA in African Americans is less well understood. We genotyped 610 African Americans with autoantibody positive RA and 933 African American controls on the ImmunoChip (iChip) array. Using multivariable regression we evaluated the association between iChip markers and the risk of RA and radiographic severity. The single nucleotide polymorphism (SNP) rs1964995 (OR = 1.97, p = 1.28 × 10-15) near HLA-DRB1 was the most strongly associated risk SNP for RA susceptibility; SNPs in AFF3, TNFSF11, and TNFSF18 loci were suggestively associated (10-4 < p < 3.1 × 10-6). Trans-ethnic fine mapping of AFF3 identified a 90% credible set containing previously studied variants including rs9653442, rs7608424, and rs6712515 as well as the novel candidate variant rs11681966; several of these likely influence AFF3 gene expression level. Variants in TNFRSF9, CTLA4, IL2RA, C5/TRAF1, and ETS1 - but no variants within the major histocompatibility complex - were associated with RA radiographic severity. Conditional regression and pairwise linkage disequilibrium (LD) analyses suggest that additional pathogenic variants may be found in ETS1 and IL2RA beyond those found in other ethnicities. In summary, we use the dense genotyping of the iChip array and unique LD structure of African Americans to validate known risk loci for RA susceptibility and radiographic severity, and to better characterize the associations of AFF3, ETS1, and IL2RA.
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Affiliation(s)
- Maria I Danila
- University of Alabama at Birmingham, Division of Clinical Immunology and Rheumatology
| | - Vincent Albert Laufer
- University of Alabama at Birmingham, Division of Clinical Immunology and Rheumatology
| | - Richard J Reynolds
- University of Alabama at Birmingham, Division of Clinical Immunology and Rheumatology
| | - Qi Yan
- University of Pittsburgh, Division of Pulmonary Medicine, Allergy and Immunology; Department of Pediatrics
| | - Nianjun Liu
- Indiana University School of Public Health - Bloomington, Department of Epidemiology and Biostatistics
| | | | | | | | | | | | - S Louis Bridges
- University of Alabama at Birmingham, Division of Clinical Immunology and Rheumatology
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Zhang YH, Song J, Zhang J, Shao J. Deleterious effects of non-synonymous single nucleotide variants of human IL-1β gene. Chem Biol Drug Des 2017; 90:545-553. [PMID: 28296211 DOI: 10.1111/cbdd.12976] [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: 12/25/2016] [Accepted: 02/28/2017] [Indexed: 11/29/2022]
Abstract
The IL-1β gene is currently topic of interest for its important role in the pathogenesis of intervertebral disk degeneration. The new sequencing technology makes it crucial to study the effects of variants in IL-1β. Thus, 714 IL-1β variants with evidence supporting were collected from the EMBL database. Among them, 62 were non-synonymous single nucleotide variants (nsSNVs). Furthermore, six common nsSNVs were predicted to have damaging effects by SIFT, PolyPhen, PROVEAN and SNPs&GO. Based on the constructed three-dimensional structure of pro-IL-1β, rs375479974 with a mutation of Phe to Ser was proposed to reduce the stability of the pro-IL-1β protein. The rs375479974 variant was found to cause least common stabilizing amino acid residues, decrease hydrophilic and increase hydrophobic surface areas in the greatest degree, and have the lowest free energy alterations in I-Mutant 2.0 sequence analysis. When analyzing the interaction between the experimental 3D structure of mature IL-1β and its neutralizing McAb canakinumab complex, the rs775174784 substitution of Leu with Phe was found to attenuate this interaction by reducing binding energy, while rs375479974 not. Molecular dynamics simulation results in intervertebral disk environment supported rs775174784's effects. These results suggest that both rs375479974 and rs775174784 may have potential clinical and drug target implications.
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Affiliation(s)
- Yue-Hui Zhang
- Department of Orthopedic Surgery, Xinhua Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Jia Song
- Department of Orthopedic Surgery, Xinhua Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Jing Zhang
- Department of Orthopedic Surgery, Xinhua Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Jiang Shao
- Department of Orthopedic Surgery, Xinhua Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, China
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Wang K, Zhu Q, Lu Y, Lu H, Zhang F, Wang X, Fan Y. CTLA-4 +49 G/A Polymorphism Confers Autoimmune Disease Risk: An Updated Meta-Analysis. Genet Test Mol Biomarkers 2017; 21:222-227. [PMID: 28384040 DOI: 10.1089/gtmb.2016.0335] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Cytotoxic T lymphocyte antigen-4 (CTLA-4) plays a pivotal role in immune homeostasis. Dysregulated expression of CTLA-4 leads to many autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes (T1D). There has been a controversial association between the CTLA-4 +49 G/A SNP (rs231775) and autoimmune diseases. Therefore, this meta-analysis was performed to assess the link between rs231775 and autoimmune disease risk. MATERIALS AND METHODS We retrieved the available studies from PUBMED and EMBASE through February, 2016 and then performed meta-analyses that included all populations, as well as by ethnicity. RESULTS After evaluating data from 4732 patients and 6270 healthy controls that included both Caucasian and Asian ethnicities, we found that rs231775 is strongly associated with autoimmune disease incidence in a homozygote comparison (GG vs. AA, 95% confidence interval [95% CI] 1.382-2.401), in a heterozygote comparison (AG vs. AA, 95% CI 1.151-1.611), in an allelic model (T allele vs. G allele, 95% CI 1.109-1.441), in a dominant model (GG/AG vs. AA, 95% CI 1.220-1.787), and in a recessive model (GG vs. AA/AG, 95% CI 1.128-1.661). The OR (odds ratio) from all models suggested a very significant association between rs231775 and autoimmune diseases. CONCLUSION Our present study indicates that CTLA-4 +49 G/A (rs231775) is associated with the susceptibility of autoimmune disease. Hence, rs231775 might be utilized as a diagnostic biomarker in both Asian and Caucasian populations.
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Affiliation(s)
- Ke Wang
- Key Laboratory on Living Donor Liver Transplantation, Ministry of Health, Department of Liver Surgery, First Affiliated Hospital of Nanjing Medical University , Nanjing, P.R. China
| | - Qin Zhu
- Key Laboratory on Living Donor Liver Transplantation, Ministry of Health, Department of Liver Surgery, First Affiliated Hospital of Nanjing Medical University , Nanjing, P.R. China
| | - Yunjie Lu
- Key Laboratory on Living Donor Liver Transplantation, Ministry of Health, Department of Liver Surgery, First Affiliated Hospital of Nanjing Medical University , Nanjing, P.R. China
| | - Hao Lu
- Key Laboratory on Living Donor Liver Transplantation, Ministry of Health, Department of Liver Surgery, First Affiliated Hospital of Nanjing Medical University , Nanjing, P.R. China
| | - Feng Zhang
- Key Laboratory on Living Donor Liver Transplantation, Ministry of Health, Department of Liver Surgery, First Affiliated Hospital of Nanjing Medical University , Nanjing, P.R. China
| | - Xuehao Wang
- Key Laboratory on Living Donor Liver Transplantation, Ministry of Health, Department of Liver Surgery, First Affiliated Hospital of Nanjing Medical University , Nanjing, P.R. China
| | - Ye Fan
- Key Laboratory on Living Donor Liver Transplantation, Ministry of Health, Department of Liver Surgery, First Affiliated Hospital of Nanjing Medical University , Nanjing, P.R. China
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T‐cell exhaustion: understanding the interface of chronic viral and autoinflammatory diseases. Immunol Cell Biol 2016; 94:935-942. [DOI: 10.1038/icb.2016.81] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 08/25/2016] [Accepted: 08/27/2016] [Indexed: 12/19/2022]
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Fang S, Zhang Y, Xu M, Xue C, He L, Cai L, Xing X. Identification of Damaging nsSNVs in HumanERCC2 Gene. Chem Biol Drug Des 2016; 88:441-50. [PMID: 27085493 DOI: 10.1111/cbdd.12772] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Revised: 03/29/2016] [Accepted: 03/30/2016] [Indexed: 01/05/2023]
Abstract
The hERCC2 gene is an important DNA repair molecule for initiating Cutaneous melanoma (CM). Therefore, it is advisable to study the possible functional SNVs in hERCC2. To achieve this goal, we collected total 2, 253 SNVs in hERCC2from the EMBL website, of which 303 are non-synonymous single nucleotide variants (nsSNVs). Then, SIFT and PolyPhen were used to predict the damaging nsSNVs, and four nsSNVs (rs368866996, rs377739017, rs370819591, and rs121913022) were suggested to be damaging mutations. Since I-Mutant2.0 showed a decrease in stability for the mutants containing each of the four nsSNVs, a 3D protein structure was modeled. Based on the comparison of the energy after minimization, RMSD and stabilizing residues between the native and mutant proteins' structure, rs121913022 was proposed to be the most damaging variant among the nsSNVs in hERCC2 gene by decreasing the stability of protein. The mutant G713R of hERCC2 protein caused by rs121913022 was found to have less expression level than native hERCC2 protein in melanoma cells. These results suggest that rs121913022 may have potentially important clinical and drug target implications.
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Affiliation(s)
- Shuo Fang
- Department of Plastic and Reconstruction, Shanghai Changhai Hospital Affiliated to Second Military Medical University, Shanghai, 200433, China.,Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychotic Disorders (No. 13dz2260500), Bio-X Institutes, Shanghai Jiaotong University, Shanghai, 200240, China
| | - Yuntong Zhang
- Department of Orthopedics, Shanghai Changhai Hospital Affiliated to Second Military Medical University, Shanghai, 200433, China
| | - Miao Xu
- Department of Plastic and Reconstruction Surgery, Xinhua Hospital, Shanghai Jiaotong University, Shanghai, 200092, China
| | - Chunyu Xue
- Department of Plastic and Reconstruction, Shanghai Changhai Hospital Affiliated to Second Military Medical University, Shanghai, 200433, China
| | - Lin He
- Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychotic Disorders (No. 13dz2260500), Bio-X Institutes, Shanghai Jiaotong University, Shanghai, 200240, China
| | - Lei Cai
- Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychotic Disorders (No. 13dz2260500), Bio-X Institutes, Shanghai Jiaotong University, Shanghai, 200240, China
| | - Xin Xing
- Department of Plastic and Reconstruction, Shanghai Changhai Hospital Affiliated to Second Military Medical University, Shanghai, 200433, China
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Fang W, Zhang Z, Zhang J, Cai Z, Zeng H, Chen M, Huang J. Association of the CTLA4 gene CT60/rs3087243 single-nucleotide polymorphisms with Graves' disease. Biomed Rep 2015; 3:691-696. [PMID: 26405547 DOI: 10.3892/br.2015.493] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Accepted: 06/10/2015] [Indexed: 12/24/2022] Open
Abstract
It has been widely reported that the CT60 single-nucleotide polymorphism (SNP), which is in the 3'-untranslated region of the cytotoxic T lymphocyte associated 4 (CTLA4) gene, is strongly correlated with certain immune-mediated diseases. The present case-control study aimed to investigate the genetic association between the CT60 SNP within the CTLA4 gene and Graves' disease (GD). A total of 288 patients with GD and 290 control subjects were recruited for the study. The CT60 SNP of the CTLA4 gene was detected by direct DNA sequencing. The results indicated that the frequencies of the GG genotype and G allele in the case group were evidently higher than that in the control group (P=4×10-6 and P=2.9×10-5, respectively). Furthermore, the G/G genotype of the CT60 SNP was associated with an increased risk for GD (odds ratio=2.223). In conclusion, these results suggested that the CT60 SNP is associated with susceptibility to GD. The frequency of the disease-susceptible G allele of CT60 was significantly associated with an increased risk of GD development.
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Affiliation(s)
- Weizhen Fang
- Department of Clinical Laboratory, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Zhixian Zhang
- Department of Clinical Laboratory, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Jin Zhang
- Department of Endocrinology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Zhenhua Cai
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong 510405, P.R. China
| | - Hua Zeng
- Department of Clinical Laboratory, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Mei Chen
- Department of Clinical Laboratory, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Junqi Huang
- Department of Immunology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
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Li X, Xia Q, Fan D, Cai G, Yang X, Wang L, Xin L, Ding N, Hu Y, Liu L, Xu S, Xu J, Wang K, Pan F. Association between KIR gene polymorphisms and rheumatoid arthritis susceptibility: A meta-analysis. Hum Immunol 2015; 76:565-70. [PMID: 26187163 DOI: 10.1016/j.humimm.2015.06.017] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Revised: 06/26/2015] [Accepted: 06/30/2015] [Indexed: 01/04/2023]
Abstract
OBJECTIVES The results of studies on association between KIR (killer cell immunoglobulin-like receptors) polymorphisms and susceptibility to RA (rheumatoid arthritis) are inconsistent. To comprehensively evaluate the effect of KIR polymorphisms on the risk of RA, a meta-analysis was carried out. METHODS The Web of Science, PubMed, the Chinese Biomedical Database (CBM) and Chinese National Knowledge Infrastructure (CNKI) databases were systematically searched to select studies on the association between KIR polymorphisms and RA. The odds ratio (OR) with 95% confidence interval (95%CI) was obtained. RESULTS Nine qualified case-control studies were included in this meta-analysis. The results showed there were two positive associations of 2DL1, 2DS1 (OR2DL1=2.20, 95%CI=1.20-4.01, Praw=0.01, PFDR=0.03; OR2DS1=1.84, 95%CI=1.19-2.85, Praw=0.006, PFDR=0.018) and one negative association of 2DL3 (OR2DL3=0.42, 95%CI=0.22-0.79, Praw=0.006, PFDR=0.018) with susceptibility to RA in East Asians, but not in Caucasians. CONCLUSION The current meta-analysis provides evidence that 2DL3 might be a potential protective factor and 2DL1, 2DS1 might be risk factors for RA in East Asians but not in Caucasians.
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Affiliation(s)
- Xiaona Li
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Qing Xia
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Dazhi Fan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Guoqi Cai
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Xiao Yang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Li Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Lihong Xin
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Ning Ding
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Yanting Hu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Li Liu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Shengqian Xu
- Department of Rheumatism and Immunity, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Jianhua Xu
- Department of Rheumatism and Immunity, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Kang Wang
- Department of Rheumatism and Immunity, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Faming Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China.
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Li YY, Gong G, Geng HY, Yang ZJ, Zhou CW, Lu XZ. CTLA-4 +49A/G gene polymorphism and type 1 diabetes mellitus in the Chinese population: a meta-analysis of 2238 subjects. Int J Diabetes Dev Ctries 2015. [DOI: 10.1007/s13410-015-0414-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
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Jin P, Xiang B, Huang G, Zhou Z. The association of cytotoxic T-lymphocyte antigen-4 + 49A/G and CT60 polymorphisms with type 1 diabetes and latent autoimmune diabetes in Chinese adults. J Endocrinol Invest 2015; 38:149-54. [PMID: 25185645 DOI: 10.1007/s40618-014-0162-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2014] [Accepted: 08/11/2014] [Indexed: 11/25/2022]
Abstract
OBJECTIVE The aim of this study was to investigate the association of cytotoxic T-lymphocyte antigen-4 (CTLA-4) + 49A/G and CT60 polymorphisms with latent autoimmune diabetes in adults (LADA) and the genetic differences between LADA, type 1 diabetes (T1DM), and type 2 diabetes (T2DM) in a Chinese population. SUBJECTS A total of 231 LADA, 402 T1DM, and 330 T2DM patients as well as 482 nondiabetic controls were recruited in the study. METHODS CTLA-4 + 49A/G and CT60 polymorphisms were analyzed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). The level of glutamic acid decarboxylase antibodies (GADAs) was detected by a radioligand binding assay. RESULTS The CTLA-4 + 49A/G risk genotype GG was most frequent in T1DM patients (45.3%), followed by LADA patients (44.2%) and T2DM patients (38.8%). Significantly higher frequencies of the risk genotype GG were observed in the T1DM (OR = 1.532, 95% CI 1.168-2.010, P = 0.002) and LADA patients (OR = 1.464, 95% CI 1.063-2.017, P = 0.019). The frequencies of the CTLA-4 CT60 risk genotype GG were 65.2, 61.9, 58.5, and 56.4% in the T1DM, LADA, T2DM, and control groups, respectively. The CTLA-4 CT60 GG risk genotypes were only associated with T1DM (OR = 1.445, 95% CI 1.1-1.898, P = 0.008). Compared with controls, patients having a high titer of GADA (GADA ≥ 180 IU/ml) had higher frequencies of the GG risk genotype of CTLA-4 + 49 A/G (49.4% vs. 35.1% OR = 1.807, 95% CI 1.125-2.903, P = 0.014), but there was no difference between patients having a low titer of GADA and controls. CONCLUSION The CTLA-4 + 49 A/G polymorphism confers genetic susceptibility to LADA and T1DM, while the CTLA-4 CT60 polymorphism is only associated with T1DM in Chinese population. The CTLA-4 + 49 A/G genotype distribution in LADA is associated with the GADA level.
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Affiliation(s)
- P Jin
- Department of Endocrinology, Diabetes Center, Institute of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
- Department of Endorcrinology, The Third Xiangya Hospital, Central South University, Changsha, 410007, Hunan, People's Republic of China
| | - B Xiang
- Department of Endocrinology, Diabetes Center, Institute of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - G Huang
- Department of Endocrinology, Diabetes Center, Institute of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Z Zhou
- Department of Endocrinology, Diabetes Center, Institute of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
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The contribution of genetic factors to rheumatoid arthritis. Rheumatology (Oxford) 2015. [DOI: 10.1016/b978-0-323-09138-1.00089-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Li L, Gu ZP, Bo QM, Wang D, Yang XS, Cai GH. Association of CYP17A1 gene -34T/C polymorphism with polycystic ovary syndrome in Han Chinese population. Gynecol Endocrinol 2015; 31:40-3. [PMID: 25208301 DOI: 10.3109/09513590.2014.947948] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
PURPOSE To investigate the influence of the cytochrome P450 17α (CYP17A1) gene -34T/C polymorphism in the pathogenesis of polycystic ovary syndrome (PCOS) in Han Chinese population. METHODS Three-hundred eighteen patients with PCOS and 306 controls were recruited and the CYP17A1 -34T/C polymorphism was genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Furthermore, the relationship of CYP17A1 -34T/C polymorphism and clinical feature parameters of PCOS patients was also analyzed. RESULTS The prevalence rates of CYP17A1 genotype TT, TC and CC were 49.69%, 43.71% and 6.6% in the case group and those were 44.77%, 46.08% and 9.15% in the control group. The frequencies of CYP17A1 T and C alleles were 71.54% and 28.46% in the case group, and those were 67.81% and 32.19% in the control group. Neither the genotypic nor the allelic distribution was significantly different between the cases and controls. However, the PCOS patients with the genotype of CC had significantly higher total testosterone levels and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) than those with the genotype of TT or TC. CONCLUSIONS The CYP17A1 gene -34T/C polymorphism might not be directly correlated with the PCOS, but might influence PCOS via the association of testosterone level and the HOMA-IR.
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Affiliation(s)
- Li Li
- Medical School of Shandong University , Jinan, Shandong Province , China
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Li G, Shi F, Liu J, Li Y. The effect of CTLA-4 A49G polymorphism on rheumatoid arthritis risk: a meta-analysis. Diagn Pathol 2014; 9:157. [PMID: 25128482 PMCID: PMC4160544 DOI: 10.1186/s13000-014-0157-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2014] [Accepted: 07/29/2014] [Indexed: 01/22/2023] Open
Abstract
Background Recently, a number of studies have been performed to explore the association between CTLA-4 A49G polymorphism and rheumatoid arthritis (RA). However, the results of previous works are still controversial and ambiguous. Methods In this work, we attempted to perform an updated meta-analysis of available case–control study in order to assess the association between CTLA-4 A49G polymorphism and RA risk. We searched the various citation databases without limits on languages. Article searching was performed by screening the references of retrieved studies manually. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated to evaluate the strength of the association. Results We totally compiled 27 studies in 24 articles (9805 RA patients and 10691 control subjects) into our meta-analysis work. We found significant association between CTL-A4 A49G polymorphism and RA risk (GG vs. AA: OR = 1.13, 95% CI = 1.03–1.23; GA vs. AA: OR = 1.19, 95% CI = 1.07–1.33; GA + GG vs. AA: OR = 1.18, 95% CI = 1.07–1.29). In the subgroup analysis by ethnicity, evidences of significantly increased risk was also found in both Asian (GG vs. AA: OR = 1.34, 95% CI = 1.15–1.55; GA + GG vs. AA: OR = 1.24, 95% CI = 1.08–1.41) and Caucasian population (GA vs. AA: OR = 1.19, 95% CI = 1.03–1.37; GA + GG vs. AA: OR = 1.14, 95% CI = 1.01–1.29). No evidence of publication bias was found in this work. Conclusions Our meta-analysis suggests that CTLA-4 A49G polymorphism was associated with RA risk. Virtual Slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_157
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Affiliation(s)
| | - Fengjun Shi
- Department of Orthopaedics, Daqing General Hospital Group Oilfield General Hospital, Daqing 163001, China.
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Ng JY, Luk FO, Lai TY, Pang CP. Influence of molecular genetics in Vogt-Koyanagi-Harada disease. J Ophthalmic Inflamm Infect 2014; 4:20. [PMID: 25097674 PMCID: PMC4105881 DOI: 10.1186/s12348-014-0020-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2014] [Accepted: 07/08/2014] [Indexed: 01/13/2023] Open
Abstract
Vogt-Koyanagi-Harada (VKH) disease is a systemic autoimmune disorder against melanocytes. Recent studies have identified multiple genetic factors that might be associated with the pathogenesis of VKH disease. We performed an electronic database search of PubMed, MEDLINE, and EMBASE, and all relevant papers published up to 13 June 2014 were reviewed. A total of 1,031 publications including articles relevant to the genetics of VKH disease and the references of these articles were reviewed. The review identified a number of genetic factors which might be involved in the pathogenesis of VKH disease, some of which may alter the clinical course of VKH disease. Genes which might be involved in the pathogenesis of VKH disease included genes expressing HLA, complement factor H, interleukins, cytotoxic T-lymphocyte antigen 4 (CTLA-4), killer cell immunoglobulin-like receptors (KIR), programmed cell death 1 (PDCD1), protein tyrosine phosphatase non-receptor 22 (PTPN22), osteopontin, tumor necrosis factor alpha-induced protein 3 (TNFAIP3), macrophage migration inhibitory factor (MIF), and other immune response genes. Further studies to explore the correlation among different genotypes and phenotypes of VKH disease will be useful to shed light on the pathogenesis of uveitis in VKH disease and may facilitate the development of new treatment modalities of uveitis in VKH disease.
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Affiliation(s)
- Joanne Yw Ng
- Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, 3/F Hong Kong Eye Hospital, 147K Argyle Street, Kowloon ᅟ, Hong Kong
| | - Fiona Oj Luk
- Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, 3/F Hong Kong Eye Hospital, 147K Argyle Street, Kowloon ᅟ, Hong Kong
| | - Timothy Yy Lai
- Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, 3/F Hong Kong Eye Hospital, 147K Argyle Street, Kowloon ᅟ, Hong Kong
| | - Chi-Pui Pang
- Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, 3/F Hong Kong Eye Hospital, 147K Argyle Street, Kowloon ᅟ, Hong Kong
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AlFadhli S, Nizam R. Differential expression of alternative splice variants of CTLA4 in Kuwaiti autoimmune disease patients. Gene 2014. [DOI: 10.1016/j.gene.2013.10.034] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
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Misra MK, Kapoor R, Pandey SK, Sharma RK, Agrawal S. Association of CTLA-4 gene polymorphism with end-stage renal disease and renal allograft outcome. J Interferon Cytokine Res 2013; 34:148-61. [PMID: 24313821 DOI: 10.1089/jir.2013.0069] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is upregulated in effector-T-cells after activation that may alter signal transduction and subsequently cytokine production. The present study was designed to investigate the impact of CTLA-4+49 A>G (rs231775), -318 C>T (rs5742909), -658 C>T (rs11571317), -1147 C>T (rs16840252), -1661 A>G (rs4553808), +6230 A>G (rs3087243) SNPs, and microsatellite (AT)n repeat polymorphism among end-stage renal disease (ESRD), acute allograft rejection (AR), and delayed graft function (DGF) cases. In this regard, 350 ESRD patients and 350 controls were included. Polymerase chain reaction (PCR)-restriction fragment length polymorphism analysis method was used for genotyping of CTLA-4 SNPs, while PCR-polyacrylamide gel electrophoresis method was adopted for studying CTLA4 (AT)n polymorphism. The mutant genotype GG of CTLA-4+49A>G,+6230 A>G, and longer alleles of (AT)n repeats polymorphisms were risk associated with ESRD, AR, and DGF cases. The distribution of haplotype+49G:+6230G and GCTTGG (constructed by using 6 studied SNPs) showed risk association for ESRD, DGF, and AR cases. Further, linkage analysis demonstrated strong to moderate linkage disequilibrium in our study populations. The meta-analysis also revealed risk associations for AR cases against GG genotype of CTLA-4+49A>G SNP, while CTLA-4 -318C>T polymorphism showed no correlation against TT genotype among AR cases. Subsequently, no correlation was established against the CTLA-4 -318C>T, -658 C>T, -1147 C>T, and -1661 A>G SNPs in the promoter region. Survival analysis revealed risk associations against GG genotype of CTLA-4+49A>G, +6230 A>G SNP's with overall survival (OS), and higher hazard for the OS. These results suggested that CTLA-4 variants might be involved in susceptibility to ESRD, AR, and DGF.
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Affiliation(s)
- Maneesh Kumar Misra
- 1 Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences , Lucknow, India
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Spink C, Stege G, Tenbrock K, Harendza S. The CTLA-4 +49GG genotype is associated with susceptibility for nephrotic kidney diseases. Nephrol Dial Transplant 2013; 28:2800-5. [PMID: 23975748 DOI: 10.1093/ndt/gft381] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND The pathogenesis of primary nephrotic kidney diseases is not completely understood. As T-cell involvement is suspected, cytotoxic T-lymphocyte antigen 4 (CTLA-4) expressed on activated T cells could play a role in the immune response. Single-nucleotide polymorphisms (SNPs) in the CTLA-4 gene are associated with several autoimmune-related diseases. METHODS Our goal was to study the occurrence of the SNPs -318C/T, +49A/G and CT60 on the CTLA-4 gene in healthy blood donors (N = 156) compared with nephrotic patients with biopsy-proven minimal-change disease (MCD, N = 160), focal segmental glomerulosclerosis (FSGS, N = 159) and membranous nephropathy (MN, N = 185). Odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated to estimate the strength of the association. RESULTS The +49GG genotype was significantly (P < 0.001) associated with the risk for MCD, FSGS and MN (AA versus GG: OR = 3.403, 95% CI = 1.748-6.622, OR = 3.846, 95% CI = 1.945-7.604 and OR = 2.381, 95% CI = 1.257-4.511, respectively). No further significant associations, neither with the heterozygous genotype of +49A/G nor for the -318C/T or CT60 SNP, were detected. CONCLUSIONS The +49GG genotype of the +49A/G SNP in the CTLA-4 gene is associated with the risk for MCD, FSGS and MN, suggesting a possible role for CTLA-4 in a proposed common final pathway in the pathogenesis of primary nephrotic kidney diseases.
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Affiliation(s)
- Clemens Spink
- Zentrum für Innere Medizin, III. Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
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Chatzikyriakidou A, Voulgari PV, Lambropoulos A, Drosos AA. Genetics in rheumatoid arthritis beyond HLA genes: what meta-analyses have shown? Semin Arthritis Rheum 2013; 43:29-38. [PMID: 23768941 DOI: 10.1016/j.semarthrit.2012.12.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2012] [Revised: 11/28/2012] [Accepted: 12/06/2012] [Indexed: 01/15/2023]
Abstract
OBJECTIVE Rheumatoid arthritis (RA) is a complex disorder with many genetic and environmental factors to account for disease susceptibility. Individual genetic association studies usually suffer from small sample size leading to biased results of polymorphisms association with RA liability. Therefore, meta-analyses seem to resolve this limitation, up to a point, increasing the power of statistical analyses. In this review, we summarize the current knowledge of non-HLA genetic factors contributing to RA predisposition based on meta-analyses. METHODS Using the key words: rheumatoid arthritis, meta-analysis, and polymorphism, we searched the PubMed database for the associated articles. Up to the middle of November 2012, seventy-nine articles fulfilled the criteria and highlighted the current findings on the genetic factors contributing to RA susceptibility. RESULTS The association with RA was confirmed for 32 gene polymorphisms, being population specific in some cases. However, meta-analyses did not confirm an association in case of 16 gene variants, previously studied in individual studies for their association with RA. CONCLUSIONS The use of bioinformatics tools and functional studies of the summarized implicated genes in RA pathogenesis could shed light on the molecular pathways related to the disorder, helping to the development of new drug targets for a better treatment of RA.
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Affiliation(s)
- Anthoula Chatzikyriakidou
- Laboratory of General Biology and Genetics, Medical School, Aristotle University of Thessaloniki, Greece
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The −319C/+49G/CT60G Haplotype of CTLA-4 Gene Confers Susceptibility to Rheumatoid Arthritis in Mexican Population. Cell Biochem Biophys 2013; 67:1217-28. [DOI: 10.1007/s12013-013-9640-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Tang MJ, Zhou ZB. Association of the CTLA-4 +49A/G polymorphism with rheumatoid arthritis in Chinese Han population. Mol Biol Rep 2012; 40:2627-31. [PMID: 23264071 DOI: 10.1007/s11033-012-2349-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2012] [Accepted: 12/09/2012] [Indexed: 01/25/2023]
Abstract
Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is an important molecule in the regulation of T cells, so the CTLA-4 gene has been considered as a strong candidate associated with T cell-mediated autoimmune diseases such as rheumatoid arthritis (RA). CTLA-4 has many variants and polymorphic forms, among which the +49A/G polymorphism, causing a non-synonymous substitution, has been studied most. However, previous studies of the association between the +49A/G polymorphism of the CTLA-4 gene and RA have provided conflicting results. The aim of this study was to determine the potential relationship of the CTLA-4 +49A/G polymorphism and the risk of RA in Chinese Han population. TaqMan assay was used to genotype the +49A/G polymorphism in 1,489 RA patients and 1,200 healthy controls. Furthermore, a meta-analysis of all studies relating this polymorphism in Chinese population to the risk of RA was performed. The genotype and allele frequencies of the CTLA-4 +49A/G in patients with RA differed significantly from those of controls (P = 0.03 and P = 0.007, respectively). The meta-analysis also revealed that the CTLA-4 +49G allele was associated with an increased risk of RA in Chinese population. Our results suggested that the CTLA-4 gene might contribute to the pathogenesis of RA, and the +49A/G polymorphism of this gene was a risk factor associated with increased RA susceptibility in Chinese Han population.
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Affiliation(s)
- Ming-Jie Tang
- Orthopaedics Department, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, No.600, Yishan Road, Shanghai, 200233, People's Republic of China
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Identification of genetic associations of SP110/MYBBP1A/RELA with pulmonary tuberculosis in the Chinese Han population. Hum Genet 2012; 132:265-73. [PMID: 23129390 DOI: 10.1007/s00439-012-1244-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2012] [Accepted: 10/17/2012] [Indexed: 10/27/2022]
Abstract
Genetic factors play important roles in the development of tuberculosis (TB). SP110 is a promising candidate target for controlling TB infections. However, several studies associating SP110 single nucleotide polymorphisms (SNPs) with TB have yielded conflicting results. This may be partly resolved by studying other genes associated with SP110, such as MYBBP1A and RELA. Here, we genotyped 6 SP110 SNPs, 8 MYBBP1A SNPs and 5 RELA SNPs in 702 Chinese pulmonary TB patients and 425 healthy subjects using MassARRAY and SNaPshot methods. Using SNP-based analysis with Bonferroni correction, rs3809849 in MYBBP1A [Pcorrected (cor) = 0.0038] and rs9061 in SP110 (Pcor = 0.019) were found to be significantly associated with TB. Furthermore, meta-analysis of rs9061 in East Asian populations showed that the rs9061 T allele conferred significant risk for TB [P = 0.002, pooled odds ratio (OR), 1.24, 95% confidence interval (CI) = 1.08-1.43]. The MYBBP1A GTCTTGGG haplotype and haplotypes CGACCG/TGATTG within SP110 were found to be markedly and significantly associated with TB (P = 2.00E-06, 5.00E-6 and 2.59E-4, respectively). Gene-based analysis also demonstrated that SP110 and MYBBP1A were each associated with TB (Pcor = 0.011 and 0.035, respectively). The logistic regression analysis results supported interactions between SP110 and MYBBP1A, indicating that subjects carrying a GC/CC genotype in MYBBP1A and CC genotype in SP110 possessed the high risk of developing TB (P = 1.74E-12). Our study suggests that a combination of SP110 and MYBBP1A gene polymorphisms may serve as a novel marker for identifying the risk of developing TB in the Chinese Han population.
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Wang JJ, Shi YP, Yue H, Chun W, Zou LP. CTLA-4 exon 1 +49A/G polymorphism is associated with renal involvement in pediatric Henoch-Schönlein purpura. Pediatr Nephrol 2012; 27:2059-2064. [PMID: 22700162 DOI: 10.1007/s00467-012-2216-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2012] [Revised: 04/26/2012] [Accepted: 04/27/2012] [Indexed: 10/28/2022]
Abstract
BACKGROUND Henoch-Schönlein purpura (HSP) is a multisystemic vasculitis of unknown etiology. Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and CD28 have been reported to be important candidate genes for conferring susceptibility to autoimmunity. In this study, we investigated the correlation of CTLA-4 and CD28 gene polymorphisms with HSP in children with and without renal involvement. METHODS The CTLA-4 exon 1 +49A/G, promoter -318C/T and CD28 IVS3 +17T/C single nucleotide polymorphisms (SNPs) were genotyped in 110 children with HSP and 90 ethnically matched healthy controls through restriction fragment-length polymorphism (RFLP). RESULTS The CTLA-4 (+49) GG genotype and G allele (GG + AG genotype) were more common in HSP patients with renal involvement (n = 52) than in HSP patients without renal involvement (n = 58) (P = 0.019 and 0.001, respectively). There were no significant differences in the prevalence of CTLA-4 (+49 A/G), (-318C/T) and CD28 IVS3 (+17 /T/C) polymorphisms between HSP patients and controls. CONCLUSIONS Our findings suggest that the CTLA-4 +49 GG genotype and G allele may contribute to increased risk for the development of renal damage in HSP patients.
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Affiliation(s)
- Jian-Jun Wang
- Department of Pediatrics, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, 637000, People's Republic of China
| | - Yan-Ping Shi
- Department of Traditional Chinese Medicine, Xi'an Children's Hospital, Xi'an University of Medicine, Xi'an, Shanxi, 710033, People's Republic of China
| | - Huang Yue
- Department of Pediatrics, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, 637000, People's Republic of China
| | - Wu Chun
- Department of Pediatrics, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, 637000, People's Republic of China
| | - Li-Ping Zou
- Department of Pediatrics, Chinese PLA General Hospital, Beijing, 100853, People's Republic of China.
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Li X, Zhang C, Zhang J, Zhang Y, Wu Z, Yang L, Xiang Z, Qi Z, Zhang X, Xiao X. Polymorphisms in the CTLA-4 gene and rheumatoid arthritis susceptibility: a meta-analysis. J Clin Immunol 2012; 32:530-9. [PMID: 22354566 DOI: 10.1007/s10875-012-9650-y] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2011] [Accepted: 10/25/2011] [Indexed: 01/07/2023]
Abstract
INTRODUCTION The +49A/G polymorphism and CT60 polymorphism in the CTLA-4 gene have been extensively examined for the association with rheumatoid arthritis (RA); however, results of different studies have been inconclusive. The aim of this study is to comprehensively evaluate the genetic risks of +49A/G and CT60 polymorphisms in the CTLA-4 gene for RA. METHODS A meta-analysis was carried out to analyze the association of +49A/G and CT60 polymorphisms with RA risk. RESULTS A total of 30 case-control studies in 20 articles were included in this meta-analysis. The results indicated that the variant G allele carriers (GG + GA) of +49A/G polymorphism had an 18% increased risk of RA when compared with the homozygote AA (odds ratio (OR) = 1.18, 95% confidence interval (CI): 1.04-1.34 for GG + AG vs. AA). In addition, the variant CT60 A allele carriers of CT60 polymorphism had a 14% decreased risk of RA when compared with the homozygote GG (OR = 0.86, 95%CI = 0.78-0.95 for AA + AG vs. GG). In the subgroup analysis by ethnicity, significant elevated RA risks were associated with +49G allele carriers in Asians, but not in Europeans. However, for CT60 polymorphism, significant decreased RA risks were associated with CT60 A allele carriers in Europeans, but not in Asians. CONCLUSIONS This meta-analysis suggested that the +49A/G and CT60 polymorphisms in the CTLA-4 gene may be risk factors for RA.
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Affiliation(s)
- Xiaobo Li
- The 452nd Military Hospital of China, Chengdu, Sichuan, 610041, China.
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Association between the CTLA-4 +49 A/G polymorphism and susceptibility to rheumatoid arthritis: a meta-analysis. Mol Biol Rep 2011; 39:5599-605. [DOI: 10.1007/s11033-011-1364-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2011] [Accepted: 12/12/2011] [Indexed: 10/14/2022]
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