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Duc Nguyen H, Ardeshir A, Fonseca VA, Kim WK. Cluster of differentiation molecules in the metabolic syndrome. Clin Chim Acta 2024; 561:119819. [PMID: 38901629 DOI: 10.1016/j.cca.2024.119819] [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: 05/09/2024] [Revised: 06/12/2024] [Accepted: 06/13/2024] [Indexed: 06/22/2024]
Abstract
Metabolic syndrome (MetS) represents a significant public health concern due to its association with an increased risk of cardiovascular disease, type 2 diabetes, and other serious health conditions. Despite extensive research, the underlying molecular mechanisms contributing to MetS pathogenesis remain elusive. This review aims to provide a comprehensive overview of the molecular mechanisms linking MetS and cluster of differentiation (CD) markers, which play critical roles in immune regulation and cellular signaling. Through an extensive literature review with a systematic approach, we examine the involvement of various CD markers in MetS development and progression, including their roles in adipose tissue inflammation, insulin resistance, dyslipidemia, and hypertension. Additionally, we discuss potential therapeutic strategies targeting CD markers for the management of MetS. By synthesizing current evidence, this review contributes to a deeper understanding of the complex interplay between immune dysregulation and metabolic dysfunction in MetS, paving the way for the development of novel therapeutic interventions.
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Affiliation(s)
- Hai Duc Nguyen
- Division of Microbiology, Tulane National Primate Research Center, Tulane University, Covington, LA, USA
| | - Amir Ardeshir
- Division of Microbiology, Tulane National Primate Research Center, Tulane University, Covington, LA, USA; Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA, USA
| | - Vivian A Fonseca
- Department Endocrinology Metabolism & Diabetes, Tulane University School of Medicine, New Orleans, LA, USA
| | - Woong-Ki Kim
- Division of Microbiology, Tulane National Primate Research Center, Tulane University, Covington, LA, USA; Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA, USA.
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Akhtar MS. The Variant Allele Frequency of CTLA-4 rs11571317 (-658 C/T) Polymorphism With Colorectal Cancer Susceptibility in the Saudi Population and Other Ethnic Groups. Cureus 2023; 15:e50091. [PMID: 38186404 PMCID: PMC10770638 DOI: 10.7759/cureus.50091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/05/2023] [Indexed: 01/09/2024] Open
Abstract
The single nucleotide polymorphisms (SNPs) in the promoter region of the cytotoxic T-lymphocyte antigen-4 (CTLA-4) gene are directly associated with the progression and onset of various human cancers. These SNPs are important prognostic biomarkers for the prediction and early onset of cancer risk. The variant frequency of the CTLA-4 rs11571317 (-658 C/T) polymorphism may be affecting the various ethnic groups differently. In the present study, the allelic frequency distribution of -658 C/T polymorphism was assessed in the population of Saudi Arabia and compared with other world populations. The data from different cancers were extracted from case-control studies in the various ethnic groups by using PubMed (MEDLINE) and similar web databases. The frequency of CTLA-4 rs11571317 (-658 C/T) variant allele (T) was observed to be 25.5% and different frequencies were found significant for India (p = 0.001), USA (p = 0.03), and China (p = 0.04), when the prevalence of Saudi Arabian population was compared to that of other population groups. The current finding reveals that there is a distinct pattern of CTLA-4 rs11571317 (-658 C/T) polymorphism variant allele in the populations of Saudi Arabia, may be because of the differences in ethnicity. The observed findings can help in the assessment of the risk for the population harboring the risk allele of rs11571317 (-658 C/T) SNP and toward their subsequent susceptibility to cancer.
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Affiliation(s)
- Mohammad Salman Akhtar
- Department of Basic Medical Sciences, Faculty of Applied Medical Sciences, Al Baha University, Al Baha, SAU
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A negative association of CTLA-4 genetic variant (rs11571317) with breast cancer risk in Moroccan population. GENE REPORTS 2022. [DOI: 10.1016/j.genrep.2022.101513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Kailashiya J, Kailashiya V, Singh U. CTLA4 gene polymorphism and its association with disease occurrence, clinical manifestations, serum markers and cytokine levels in SLE patients from North India. Indian J Dermatol 2022; 67:311. [DOI: 10.4103/ijd.ijd_82_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
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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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Investigation of the relationship between CTLA4 and the tumor suppressor RASSF1A and the possible mediating role of STAT4 in a cohort of Egyptian patients infected with hepatitis C virus with and without hepatocellular carcinoma. Arch Virol 2021; 166:1643-1651. [PMID: 33796885 DOI: 10.1007/s00705-021-04981-8] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Accepted: 12/19/2020] [Indexed: 12/17/2022]
Abstract
The Ras association domain family 1 isoform A (RASSF1A), cytotoxic T lymphocyte antigen 4 (CTLA-4), and signal transducer and activator of transcription 4 (STAT4) genes play a role in regulating the cell cycle, apoptosis, and the autoimmune response against cancer. We investigated the genotype frequency and the possible association of the rs2073498 (RASSF1A), rs5742909 (CTLA-4) and rs7574865 (STAT4) genetic variants with hepatitis C virus (HCV)-G4-mediated hepatocellular carcinoma (HCC) progression in Egyptian patients. Fifty patients with HCV infection, 50 patients with HCV-mediated HCC, and 50 age- and sex-matched healthy controls were recruited. The investigated variants were genotyped based on polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). The Ser133 mutant G4 variant of the rs2073498 SNP in RASSF1A exhibited a positive correlation with HCC incidence risk (OR = 0.571, 95% CI = 0.175-1.865, P < 0.001). The rs7574865 variant in STAT4 (G/T) occurred frequently in both HCV groups, with a significant incidence risk (OR = 1.583, 95% CI = 1.123-2.232, P = 0.005). The rs5742909 change in CTLA4 (C/T) did not show a significant difference between HCV-mediated HCC cases and the control group (OR = 4.5, 95% CI = 1.326-15.277, P > 0.001). Activation of the immune checkpoint gene CTLA4 or polymorphism in the encoded CTLA4 protein causes phosphorylation of kinases needed for RAS gene activation. This in turn downregulates the tumor suppressor RASSF1, inhibiting apoptosis and leading to HCC development, indicating a negative impact of CTLA4 gene polymorphism on HCV-mediated HCC cases. A major determinant of disease progression could be immune system genetic variants, together with the presence of costimulatory factors. The rs2073498 and rs7574865 variations in the RASSF1A and STAT4 genes, respectively, could be genetic susceptibility factors for Egyptian patients with HCV-mediated HCC.
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A significant association of the CTLA4 gene variants with the risk of autoimmune Graves' disease in ethnic Kashmiri population. Cell Immunol 2019; 347:103995. [PMID: 31708111 DOI: 10.1016/j.cellimm.2019.103995] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 10/08/2019] [Accepted: 10/19/2019] [Indexed: 01/03/2023]
Abstract
Graves' disease (GD) is the commonest cause of hyperthyroidism in populations with adequate iodine intake. It results from an abnormality in the immune system, which produces unique antibodies causing over production of thyroid hormones and glandular hyperplasia in individuals with genetic susceptibility. The Cytotoxic Lymphocyte Associated Antigen-4 (CTLA4) gene product serves the important function of immunomodulation, thereby helping in maintenance of peripheral self-tolerance. Studies on the association of the CTLA4 SNPs with GD have shown variations in the results from different populations. Since no such study has been carried out in ethnic Kashmiri population, we aimed to study a possible association of the CTLA4 SNPs (+49 A/G, -318C/T, CT 60 A/G and -1661 A/G) with GD. A total of 285 individuals (135 patients with GD and 150 healthy individuals) were genotyped using PCR-RFLP method and the results showed statistically significant differences in genotypic and allelic frequencies of cases and controls for + 49 A/G SNP (p=<0.001; OR = 5.14; CI = 2.17-12.19) and CT 60 A/G SNP (p = < 0.001; OR = 6.9; CI = 2.8-16.6), while -318C/T and -1661 A/G SNPs showed no significant association. We also studied the mRNA expression of the CTLA4 in patients with GD and healthy individuals by Real-Time PCR and found a decreased expression of the CTLA4 mRNA in PBMCs of patients with GD as compared to healthy controls with a -3.71-fold change. We conclude that the CTLA4 + 49 A/G and CT 60 A/G SNPs have a significant association with the risk of GD development in Kashmiri population and CTLA4 mRNA expression is significantly decreased in GD.
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Abdulqader AMR, Mohammed AI, Rachid S. Polymorphisms in the cytotoxic T lymphocyte-associated protein-4 immune regulatory gene and their impact on inhibitor development in patients with hemophilia A. J Int Med Res 2019; 47:4981-4992. [PMID: 31524022 PMCID: PMC6833422 DOI: 10.1177/0300060519860329] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Objective The development of inhibitors against infused factor VIII represents the most severe complication of substitution therapy in hemophilia A (HA) patients. Data on risk factors for inhibitor formation in Iraqi Kurdish patients with HA are unavailable. This study aimed to evaluate the impact of two single nucleotide polymorphisms (SNPs) in an immune regulatory gene in the emergence of inhibitors. Methods We focused on 126 patients with either severe or mild/moderate HA presenting with and without inhibitors. We analyzed the frequency of two polymorphisms in the cytotoxic T lymphocyte-associated protein-4 gene (CTLA-4; CTLA-4-318C > T and CTLA-4 + 49A > G). Genotyping was performed using restriction fragment length polymorphism–PCR and direct sequencing. Results We found no significant correlation between the CTLA-4-318 C > T T allele and inhibitor development among patients with severe or mild/moderate HA. However, a significantly high inhibitor risk was detected for the CTLA-4 + 49 A > G G allele (odds ratio [OR] = 3.1, 95% confidence interval [CI] = 1.383–7.024) and (OR = 4, 95% CI = 1.719–9.437) among patients with severe and mild/moderate HA, respectively. Conclusion We conclude that the CTLA-4 +49 A > G SNP plays a substantial role as a potential risk determinant for inhibitor formation in Iraqi Kurdish patients with HA.
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Affiliation(s)
- Aveen M Raouf Abdulqader
- Department of Pathology, College of Medicine, University of Sulaymaniyah, Sulaymaniyah 46001, Iraq
| | - Ali Ibrahim Mohammed
- Department of Pathology, College of Medicine, University of Sulaymaniyah, Sulaymaniyah 46001, Iraq
| | - Shwan Rachid
- Charmo Center for Research, Training and Consultancy, Charmo University, Chamchamal, Sulaymaniyah 46023, Iraq
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Kailashiya V, Sharma HB, Kailashiya J. Role of CTLA4 A49G polymorphism in systemic lupus erythematosus and its geographical distribution. J Clin Pathol 2019; 72:659-662. [DOI: 10.1136/jclinpath-2019-206013] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 07/03/2019] [Accepted: 07/11/2019] [Indexed: 01/15/2023]
Abstract
CTLA-4 (cytotoxic T-lymphocyte-associated protein-4) or CD152 is an inhibitory receptor expressed constitutively on CD4+ CD25+ T regulatory lymphocytes and transiently on activated CD4+ and CD8+ T lymphocytes. Its inhibitory function promotes long-lived anergy in immune cells and prevents autoimmunity. Therefore, it plays a crucial role in T cell-mediated autoimmunity, and thus in susceptibility to autoimmune diseases, including systemic lupus erythematosus (SLE). It is encoded by CTLA4 gene in humans. AtoG polymorphism at position +49 of CTLA4 gene is the only polymorphism which changes amino acid sequence from alanine to threonine in the leader sequence, which may affect the function of CTLA-4. Association of CTLA4 polymorphisms with SLE has been investigated in several reports in different ethnic populations from different countries, which have shown highly inconsistent findings. In this review, we have compiled previous studies which have reported the association of CTLA4 A49G polymorphism in SLE and its geographical distribution.
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Gunavathy N, Asirvatham A, Chitra A, Jayalakshmi M. Association of CTLA-4 and CD28 Gene Polymorphisms with Type 1 Diabetes in South Indian Population. Immunol Invest 2019; 48:659-671. [PMID: 31094250 DOI: 10.1080/08820139.2019.1590395] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Each functional gene illustrates the complexity of genetic predisposition to disease; however, it is difficult to bring out these traits with reference to autoimmune diseases like type 1 diabetes (T1D). To find out the genetic contribution of CTLA-4 + 49A/G, CTLA-4 -318C/T and CD28 + 17T/C polymorphisms toward T1D, the present study was performed with 124 T1D patients, 54 siblings and 125 parents including 39 trios in South Indian population. The association and linkage of CTLA-4 + 49A/G, CTLA-4 -318C/T and CD28 + 17T/C polymorphisms with T1D were analyzed and transmission disequilibrium test was performed. CTLA-4 G allele carrying genotypes (GG+AG) showed a higher risk association and can be considered as susceptible to develop T1D among patients with age at diagnosis from 0 to 10 years as compared to siblings (OR = 2.9; pc = 0.047) and parents (OR = 2.7; pc = 0.036). On the other hand, a strong protection against the disease (age at diagnosis; 0-10 years) was observed with CTLA-4 + 49AA genotype (OR = 0.37; pc = 0.036) and combined AA/CC genotype (OR = 0.31; pc = 0.034) of CTLA-4 + 49A/G and CTLA-4 -318C/T polymorphisms. However, a significant association was not observed between CTLA-4 -318C/T and CD28 + 17T/C polymorphisms and T1D. This family-based study reports a strong association between possible genotypes of CTLA-4 gene polymorphism and T1D in South Indian population, particularly in younger individuals.
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Affiliation(s)
- Nagarajan Gunavathy
- a Department of Immunology, School of Biological Sciences , Madurai Kamaraj University , Madurai , Tamil Nadu , India
| | - Arthur Asirvatham
- b Department of Diabetology , Government Rajaji Hospital , Madurai , Tamil Nadu , India
| | - Ayyappan Chitra
- c Institute of Child health and Research Centre , Government Rajaji Hospital , Madurai , Tamil Nadu , India
| | - Mariakuttikan Jayalakshmi
- a Department of Immunology, School of Biological Sciences , Madurai Kamaraj University , Madurai , Tamil Nadu , India
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Lingel H, Brunner-Weinzierl MC. CTLA-4 (CD152): A versatile receptor for immune-based therapy. Semin Immunol 2019; 42:101298. [DOI: 10.1016/j.smim.2019.101298] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Accepted: 08/05/2019] [Indexed: 12/31/2022]
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12
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Fonctions de CD28, CTLA-4 et PD-1. Bull Cancer 2019; 105 Suppl 1:S3-S15. [PMID: 30595196 DOI: 10.1016/s0007-4551(18)30385-0] [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: 11/20/2022]
Abstract
FUNCTIONS OF CD28, CTLA-4 AND PD-1: 2018 is time in between since immunotherapies are recognized as treatments in cancer even in patients where they were supposed to be not or poorly active. We will focus on a review on facts meaning data reproduced during the last thirty-five years and what they have provided. We will focus on these data and question them regarding the novel and unexpected clinical that were not anticipated by the preclinical data. Consequently we will mainly present data regarding CD28, CTLA-4PD-1 and their ligands. We will not address the complex network of proteins involved in cosignalling in tissues.
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Schildberg FA, Klein SR, Freeman GJ, Sharpe AH. Coinhibitory Pathways in the B7-CD28 Ligand-Receptor Family. Immunity 2017; 44:955-72. [PMID: 27192563 DOI: 10.1016/j.immuni.2016.05.002] [Citation(s) in RCA: 431] [Impact Index Per Article: 53.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Indexed: 01/10/2023]
Abstract
Immune responses need to be controlled for optimal protective immunity and tolerance. Coinhibitory pathways in the B7-CD28 family provide critical inhibitory signals that regulate immune homeostasis and defense and protect tissue integrity. These coinhibitory signals limit the strength and duration of immune responses, thereby curbing immune-mediated tissue damage, regulating resolution of inflammation, and maintaining tolerance to prevent autoimmunity. Tumors and microbes that cause chronic infections can exploit these coinhibitory pathways to establish an immunosuppressive microenvironment, hindering their eradication. Advances in understanding T cell coinhibitory pathways have stimulated a new era of immunotherapy with effective drugs to treat cancer, autoimmune and infectious diseases, and transplant rejection. In this review we discuss the current knowledge of the mechanisms underlying the coinhibitory functions of pathways in the B7-CD28 family, the diverse functional consequences of these inhibitory signals on immune responses, and the overlapping and unique functions of these key immunoregulatory pathways.
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Affiliation(s)
- Frank A Schildberg
- Department of Microbiology and Immunobiology, and Evergrande Center for Immunologic Diseases, Harvard Medical School, Boston, MA 02115, USA
| | - Sarah R Klein
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
| | - Gordon J Freeman
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
| | - Arlene H Sharpe
- Department of Microbiology and Immunobiology, and Evergrande Center for Immunologic Diseases, Harvard Medical School, Boston, MA 02115, USA.
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Marchione VD, Zuccoli JR, Abelleyro MM, Radic CP, Neme D, Candela M, de Tezanos Pinto M, De Brasi CD, Rossetti LC. A prevalent CTLA4 missense variant significantly associates with inhibitor development in Argentine patients with severe haemophilia A. Haemophilia 2017; 23:e166-e169. [PMID: 28220572 DOI: 10.1111/hae.13194] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/13/2017] [Indexed: 01/22/2023]
Affiliation(s)
- V D Marchione
- Instituto de Medicina Experimental (IMEX) CONICET-Academia Nacional de Medicina, Buenos Aires, Argentina
| | - J R Zuccoli
- CIPYP (Centro de Investigaciones sobre Porfirinas y Porfirias), Buenos Aires, Argentina
| | - M M Abelleyro
- Instituto de Medicina Experimental (IMEX) CONICET-Academia Nacional de Medicina, Buenos Aires, Argentina
| | - C P Radic
- Instituto de Medicina Experimental (IMEX) CONICET-Academia Nacional de Medicina, Buenos Aires, Argentina
| | - D Neme
- Fundación de la Hemofilia Alfredo Pavlovsky, Buenos Aires, Argentina
| | - M Candela
- Instituto de Investigaciones Hematológicas Mariano R Castex, Academia Nacional de Medicina, Buenos Aires, Argentina
| | - M de Tezanos Pinto
- Fundación de la Hemofilia Alfredo Pavlovsky, Buenos Aires, Argentina.,Instituto de Investigaciones Hematológicas Mariano R Castex, Academia Nacional de Medicina, Buenos Aires, Argentina
| | - C D De Brasi
- Instituto de Medicina Experimental (IMEX) CONICET-Academia Nacional de Medicina, Buenos Aires, Argentina.,Instituto de Investigaciones Hematológicas Mariano R Castex, Academia Nacional de Medicina, Buenos Aires, Argentina
| | - L C Rossetti
- Instituto de Medicina Experimental (IMEX) CONICET-Academia Nacional de Medicina, Buenos Aires, Argentina
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Fattah SA, Ghattas MH, Saleh SM, Abo-Elmatty DM. Cytotoxic T-lymphocyte-associated protein 4 gene polymorphism is related to rheumatoid arthritis in Egyptian population. Arch Physiol Biochem 2017; 123:50-53. [PMID: 27808571 DOI: 10.1080/13813455.2016.1230135] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
CONTEXT Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a CD28-family receptor expressed on T-cells which suppresses T cell proliferation. CTLA-4 -318C/T polymorphism is involved in regulation of CTLA-4 expression. OBJECTIVE The study aimed to investigate the genetic association of CTLA-4 -318C/T polymorphism with rheumatoid arthritis (RA) and the activity and severity of the disease in the Egyptian population. METHODS A single nucleotide polymorphism (rs5742909) in CTLA-4 was genotyped in 100 RA patients and 100 healthy controls using polymerase chain reaction-restriction fragment length polymorphism. Diagnostic tests were measured for RA patients. RESULTS The frequency of T allele in RA patients was significantly higher than in the control subjects (p = 0.002). CT and TT genotypes had high C-reactive protein, erythrocyte sedimentation rate and disease activity score 28 while CC genotype had a high rheumatoid factor. CONCLUSION A minor allele of CTLA-4 rs5742909 polymorphism was associated with RA and the activity but not the severity of the disease.
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Affiliation(s)
- Shaimaa A Fattah
- a Department of Biochemistry , Faculty of Pharmacy, Suez Canal University , Ismailia , Egypt and
| | - Maivel H Ghattas
- b Department of Medical Biochemistry , Faculty of Medicine, Port Said University , Port Said , Egypt
| | - Samy M Saleh
- a Department of Biochemistry , Faculty of Pharmacy, Suez Canal University , Ismailia , Egypt and
| | - Dina M Abo-Elmatty
- a Department of Biochemistry , Faculty of Pharmacy, Suez Canal University , Ismailia , Egypt and
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Ting WH, Chien MN, Lo FS, Wang CH, Huang CY, Lin CL, Lin WS, Chang TY, Yang HW, Chen WF, Lien YP, Cheng BW, Lin CH, Chen CC, Wu YL, Hung CM, Li HJ, Chan CI, Lee YJ. Association of Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA4) Gene Polymorphisms with Autoimmune Thyroid Disease in Children and Adults: Case-Control Study. PLoS One 2016; 11:e0154394. [PMID: 27111218 PMCID: PMC4844099 DOI: 10.1371/journal.pone.0154394] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2015] [Accepted: 04/11/2016] [Indexed: 11/18/2022] Open
Abstract
Autoimmune thyroid disease (AITD), including Graves disease (GD) and Hashimoto disease (HD), is an organ-specific autoimmune disease with a strong genetic component. Although the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) polymorphism has been reported to be associated with AITD in adults, few studies have focused on children. The aim of our study was to investigate whether the CTLA4 polymorphisms, including -318C/T (rs5742909), +49A/G (rs231775), and CT60 (rs3087243), were associated with GD and HD in Han Chinese adults and children. We studied 289 adult GD, 265 pediatric GD, 229 pediatric HD patients, and 1058 healthy controls and then compared genotype, allele, carrier, and haplotype frequencies between patients and controls. We found that CTLA4 SNPs +49A/G and CT60 were associated with GD in adults and children. Allele G of +49A/G was significantly associated with GD in adults (odds ratio [OR], 1.50; 95% confidence interval [CI], 1.21–1.84; corrected P value [Pc] < 0.001) and children (OR, 1.42; 95% CI, 1.15–1.77; Pc = 0.002). Allele G of CT60 also significantly increased risk of GD in adults (OR, 1.63; 95% CI, 1.27–2.09; Pc < 0.001) and GD in children (OR, 1.58; 95% CI, 1.22–2.04; Pc < 0.001). Significant linkage disequilibrium was found between +49A/G and CT60 in GD and control subjects (D’ = 0.92). Our results showed that CTLA4 was associated with both GD and HD and played an equivalent role in both adult and pediatric GD in Han Chinese population.
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Affiliation(s)
- Wei-Hsin Ting
- Department of Pediatrics, MacKay Children’s Hospital, Taipei, Taiwan
- Department of Medicine, MacKay Medical College, New Taipei City, Taiwan
- MacKay Junior College of Medicine, Nursing and Management, New Taipei City, Taiwan
| | - Ming-Nan Chien
- Department of Endocrinology and Metabolism, MacKay Memorial Hospital, Taipei, Taiwan
- Department of Medicine, MacKay Medical College, New Taipei City, Taiwan
- Institute of Mechatronic Engineering, National Taipei University of Technology, Taipei, Taiwan
- MacKay Junior College of Medicine, Nursing and Management, New Taipei City, Taiwan
| | - Fu-Sung Lo
- Department of Pediatrics, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan
- College of Medicine, Chang Gung University, Tao-Yuan, Taiwan
| | - Chao-Hung Wang
- Department of Endocrinology and Metabolism, MacKay Memorial Hospital, Taipei, Taiwan
| | - Chi-Yu Huang
- Department of Pediatrics, MacKay Children’s Hospital, Taipei, Taiwan
- Department of Medicine, MacKay Medical College, New Taipei City, Taiwan
| | - Chiung-Ling Lin
- Department of Medical Research, MacKay Memorial Hospital Tamsui, New Taipei City, Taiwan
| | - Wen-Shan Lin
- Department of Medical Research, MacKay Memorial Hospital Tamsui, New Taipei City, Taiwan
| | - Tzu-Yang Chang
- Department of Medical Research, MacKay Memorial Hospital Tamsui, New Taipei City, Taiwan
| | - Horng-Woei Yang
- Department of Medical Research, MacKay Memorial Hospital Tamsui, New Taipei City, Taiwan
| | - Wei-Fang Chen
- Department of Medical Research, MacKay Memorial Hospital Tamsui, New Taipei City, Taiwan
| | - Ya-Ping Lien
- Department of Medical Research, MacKay Memorial Hospital Tamsui, New Taipei City, Taiwan
| | - Bi-Wen Cheng
- Department of Pediatrics, MacKay Memorial Hospital HsinChu, Hsin-Chu, Taiwan
| | - Chao-Hsu Lin
- Department of Pediatrics, MacKay Memorial Hospital HsinChu, Hsin-Chu, Taiwan
| | - Chia-Ching Chen
- Department of Pediatrics, Chiayi Christian Hospital, Chia-Yi, Taiwan
| | - Yi-Lei Wu
- Department of Pediatrics, Changhua Christian Hospital, Chang-Hua, Taiwan
| | - Chen-Mei Hung
- Department of Pediatrics, Hsinchu Cathay General Hospital, Hsin-Chu, Taiwan
| | - Hsin-Jung Li
- Department of Pediatrics, St. Martin De Porres Hospital, Chia-Yi, Taiwan
| | - Chon-In Chan
- Department of Pediatrics, MacKay Children’s Hospital, Taipei, Taiwan
| | - Yann-Jinn Lee
- Department of Pediatrics, MacKay Children’s Hospital, Taipei, Taiwan
- Department of Medicine, MacKay Medical College, New Taipei City, Taiwan
- Department of Medical Research, MacKay Memorial Hospital Tamsui, New Taipei City, Taiwan
- Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Institute of Biomedical Sciences, MacKay Medical College, New Taipei City, Taiwan
- * E-mail:
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Ksiaa Cheikhrouhou L, Lakhoua-Gorgi Y, Sfar I, Jendoubi-Ayed S, Aouadi H, Makhlouf M, Ayed K, Ben Abdallah T. Natural evolution of hepatitis C virus infection in hemodialysis Tunisian patients and CTLA-4 SNP's. World J Gastroenterol 2015; 21:10150-10158. [PMID: 26401079 PMCID: PMC4572795 DOI: 10.3748/wjg.v21.i35.10150] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2015] [Revised: 04/01/2015] [Accepted: 06/10/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To analyze the polymorphisms of CTLA-4 gene involved in the response against hepatitis C virus (HCV) infection.
METHODS: We recruited 500 hemodialysed patients from several hemodialysis centers, all HCV-antibody positive, spread over different regions of Tunisia, as part of a national survey in 2008 conducted in the laboratory of immunology at the Charles Nicolle hospital Tunisia, classified into two groups G1 (PCR+) and G2 (PCR-) according to the presence or absence of viral RNA. Of these patients, 307 were followed prospectively on a viral molecular level over a period from 2002 to 2008, divided into two groups based on the persistence and viral clearance. PCR-RFLP was performed for the analysis of SNPs (+49) A/G and (+6230) G/A CTLA-4 for these 500 patients and 358 healthy controls.
RESULTS: Analysis of clinical and virological characteristics of our cohort suggests a nosocomial infection in our hemodialysed patients with transfusion history as a primary risk factor and a predominance of genotype 1b. The haplotype analysis revealed an increase of frequencies of GG (+49)/(CT60) CTLA-4 in the entire patients group compared to controls (P = 0.0036 and OR = 1.42; 95%CI: 1.12-1.79, respectively). This haplotype is therefore associated with susceptibility to HCV infection.
CONCLUSION: Our study suggests a possible role of CTLA-4 polymorphisms in the outcome of HCV infection in the Tunisian hemodialysed population.
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18
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Karimi MH, Ebadi P, Pourfathollah AA. Association of cytokine/costimulatory molecule polymorphism and allograft rejection: a comparative review. Expert Rev Clin Immunol 2014; 9:1099-112. [PMID: 24168415 DOI: 10.1586/1744666x.2013.844462] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
One reason for genetic variations among human individuals is SNP which may confer diverse disease susceptibility or resistance in a population. Genetic variations in a key immunoregulatory agent can manifest various immunological responses, such as graft rejection. In fact, the outcome of organ transplantation can be impacted by several genetic causes including polymorphisms in genes encoding cytokines and costimulatory molecules in the donor or recipient. Thus, it can be helpful to contemplate the SNPs relating to these immunological determinants in order to achieve an improved transplantation therapy.
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Affiliation(s)
- Mohammad H Karimi
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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19
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Imran M, Manzoor S, Ashraf J, Khalid M, Tariq M, Khaliq HM, Azam S. Role of viral and host factors in interferon based therapy of hepatitis C virus infection. Virol J 2013; 10:299. [PMID: 24079723 PMCID: PMC3849893 DOI: 10.1186/1743-422x-10-299] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2013] [Accepted: 09/24/2013] [Indexed: 02/07/2023] Open
Abstract
The current standard of care (SOC) for hepatitis C virus (HCV) infection is the combination of pegylated interferon (PEG-IFN), Ribavirin and protease inhibitor for HCV genotype 1. Nevertheless, this treatment is successful only in 70-80% of the patients. In addition, the treatment is not economical and is of immense physical burden for the subject. It has been established now, that virus-host interactions play a significant role in determining treatment outcomes. Therefore identifying biological markers that may predict the treatment response and hence treatment outcome would be useful. Both IFN and Ribavirin mainly act by modulating the immune system of the patient. Therefore, the treatment response is influenced by genetic variations of the human as well as the HCV genome. The goal of this review article is to summarize the impact of recent scientific advances in this area regarding the understanding of human and HCV genetic variations and their effect on treatment outcomes. Google scholar and PubMed have been used for literature research. Among the host factors, the most prominent associations are polymorphisms within the region of the interleukin 28B (IL28B) gene, but variations in other cytokine genes have also been linked with the treatment outcome. Among the viral factors, HCV genotypes are noteworthy. Moreover, for sustained virological responses (SVR), variations in core, p7, non-structural 2 (NS2), NS3 and NS5A genes are also important. However, all considered single nucleotide polymorphisms (SNPs) of IL28B and viral genotypes are the most important predictors for interferon based therapy of HCV infection.
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Affiliation(s)
- Muhammad Imran
- Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology (NUST), 44000 Islamabad, Pakistan.
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20
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Krupińska J, Urbanowicz W, Kaczmarczyk M, Kulig G, Sowińska-Przepiera E, Andrysiak-Mamos E, Syrenicz A. Association between genetic mutations and the development of autoimmune thyroiditis in patients with chronic hepatitis C treated with interferon alpha. Thyroid Res 2012; 5:10. [PMID: 23072316 PMCID: PMC3579705 DOI: 10.1186/1756-6614-5-10] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2012] [Accepted: 10/01/2012] [Indexed: 11/10/2022] Open
Abstract
UNLABELLED BACKGROUND Considerable progress was made by the introduction of interferon to the treatment of chronic hepatitis C virus infection. This treatment, however, is associated with the risk of developing or exacerbating autoimmune diseases, with chronic autoimmune thyroiditis being one of them. The aim of our study was to evaluate the predisposition to autoimmune thyroiditis in patients with chronic hepatitis C virus during IFN-alpha therapy, depending on the presence of polymorphisms in the promoter region of CTLA-4C (-318)T gene and in exon 1 of A49G gene as well as C1858T transition of PTPN22 gene. METHODS The study was conducted in 149 patients aged between 18 and 70 years (mean of 43.9 years), including 82 men and 67 women. Control group for the assessment of the distribution of analyzed polymorphism of genotypes consisted of 200 neonates, from whom umbilical blood was drawn for the tests. The patients were divided into three groups: group 1 consisted of 114 patients without thyroid impairment before and during IFN-alpha therapy, group 2 contained 9 patients with AT with the onset prior to IFN-alpha treatment, and group 3 comprised 26 patients with AT starting after the beginning of IFN-alpha therapy. RESULTS The frequency of C1858Tand C(-318)T genotypes observed in the study group did not differ significantly from control group. A significant difference, however, was found for A49G polymorphism. CONCLUSIONS No association was demonstrated between the occurrence of autoimmune thyroiditis with the onset during IFN-alpha therapy and the presence of polymorphisms within CTLA-4 C(-318)T gene in the promoter region and A49G in exon 1, as well as C1858T transition of PTPN22 gene.
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Affiliation(s)
- Janina Krupińska
- Department of Endocrinology, Metabolic Diseases and Internal Diseases, Pomeranian Medical University, Szczecin, Poland.
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21
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Agostini D, Rosset C, Botton MR, Kappel DB, Vieira IA, Gorziza RP, Salzano FM, Bandinelli E. Immune system polymorphisms and factor VIII inhibitor formation in Brazilian haemophilia A severe patients. Haemophilia 2012; 18:e416-8. [DOI: 10.1111/hae.12015] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/15/2012] [Indexed: 12/01/2022]
Affiliation(s)
- D Agostini
- Departamento de Genética, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
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22
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Houshmand B, Rafiei A, Hajilooi M. Influence of cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms in periodontitis. Arch Oral Biol 2012; 57:1218-24. [DOI: 10.1016/j.archoralbio.2012.03.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2011] [Revised: 03/04/2012] [Accepted: 03/11/2012] [Indexed: 10/28/2022]
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Gunesacar R, Erken E, Dinkci S. Analysis of cytotoxic T lymphocyte antigen-4 (CTLA-4) promoter -318C/T and +49A/G gene polymorphisms in Turkish patients with familial Mediterranean fever. Cell Biochem Biophys 2012; 65:181-6. [PMID: 22923220 DOI: 10.1007/s12013-012-9416-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
Either the role of the adaptive immune system or the interaction between innate and adaptive immune systems in familial Mediterranean fever (FMF) is not clear so far. So, we planned to search for the interaction between the innate and adaptive immune systems in the pathogenesis of FMF by investigating polymorphism for CTLA-4 gene, which plays a role in controlling antigen presentation to T cells. We also aimed to investigate whether there is an association between -318C/T and +49A/G polymorphisms in the CTLA-4 gene and the main clinical features of the disease. 75 FMF patients and 179 controls were studied. Polymorphism was detected by the PCR-RFLP technique. The CT genotype and T allele frequencies of the -318C/T polymorphism and the haplotype frequency for the -318T/+49A in the CTLA-4 gene were higher in the FMF (21.3, 21.3, and 10.7 %) when compared with the controls (10.6, 10.6, and 5.3 %; P = 0.029, 0.044, and 0.029). However, these differences did not reach a statistically significant level after the Bonferroni correction. A significant linkage disequilibrium was found between the -318C/T and +49A/G polymorphisms in the CTLA-4 gene (D' = 0.997, r(2) = 0.027, P = 0.0002). Genotype and carrier frequencies of the CTLA-4 gene +49A/G polymorphism were not significantly different between FMF patients and healthy controls. No association was found between the studied polymorphisms and the main clinical features of the disease. Our findings suggest that although not statistically significant, higher frequencies of CTLA-4 gene -318CT genotype, T allele, and -318T/+49A haplotype in FMF patients may be related to the non-autoimmune pathogenesis of FMF.
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Affiliation(s)
- Ramazan Gunesacar
- Department of Medical Biology and Genetics, Faculty of Medicine, Kahramanmaras Sutcu Imam University, Kahramanmaras, Turkey.
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24
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Chng CL, Seah LL, Khoo DHC. Ethnic differences in the clinical presentation of Graves' ophthalmopathy. Best Pract Res Clin Endocrinol Metab 2012; 26:249-58. [PMID: 22632362 DOI: 10.1016/j.beem.2011.10.004] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Ethnic differences in a number of eye conditions have been described. The literature on ethnic differences in Graves' ophthalmopathy (GO) is limited. There is some evidence to suggest Asian patients with GO may manifest milder phenotypic features of GO, with less proptosis and evidence of extraocular muscle involvement and restriction. The reasons for these differences are likely to be multifactorial and include orbital and lid anatomy, genetic background and autoimmune responses including TSH -receptor antibodies. These differences should be kept in mind when evaluating and managing patients with GO.
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Affiliation(s)
- Chiaw-Ling Chng
- Department of Endocrinology, Singapore General Hospital, Outram Road, Singapore 169608, Singapore.
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25
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Pinto P, Ghosh K, Shetty S. Immune regulatory gene polymorphisms as predisposing risk factors for the development of factor VIII inhibitors in Indian severe haemophilia A patients. Haemophilia 2012; 18:794-7. [PMID: 22630053 DOI: 10.1111/j.1365-2516.2012.02845.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/03/2012] [Indexed: 11/28/2022]
Abstract
Development of inhibitors to factor VIII, a serious complication of replacement therapy in haemophilia A patients, leads to increased bleeding, morbidity and mortality. There is no data on the risk factors for inhibitor development in Indian patients with severe haemophilia A. Our aim was to study the role of immune regulatory gene polymorphisms in the development of inhibitors. Fourteen immune regulatory gene polymorphisms (IL1β, IL4, IL10, TNFA and CTLA4) were analysed in 120 patients with severe haemophilia A, i.e. 50 inhibitor positive patients, and 70 inhibitor negative control patients, by PCR-RFLP, DNA sequencing and allele-specific PCRs. The IL10 promoter 'GCC' haplotypes overall (P: 0.002, OR: 3.452, 95% CI: 1.607-7.416), and 'GCC/ATA' (P: 0.011, OR: 3.492, 95% CI: 1.402-8.696) haplotype, associated with high and intermediate IL10 production, respectively, were significantly higher in inhibitor positive patients, whereas the 'non-GCC' haplotypes overall (P: 0.002,OR: 0.290, 95% CI 0.135-0.622) and 'ATA/ATA' haplotype (P: 0.025, OR: 0.278, 95% CI: 0.096-0.802), associated with low IL10 synthesis, were significantly higher among inhibitor negative patients. The TNFA rs1799724 C/T heterozygote prevalence was significantly higher in the inhibitor positive group (P: 0.021, OR: 3.190, 95% CI: 1.273-7.990), whereas the other polymorphisms showed no statistically significant association with the presence of inhibitors. Different immune regulatory gene polymorphisms play a significant role as possible risk factors for the development of inhibitors in severe haemophilia A patients.
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Affiliation(s)
- P Pinto
- National Institute of Immunohaematology, ICMR, KEM Hospital Campus, Parel, Mumbai, India
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26
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Danilovic DLS, Mendes-Correa MC, Lima EU, Zambrini H, K Barros R, Marui S. Correlations of CTLA-4 gene polymorphisms and hepatitis C chronic infection. Liver Int 2012; 32:803-8. [PMID: 22136395 DOI: 10.1111/j.1478-3231.2011.02694.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2011] [Revised: 09/28/2011] [Accepted: 10/29/2011] [Indexed: 02/06/2023]
Abstract
BACKGROUND Cytotoxic T lymphocyte-associated factor 4 (CTLA-4) functions as a negative regulator of T cell-mediated immune response. Molecular changes associated to CTLA-4 gene polymorphisms could reduce its ability to suppress and control lymphocyte proliferation. AIMS To evaluate the frequency of CTLA-4 gene polymorphisms in chronic hepatitis C virus (HCV) infected patients and correlate to clinical and histological findings. METHODS We evaluated 112 HCV-infected subjects prospectively selected and 183 healthy controls. Clinical and liver histological data were analysed. -318C > T, A49G and CT60 CTLA-4 single-nucleotide polymorphisms (SNPs) were studied by PCR-RFLP and AT(n) polymorphism by DNA fragment analysis by capillary electrophoresis in automatic sequencer. RESULTS Eight AT repetitions in 3'UTR region were more frequent in HCV-infected subjects. We found a positive association of -318C and + 49G with HCV genotype 3 (P = 0.008, OR 9.13, P = 0.004, OR 2.49 respectively) and an inverse association of both alleles with HCV genotype 1 (P = 0.020, OR 0.19, P = 0.002, OR 0.38 respectively). Allele + 49G was also associated to aminotransferases quotients > 3 (qALT, P = 0.034, qAST, P = 0.041). Allele G of CT60 SNP was also associated with qAST > 3 (P = 0.012). Increased number of AT repetitions was positively associated to severe necroinflammatory activity scores in liver biopsies (P = 0.045, OR 4.62). CONCLUSION CTLA-4 gene polymorphisms were associated to HCV-infection. Eight AT repetitions were more prevalent in HCV-infected subjects. -318C and + 49G alleles were associated to genotypes 1 and 3 infections and increased number of AT repetitions in 3'UTR region favoured severe necroinflammatory activity scores in liver biopsies.
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Affiliation(s)
- Debora L S Danilovic
- Unidade de Tireóide - Laboratório de Endocrinologia Celular e Molecular - LIM 25 Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
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27
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Philip B, Isabel W. Association of cytotoxic T lymphocyte-associated antigen 4 gene single nucleotide polymorphism with type 1 diabetes mellitus in Madurai population of Southern India. INDIAN JOURNAL OF HUMAN GENETICS 2011; 17:85-9. [PMID: 22090719 PMCID: PMC3214324 DOI: 10.4103/0971-6866.86189] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Type 1 diabetes mellitus formerly called juvenile diabetes, is an organ specific T-cell mediated autoimmune disease characterized by the progressive loss of function of the insulin producing beta–cells of the islets of Langerhans. Cytotoxic T lymphocyte-associated antigen 4 gene (CTLA-4) has been proposed as a candidate gene for conferring susceptibility to autoimmunity. Association of CTLA-4 gene polymorphism is well established in autoimmune endocrinopathies across world population. The present study was conducted to investigate the association of CTLA-4 exon 1 49A/G polymorphism with TIDM in Madurai, a city in Southern India. Fifty three clinically proven T1DM patients and 53 control subjects with no history of autoimmune disease were recruited for the study. Genomic DNA was extracted from peripheral blood. CTLA-4 exon 1 49 A/G polymorphism was assessed using PCR-RFLP methods. Our findings revealed a significant association of CTLA-4 exon 1 49 A/G polymorphism with T1DM in Madurai population.
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Affiliation(s)
- Beatrice Philip
- PG and Research Department of Zoology and Biotechnology, Lady Doak College, Madurai, Tamil Nadu 625 002, India
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28
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Benhatchi K, Jochmanová I, Habalová V, Wagnerová H, Lazúrová I. CTLA4 exon1 A49G polymorphism in Slovak patients with rheumatoid arthritis and Hashimoto thyroiditis-results and the review of the literature. Clin Rheumatol 2011; 30:1319-1324. [PMID: 21503616 DOI: 10.1007/s10067-011-1752-z] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2011] [Revised: 03/22/2011] [Accepted: 04/06/2011] [Indexed: 10/18/2022]
Abstract
Autoimmune thyroid diseases frequently overlaps with rheumatoid arthritis (RA). Among genetic factors, the role of the HLA antigens and CTLA4 gene polymorphisms in the overlapping has been suggested. The aim of this study was to investigate the alleles and genotypes frequency of the CTLA4 exon1 A49G polymorphism in Slovak patients with RA, Hashimoto thyroiditis (HT), both (RA + HT) and in healthy controls. Fifty-seven unrelated adults with RA, 57 patients with HT, 34 patients with both (RA + HT), and 51 normal subjects were studied. All were ethnic Slovaks living in the same geographical area. The CTLA4 exon1 A49G polymorphism was genotyped by using small amplicon melting analysis after real-time PCR. The CTLA4 49GG genotype and G allele frequency in the group with RA was not significantly higher in comparison with controls (10.53% vs. 9.8%, p = 0.62, OR 1.39, 95% CI 0.35-5.74 and 39.47% vs. 34.31%, p = 0.43, OR 1.25, 95% CI 0.72-2.18). The frequency of GG genotype was slightly but not significantly higher in patients with HT as compared with control group (19.3% vs. 9.8%, p = 0.17, OR 2.27, 95% CI 0.67-8.45). However, the frequency of GG genotype and G allele in patients with both RA and HT was significantly higher than that in controls (29.41% vs. 9.8%, p = 0.02, OR 4.49, 95% CI 1.20-18.54 and 51.47% vs. 34.31%, p = 0.03, OR 2.02, 95% CI 1.08-3.81). The frequency of GG genotype of CTLA4 A49G gene polymorphism in Slovak patients with RA is not significantly higher in comparison to control group. However, carriers of GG genotype with RA may be susceptible to develop HT.
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Affiliation(s)
- Karim Benhatchi
- 1st Department of Internal Medicine Medical Faculty, P.J.Šafárik University, Trieda SNP 1, 04011, Košice, Slovakia
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29
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Hwang SH, Lim JA, Kim HC, Lee HW, Kim HS. Identification of a shared F8 mutation in the Korean patients with acquired hemophilia A. THE KOREAN JOURNAL OF HEMATOLOGY 2011; 46:49-51. [PMID: 21461305 PMCID: PMC3065628 DOI: 10.5045/kjh.2011.46.1.49] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/18/2010] [Revised: 12/16/2010] [Accepted: 01/26/2011] [Indexed: 11/17/2022]
Abstract
Although uncommon, acquired hemophilia A (HA) is associated with a high rate of mortality due to severe bleeding. In spite of many hypotheses regarding the cause of acquired HA, there is as yet no established theory. In this study, we investigated the possibility that mutation(s) in the F8 gene may be correlated with the development of inhibitory autoantibodies. Direct sequencing analysis was performed on all 26 exons of the F8 gene of 2 patients exhibiting acquired HA. Both patients were found to share a common point mutation (c.8899G>A) in the 3'-untranslated region (3'-UTR) of exon 26. This is the first report on the genotyping of F8 in the context of acquired HA.
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Affiliation(s)
- Sung Ho Hwang
- Department of Biological Science, College of Natural Sciences, Ajou University, Suwon, Korea
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30
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Lozano VF, Lins TC, Teixeira MM, Vieira RG, Blotta MHSL, Goes AM, Silva ICR, Pereira RW, Bocca AL, Felipe MSS. Polymorphism analysis of the CTLA-4 gene in paracoccidioidomycosis patients. Mem Inst Oswaldo Cruz 2011; 106:220-6. [DOI: 10.1590/s0074-02762011000200017] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2010] [Accepted: 01/10/2011] [Indexed: 01/15/2023] Open
Affiliation(s)
| | | | | | | | | | | | | | | | - Anamelia L Bocca
- Universidade Católica de Brasília; Universidade de Brasília, Brasil
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31
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Saverino D, Simone R, Bagnasco M, Pesce G. The soluble CTLA-4 receptor and its role in autoimmune diseases: an update. AUTO- IMMUNITY HIGHLIGHTS 2010; 1:73-81. [PMID: 26000110 PMCID: PMC4389044 DOI: 10.1007/s13317-010-0011-7] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/07/2010] [Accepted: 09/08/2010] [Indexed: 12/24/2022]
Abstract
CTLA-4, initially described as a membranebound molecule, is a costimulatory receptor transducing a potent inhibitory signal. Increasing evidence shows the CTLA-4 gene to be an important susceptibility locus for autoimmune endocrinopathies and other autoimmune disorders. A soluble form of cytotoxic T-lymphocyte-associated antigen-4 (sCTLA-4) has been established and shown to possess CD80/CD86 binding activity and in vitro immunoregulatory functions. sCTLA-4 is generated by alternatively spliced mRNA. Whereas low levels of sCTLA-4 are detected in normal human serum, increased serum levels are observed in several autoimmune diseases (e.g. Graves' disease, myasthenia gravis, systemic lupus erythematosus, type 1 diabetes, systemic sclerosis, coeliac disease, autoimmune pancreatitis and primary biliary cirrhosis). The biological significance of increased sCTLA-4 serum levels is not fully clarified yet. On the one hand, it can be envisaged that sCTLA-4 specifically inhibits early T-cell activation by blocking the interaction of CD80/CD86 with the costimulatory receptor CD28. On the other hand, higher levels of sCTLA-4 could compete for the binding of the membrane form of CTLA-4 with CD80/CD86 in the later phases of T-lymphocyte activation, causing a reduction in inhibitory signalling. This double-edged nature of sCTLA-4 to block the binding of CD28 to CD80/CD86 may result in different outcomes during the clinical course of an autoimmune disease.
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Affiliation(s)
- Daniele Saverino
- Section of Human Anatomy, Department of Experimental Medicine, University of Genova, Genova, Italy
| | - Rita Simone
- Section of Human Anatomy, Department of Experimental Medicine, University of Genova, Genova, Italy
| | - Marcello Bagnasco
- Medical and Radiometabolic Therapy Unit, Department of Internal Medicine, University of Genova, Viale Benedetto XV, 6, 16132 Genova, Italy
| | - Giampaola Pesce
- Medical and Radiometabolic Therapy Unit, Department of Internal Medicine, University of Genova, Viale Benedetto XV, 6, 16132 Genova, Italy
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The influence of CTLA-4 gene polymorphism on long-term kidney allograft function in Caucasian recipients. Transpl Immunol 2010; 23:121-4. [PMID: 20470888 DOI: 10.1016/j.trim.2010.05.002] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2009] [Revised: 02/15/2010] [Accepted: 05/04/2010] [Indexed: 11/22/2022]
Abstract
The aim of the study was to examine whether CTLA-4 (CD152) and CD28 gene polymorphisms affect the outcome of kidney transplantation (KTx). Polymorphisms of the CTLA-4 gene (-318 C>T, +49 A>G, and the microsatellite polymorphism in the 3'UTR of exon 4 (AT)(n)) and a CD28 gene (IVS3 +17T>C) were investigated in 314 allograft recipients with a mean age of 41.9+/-12 years. The median time since KTx was 97.5 months. The genotypes of the SNPs were determined by SSP-PCR and (AT)(n) genotype by PCR and capillary electrophoresis (ABI Prism 310). In general, no relationship was found between the allele variants and acute rejection or graft function. Univariate and multivariate analyses showed no influence of CTLA-4 or CD28 polymorphism on graft/patient survival. In the individuals bearing the combination of the homozygous variant of low AT repeat number (82 bp) and the homozygous variant A (adenine) in CTLA-4 +49 A>G, higher eGFR was observed at one year after KTx, which was also maintained at 10 years. In summary, 24.2% of the studied patients carrying the "favorable" CTLA-4 genotype exhibited significantly higher allograft function than the 16.9% recipients with the "unfavorable" genotype up to 10 years post transplantation.
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Pincerati MR, Dalla-Costa R, Pavoni DP, Petzl-Erler ML. Genetic polymorphisms of the T-cell coreceptors CD28 and CTLA-4 in Afro- and Euro-Brazilians. Int J Immunogenet 2010; 37:253-61. [DOI: 10.1111/j.1744-313x.2010.00917.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
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Qi P, Ruan CP, Wang H, Zhou FG, Xu XY, Gu X, Zhao YP, Dou TH, Gao CF. CTLA-4 +49A>G polymorphism is associated with the risk but not with the progression of colorectal cancer in Chinese. Int J Colorectal Dis 2010; 25:39-45. [PMID: 19787358 DOI: 10.1007/s00384-009-0806-z] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/11/2009] [Indexed: 02/04/2023]
Abstract
PURPOSE Colorectal cancer (CRC) is one of the most common malignancies in the world and a multipathway disease. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a potent immunoregulatory molecule that suppresses antitumor response by down-regulating T-cell activation. The most studied +49A>G polymorphism of CTLA-4 gene has been associated with several autoimmune or cancer diseases. Our aim was to investigate the association between this genetic variant and the risk as well as progression of colorectal cancer in Chinese. METHODS We conducted a case-control study of 124 colorectal cancer cases and 407 healthy controls. DNA was extracted from blood specimens, and +49A>G polymorphism in the CTLA-4 gene was genotyped by polymerase chain reaction-ligation detection reaction (PCR-LDR). RESULTS In our study group, the frequency of AG or GG or carrying at least one G allele at position +49 was significantly different in colorectal cancer patients and the control group, indicating that the risk of CRC was significantly higher among subjects with the AG or GG genotype or carrying at least one G allele at position +49 than among the subjects with the AA genotype. However, we observed no association between CTLA-4 +49A>G polymorphism and the progression of CRC. Interestingly, the CTLA-4 +49A allele was in non-significantly higher numbers in CRC patients with distant metastasis. CONCLUSIONS Our results suggested that CTLA-4 +49A>G polymorphism was associated with an increased risk of colorectal cancer, but this polymorphism did not play an important role in the progression of CRC in Chinese.
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Affiliation(s)
- Peng Qi
- Department of Laboratory Medicine, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai, China
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Chua KH, Puah SM, Chew CH, Tan SY, Lian LH. Study of the CTLA-4 gene polymorphisms in systemic lupus erythematosus (SLE) samples from Malaysia. Ann Hum Biol 2009; 37:274-80. [DOI: 10.3109/03014460903325185] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Jung MH, Yu J, Shin CH, Suh BK, Yang SW, Lee BC. Association of cytotoxic T lymphocyte antigen-4 gene polymorphisms and HLA class II alleles with the development of type 1 diabetes in Korean children and adolescents. J Korean Med Sci 2009; 24:1004-9. [PMID: 19949652 PMCID: PMC2775844 DOI: 10.3346/jkms.2009.24.6.1004] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2009] [Accepted: 06/16/2009] [Indexed: 11/20/2022] Open
Abstract
We studied the association of cytotoxic T lymphocyte antigen-4 gene (CTLA4) polymorphisms with the development of type 1 diabetes (T1D) in Korean children and adolescents. A total of 176 Korean subjects (92 females and 84 males) with childhood-onset T1D were studied. The A/G polymorphism at position 49 in CTLA4 exon 1 and the C/T polymorphism at position -318 in the CTLA4 promoter were analyzed by PCR-RFLP methods. The genotype and allele frequencies of the CTLA4 polymorphisms in the T1D patients were not different from those in the controls. These polymorphisms were not associated with the clinical characteristics or the development of autoimmune thyroid disease in the T1D patients. The frequency of the A allele was significantly higher in the patients that did not have two out of the three susceptible HLA-DRB1 alleles, which were DRB1*0301, *0405 and *09012, compared to the controls (P<0.05). These results suggest that CTLA4 polymorphisms do not directly confer any susceptibility to T1D. However, a CTLA4-mediated susceptibility effect on the development of T1D might be significant in children and adolescents that do not have susceptible HLA class II alleles.
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Affiliation(s)
- Min Ho Jung
- Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jeesuk Yu
- Department of Pediatrics, College of Medicine, Dankook University, Cheonan, Korea
| | - Choong Ho Shin
- Department of Pediatrics, College of Medicine, Seoul National University, Seoul, Korea
| | - Byung Kyu Suh
- Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sei Won Yang
- Department of Pediatrics, College of Medicine, Seoul National University, Seoul, Korea
| | - Byung Churl Lee
- Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Korea
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Yousefipour G, Erfani N, Momtahan M, Moghaddasi H, Ghaderi A. CTLA4 exon 1 and promoter polymorphisms in patients with multiple sclerosis. Acta Neurol Scand 2009; 120:424-9. [PMID: 19737153 DOI: 10.1111/j.1600-0404.2009.01177.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
OBJECTIVE The polymorphisms of exon 1 (+49 A/G) and promoter regions (-1722 T/C, -1661 A/G and -318 C/T)of cytotoxic T lymphocyte antigen 4 (CTLA4) and also haplotypes constructed from mentioned loci were investigated amongst 153 Iranian patients with definite multiple sclerosis (MS) and 190 healthy controls. METHODS The polymorphisms were genotyped by PCR-restriction fragment length polymorphisms and PCR-amplification refractory mutation system. The 4-locus haplotypes were estimated by Arlequin software (University of Berne, Berne, Switzerland). RESULTS Preliminary results showed significant increase of +49 G allele and -1661 AG genotype, as well as TGCA haplotype among patients than controls (P < 0.036, P = 0.009 and P < 0.010, respectively). The distribution of -1722 T/C, -1661 A/G, -318 C/T and +49 A/G (TACA) haplotype, from the contrary, was observed to be significantly increased among controls (P < 0.001). CONCLUSIONS After Bonferroni correction, the results provide preliminary evidence that CTLA4 genetic variation at -1661 locus may render Iranian individuals to be more susceptible to MS, whereas harboring TACA haplotype might be protective.
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Affiliation(s)
- G Yousefipour
- Department of Neurology, Shiraz University of Medical Sciences, Shiraz, Iran
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Fernández-Mestre M, Sánchez K, Balbás O, Gendzekhzadze K, Ogando V, Cabrera M, Layrisse Z. Influence of CTLA-4 gene polymorphism in autoimmune and infectious diseases. Hum Immunol 2009; 70:532-5. [DOI: 10.1016/j.humimm.2009.03.016] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2008] [Revised: 03/17/2009] [Accepted: 03/31/2009] [Indexed: 10/20/2022]
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Ben Dhifallah I, Chelbi H, Braham A, Hamzaoui K, Houman MH. CTLA-4 +49A/G polymorphism is associated with Behçet’s disease in a Tunisian population. ACTA ACUST UNITED AC 2009; 73:213-7. [DOI: 10.1111/j.1399-0039.2008.01186.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Dilmec F, Ozgonul A, Uzunkoy A, Akkafa F. Investigation of CTLA-4 and CD28 gene polymorphisms in a group of Turkish patients with colorectal cancer. Int J Immunogenet 2009; 35:317-21. [PMID: 18680513 DOI: 10.1111/j.1744-313x.2008.00782.x] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Colorectal cancer (CRC), also called colon cancer or bowel cancer, includes cancerous growths in the colon, rectum and appendix. The immune system is an important defence mechanism against cancer and is often dysfunctional in patients with malignancies. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and CD28 genes encode receptors that provide negative and positive signals, respectively. Polymorphisms in these genes can affect their functions. In this study, we aimed to investigate the association of cancer with the frequencies and roles of CTLA-4/+49A > G (exon 1) and -318C > T (promoter), and CD28/IVS3 + 17T > C (intron 3 position + 17). These polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 218 Turkish subjects (56 patients with CRC and 162 healthy controls). No statistically significant differences in the genotype distributions of CTLA-4/+49GG (1.8% vs. 6.8%, odds ratio (OR) = 0.250, P = 0.305) and CTLA-4/-318TT (0% vs. 0.6%, OR = 1.006, P = 1.000), and CD28/IVS3 + 17CC (8.9% vs. 3.7%, OR = 0.2411, P = 0.155) between patients with CRC and healthy controls, were observed. We also found that there were no significant differences in the frequencies of CTLA-4/+49G (18.8% vs. 20.1%, OR = 0.920, P = 0.891) and CTLA-4/-318T (7.1% vs. 4.3%, OR = 1.653, P = 0.314), and CD28/IVS3 + 17C alleles (25.9% vs. 19.1%, OR = 1.353, P = 0.139) between two study groups. Present results suggested that CTLA-4 and CD28 gene polymorphisms did not play an important role in Turkish patients with CRC.
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Affiliation(s)
- F Dilmec
- Department of Medical Biology, Faculty of Medicine, Harran University, Sanliurfa, Turkey.
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Jääskeläinen E, Toivonen S, Keski-Nisula L, Paattiniemi EL, Helisalmi S, Punnonen K, Heinonen S. CTLA-4 polymorphism 49A-G is associated with placental abruption and preeclampsia in Finnish women. Clin Chem Lab Med 2008; 46:169-73. [PMID: 18076363 DOI: 10.1515/cclm.2008.034] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Our aim was to study genetic variability in the gene encoding cytotoxic T-lymphocyte antigen (CTLA-4) and individual susceptibility to the development of preeclampsia or placental abruption. METHODS A total of 361 women (132 with preeclampsia, 117 with placental abruption and 112 healthy controls) were genotyped for 49A-G polymorphism (dbSNP: rs231775) in the CTLA-4 gene. RESULTS The frequency of the G alleles was significantly higher in women with preeclampsia than in controls (51.1% vs. 42.0%; OR 1.44, 95% CI 1.01-3.48, p<0.043). Women with placental abruption had decreased frequency of AA genotype (22.2% vs. 35.7%) and significantly more AG or GG genotypes compared with controls (OR 1.94, 95% CI 1.09-2.07, p<0.024). No significant differences were detected in the frequencies of genotype GG (29.5%, 21.4% and 19.6%, respectively) between the three groups. CONCLUSIONS Our data suggest that the 49A-G polymorphism in the CTLA-4 gene is associated with the development of placental abruption and preeclampsia, with women having the G allele being at risk.
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Affiliation(s)
- Ester Jääskeläinen
- Department of Obstetrics and Gynecology, Kuopio University Hospital, Kuopio, Finland
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Slot MC, Sokolowska MG, Savelkouls KG, Janssen RGJH, Damoiseaux JGMC, Tervaert JWC. Immunoregulatory gene polymorphisms are associated with ANCA-related vasculitis. Clin Immunol 2008; 128:39-45. [PMID: 18448390 DOI: 10.1016/j.clim.2008.03.506] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2007] [Revised: 01/28/2008] [Accepted: 03/17/2008] [Indexed: 11/27/2022]
Abstract
T cell activation is regulated by inhibitory molecules such as PD-1 and CTLA-4, whose expression may be affected by gene polymorphisms. Increased T cell activation is present in patients with ANCA-associated vasculitis (AAV). We investigated two single-nucleotide polymorphisms (SNPs) in PDCD1 and five polymorphisms in CTLA4 in 102 patients with AAV and 188 healthy controls (HC). The distributions of the PD-1.3 and PD-1.5 SNPs, and the distributions of the CTLA4 promoter polymorphisms -1722T/C, -1661A/G, -318 C/T, and the (AT)(n) microsatellite in the 3'-untranslated region of CTLA4, did not differ between patients and HC. However, the +49 G allele was significantly more often present in patients with AAV. Furthermore, the co-occurrence of the PD-1.5 T allele with CTLA4 +49 AA homozygosity (i.e., the absence of a G allele) was less often present in patients compared to HC. These genetic polymorphisms may lead to hyperreactivity of T cells and thus may contribute to the pathogenesis of AAV.
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Affiliation(s)
- Marjan C Slot
- Department of Clinical and Experimental Immunology, University Hospital Maastricht, Maastricht, The Netherlands
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PAVLOVA A, DIAZ-LACAVA A, ZEITLER H, SATOGUINA J, NIEMANN B, KRAUSE M, SCHARRER I, HOERAUF A, WIENKER T, OLDENBURG J. Increased frequency of the CTLA-4 49 A/G polymorphism in patients with acquired haemophilia A compared to healthy controls. Haemophilia 2008; 14:355-60. [DOI: 10.1111/j.1365-2516.2007.01618.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Abstract
Graves' disease is a complex autoimmune disorder characterized by multiple systemic manifestations of overproduction of thyroid hormone, and in some cases, orbitopathy. The etiology of this disorder is multifactorial, involving heritable abnormalities of immune regulation as well as environmental triggers. The goal of this paper is to provide a review of recent research investigating candidate genes involved in the pathophysiology of both Graves' disease per se and of thyroid orbitopathy.
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Affiliation(s)
- Nancy Kim
- Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA.
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Association of CTLA4 single nucleotide polymorphisms with viral but not autoimmune liver disease. Eur J Gastroenterol Hepatol 2007; 19:947-51. [PMID: 18049163 DOI: 10.1097/meg.0b013e3282efa240] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
BACKGROUND CTLA4 is an inhibitory receptor expressed on a subset of T lymphocytes. Single nucleotide polymorphisms of the CTLA4 gene have been implicated in autoimmune diseases, including autoimmune hepatitis and primary biliary cirrhosis. In reverse form, CTLA4 variations are associated with chronic infections such as chronic hepatitis B. METHODS CTLA4 variations -318C>T and +49A>G were analyzed in 2366 patients with chronic liver disease of various etiologies, including 323 patients with chronic hepatitis B virus (HBV) infection, 1181 patients with chronic hepatitis C virus infection, 180 patients with primary biliary cirrhosis, and 127 patients with autoimmune hepatitis, as well as 202 healthy control individuals. Genotyping was performed by melting curve analysis. RESULTS The -318C>T variation was underrepresented in patients with chronic HBV infection compared with healthy controls (14.6 vs. 25.7%, P=0.002) and with patients with chronic liver disease of other origin (14.6 vs. 20.7%, P=0.011). Patients with cryptogenic cirrhosis also showed a lower frequency of the -318T allele than healthy controls (12.0 vs. 25.7%, P=0.014). No association of the +49G>A variation was found with any diagnosis, including autoimmune hepatitis and primary biliary cirrhosis. CONCLUSION We describe the association of the CTLA4 -318C>T variation with chronic HBV infection and cryptogenic cirrhosis but find no association of the +49G>A variation with autoimmune liver disease.
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Sohn MH, Kim SH, Song TW, Kim KW, Kim ES, Park HS, Kim KE. Cytotoxic T lymphocyte-associated antigen-4 gene polymorphisms confer susceptibility to atopic asthma in Korean children. Pediatr Pulmonol 2007; 42:542-7. [PMID: 17469155 DOI: 10.1002/ppul.20622] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is a negative regulator of T lymphocyte activation. The gene encoding CTLA-4 is a candidate gene for conferring susceptibility to allergic disease. The purpose of this study was to evaluate the potential effects of CTLA-4 gene polymorphisms in Korean children on asthma. We genotyped 272 children with atopic asthma, 54 children with nonatopic asthma (NAA), and 254 control children for allelic determinants at two polymorphic sites in the region at positions promoter - 318 C > T and exon 1 + 49 G > A using restriction fragment length polymorphism methods. As a result, allele and genotype frequencies of the CTLA-4 exon 1 + 49 G > A polymorphism were different to some extent between the atopic asthma children and the controls with P<0.05, which did not reach statistical significance after the correction of multiple comparisons. In addition, CTLA-4 + 49 G > A polymorphism was significantly associated with elevated serum IgE levels (P=0.01). Of the four haplotype, haplotype 1 (C-G) was only associated with atopic asthma susceptibility after the correction of multiple comparisons (P=0.01, OR=0.702, 95% CI= 0.541-0.911). Polymorphisms in the CTLA-4 gene likely confer susceptibility to atopic asthma in Korean children.
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Affiliation(s)
- Myung Hyun Sohn
- Department of Pediatrics and Institute of Allergy, BK21 Project for Medical Science, Biomolecule Secretion Research Center, Yonsei University College of Medicine, Seoul, Korea
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Schott E, Witt H, Hinrichsen H, Neumann K, Weich V, Bergk A, Halangk J, Müller T, Tinjala S, Puhl G, Neuhaus P, Wiedenmann B, Berg T. Gender-dependent association of CTLA4 polymorphisms with resolution of hepatitis C virus infection. J Hepatol 2007; 46:372-80. [PMID: 17150279 DOI: 10.1016/j.jhep.2006.09.011] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2006] [Revised: 08/03/2006] [Accepted: 09/05/2006] [Indexed: 01/14/2023]
Abstract
BACKGROUND/AIMS A vigorous T-cell response is essential for the resolution of HCV infection. It is modified by co-stimulatory molecules that attenuate T-lymphocyte responses by binding to CTLA4. We investigated whether CTLA4 single nucleotide polymorphisms are associated with the resolution of infection or with the course of disease. METHODS We enrolled 127 individuals with self-limited and 947 patients with chronic HCV infection, of whom 560 were treated with interferon-alpha-based therapies, and 200 healthy controls. We analyzed CTLA4 polymorphisms -318C>T and +49A>G by melting curve analysis and reconstructed haplotypes. RESULTS CTLA4 haplotypes were distributed differently between men but not women with self-limited and chronic infection (p=0.043) but were not predictive of the stage of fibrosis in chronic carriers. Haplotypes were distributed differently between male but not female end-of-treatment responders and non-responders (p=0.025). The influence of CTLA4 haplotypes was more pronounced in "hard-to-treat" situations, i.e., treatment with interferon-alpha monotherapy or infection with HCV genotypes 1/4. Logistic regression analysis confirmed gender-specific risk factors for a virological non-response. CONCLUSIONS CTLA4 polymorphisms are associated with the resolution of HCV infection. This study underlines the role of an efficient T-cell response in the clearance of HCV and sheds light on a gender-dependent difference of immune regulation.
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Affiliation(s)
- Eckart Schott
- Department of Hepatology and Gastroenterology, CVK, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
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Gunesacar R, Erken E, Bozkurt B, Ozer HT, Dinkci S, Erken EG, Ozbalkan Z. Analysis of CD28 and CTLA-4 gene polymorphisms in Turkish patients with Behcet's disease. Int J Immunogenet 2007; 34:45-9. [PMID: 17284227 DOI: 10.1111/j.1744-313x.2007.00655.x] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
In this study we aimed to investigate IVS3 +17T/C single nucleotide polymorphism (SNP) of CD28 gene, +49A/G and -318C/T SNPs of CTLA-4 gene in patients with Behçet's disease (BD) and their potential association to the main clinical features of the disease. These polymorphisms were investigated in a Turkish population of 123 patients with BD and 179 healthy controls, by using PCR-RFLP technique. HLA-B*51 genotype was also studied in both groups by using PCR-SSP. The frequency of IVS3 +17TC genotype of the CD28 gene was significantly increased in BD patients compared to controls (43.6% vs. 31.2%, OR = 1.663, 95% CI = 1.033-2.679, P = 0.039). CTLA-4 +49GG genotype frequency was found to be significantly lower in patients with BD than those of healthy controls (4% vs. 10.6%, OR = 0.357, 95% CI = 0.130-0.983, P = 0.05). Genotype and allele frequencies of the CTLA-4-318C/T polymorphism between the BD and healthy control groups were not significantly different (12.2% vs. 10.6%, OR = 1.170, 95% CI = 0.570-2.402, P = 0.713). There were no associations between the studied polymorphisms and the main clinical features of BD. The frequencies of HLA-B*51 were 60.3% and 30.7% in BD and control groups, respectively (OR = 3.429, 95% CI = 2.115-5.559, P = 0.0001). Association between HLA-B*51 and each studied polymorphism did not reach to significant levels (OR = 0.479, 95% CI = 0.228-1.004, P = 0.064 for CD28 IVS3 +17TT genotype; OR = 2.180, 95% CI = 1.025-4.639, P = 0.061 for TC genotype; OR = 1.570, 95% CI = 0.870-2.836, P = 0.146 for C allele). These results may suggest that CD28 IVS3 +17TC genotype may be a risk factor for the development of BD, on the contrary CTLA-4 +49GG genotype may be protective in the studied Turkish population.
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Affiliation(s)
- R Gunesacar
- Department of Rheumatology-Immunology, Cukurova University Faculty of Medicine, Balcali, Tr-01330, Adana, Turkey.
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Astermark J, Wang X, Oldenburg J, Berntorp E, Lefvert AK. Polymorphisms in the CTLA-4 gene and inhibitor development in patients with severe hemophilia A. J Thromb Haemost 2007; 5:263-5. [PMID: 17269936 DOI: 10.1111/j.1538-7836.2007.02290.x] [Citation(s) in RCA: 117] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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