|
1
|
Ashton JJ, Latham K, Beattie RM, Ennis S. Review article: the genetics of the human leucocyte antigen region in inflammatory bowel disease. Aliment Pharmacol Ther 2019; 50:885-900. [PMID: 31518029 DOI: 10.1111/apt.15485] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 07/05/2019] [Accepted: 08/10/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND The human leucocyte antigen (HLA) complex, located at chromosome 6p21.3 is a highly polymorphic region containing the classical class I and II HLA genes. The region is highly associated with inflammatory bowel disease (IBD), largely through genome-wide association studies (GWAS). AIMS To review the role of HLA in immune function, summarise data on risk/protective HLA genotypes for IBD, discuss the role of HLA in IBD pathogenesis, treatment and examine limitations that might be addressed by future research. METHODS An organised search strategy was used to collate articles describing HLA genes in IBD, including Crohn's disease and ulcerative colitis. RESULTS All classical HLA genes with variation (including HLA-A, B, C, DRB1, DQA1, DQB1, DPA1 and DPB1) harbour IBD-associated genotypes. The most implicated gene is HLA-DRB1, with HLA-DRB1*03:01 the most associated risk allele in both Crohn's disease and ulcerative colitis. Elucidating precise disease associations is challenging due to high linkage disequilibrium between HLA genotypes. The mechanisms by which risk alleles cause disease are multifactorial, with the best evidence indicating structural and electrostatic alteration impacting antigen binding and downstream signalling. Adverse medication events have been associated with HLA genotypes including with thiopurines (pancreatitis) and anti-TNF agents (antibody formation). CONCLUSIONS The HLA complex is associated with multiple risk/protective alleles for IBD. Future research utilising long-read technology, ascertainment of zygosity and integration in disease modelling will improve the functional understanding and clinical translation of genetic findings.
Collapse
Affiliation(s)
- James J Ashton
- Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.,Department of Paediatric Gastroenterology, Southampton Children's Hospital, Southampton, UK
| | - Katy Latham
- Anthony Nolan Research Institute, University College London, London, UK
| | - Robert Mark Beattie
- Department of Paediatric Gastroenterology, Southampton Children's Hospital, Southampton, UK
| | - Sarah Ennis
- Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK
| |
Collapse
|
|
2
|
Iwamoto T, Yashima K, Morio K, Ueda N, Ikebuchi Y, Kawaguchi K, Harada K, Isomoto H. Association of Clinical Features with Human Leukocyte Antigen in Japanese Patients with Ulcerative Colitis. Yonago Acta Med 2018. [DOI: 10.33160/yam.2018.03.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- Taku Iwamoto
- Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan
| | - Kazuo Yashima
- Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan
| | - Keiko Morio
- Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan
| | - Naoki Ueda
- Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan
| | - Yuichiro Ikebuchi
- Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan
| | - Koichiro Kawaguchi
- Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan
| | - Kenichi Harada
- Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan
| | - Hajime Isomoto
- Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan
| |
Collapse
|
|
3
|
Martinez-Chamorro A, Moreno A, Gómez-García M, Cabello MJ, Martin J, Lopez-Nevot MÁ. MICA*A4 protects against ulcerative colitis, whereas MICA*A5.1 is associated with abscess formation and age of onset. Clin Exp Immunol 2016; 184:323-31. [PMID: 26940143 DOI: 10.1111/cei.12786] [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] [Accepted: 03/01/2016] [Indexed: 12/15/2022] Open
Abstract
Ulcerative colitis (UC) is one of the two major forms of inflammatory bowel disease, the aetiology of which remains unknown. Several studies have demonstrated the genetic basis of disease, identifying more than 130 susceptibility loci. The major histocompatibility complex class I chain-related gene A (MICA) is a useful candidate to be involved in UC pathogenesis, because it could be important in recognizing the integrity of the epithelial cell and its response to stress. The aim of this study was to analyse the relationship between polymorphisms in the transmembrane domain of MICA and susceptibility to develop UC. A total of 340 patients with UC and 636 healthy controls were genotyped for MICA transmembrane polymorphism using a polymerase chain reaction (PCR) combined with fluorescent technology. Different MICA alleles were determined depending on the PCR product size. The allele MICA*A4 was less frequent in patients than in controls (P = 0·003; OR = 0·643), and this protective role is higher when it forms haplotype with B*27 (P = 0·002; OR = 0·294). The haplotype HLA-B*52/MICA*A6 was also associated with UC [P = 0·001; odds ratio (OR) = 2·914]. No other alleles, genotypes or haplotypes were related with UC risk. Moreover, MICA*A5.1 is associated independently with abscesses (P = 0·002; OR = 3·096) and its frequency is lower in patients diagnosed between ages 17 and 40 years (P = 0·007; OR = 0·633), meaning an extreme age on onset. No association with location, extra-intestinal manifestations or need for surgery was found.
Collapse
Affiliation(s)
| | - A Moreno
- Section of Immunology, Hospital Virgen de las Nieves
| | | | - M J Cabello
- Digestive Section, Hospital Virgen de las Nieves
| | - J Martin
- Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Spain
| | - M Á Lopez-Nevot
- Section of Immunology, Hospital Virgen de las Nieves.,University of Granada
| |
Collapse
|
|
4
|
Wang Q, Zhou X. Associations of MICA Polymorphisms with Inflammatory Rheumatic Diseases. Open Rheumatol J 2015; 9:94-100. [PMID: 26862354 PMCID: PMC4740962 DOI: 10.2174/1874312901409010094] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2015] [Revised: 08/27/2015] [Accepted: 08/28/2015] [Indexed: 01/01/2023] Open
Abstract
Inflammatory rheumatic diseases are characterized by inflammation resulting from the immune dysregulation that usually attacks joints, skin and internal organs. Many of them are considered as complex disease that may be predisposed by multiple genes and/or genetic loci, and triggered by environmental factors such as microbiome and cellular stress. The major histocompatibility complex class I chain-related gene A (MICA) is a highly polymorphic gene that encodes protein variants expressed under cellular stress conditions, and these MICA variants play important roles in immune activation and surveillance. Recently, accumulating evidences from both genetic and functional studies have suggested that MICA polymorphisms may be associated with various rheumatic diseases, and the expression of MICA variants may attribute to the altered immune responses in the diseases. The objective of this review is to discuss potential genetic associations and pathological relevance of MICA in inflammatory rheumatic diseases that may help us to understand pathogenesis contributing to the development of these diseases.
Collapse
Affiliation(s)
- Qingwen Wang
- Department of Rheumatism and Immunology, Peking University Shenzhen Hospital, China
| | - Xiaodong Zhou
- Department of Internal Medicine, The University of Texas Health Science Center at Houston, USA
| |
Collapse
|
|
5
|
Characteristics of Japanese inflammatory bowel disease susceptibility loci. J Gastroenterol 2014; 49:1217-30. [PMID: 23942620 DOI: 10.1007/s00535-013-0866-2] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2013] [Accepted: 07/29/2013] [Indexed: 02/04/2023]
Abstract
BACKGROUND There are substantial differences in inflammatory bowel disease (IBD) genetics depending on the populations examined. We aimed to identify Japanese population-specific or true culprit susceptibility genes through a meta-analysis of past genetic studies of Japanese IBD. METHODS For this study, we reviewed 2,703 articles. The review process consisted of three screening stages: we initially searched for relevant studies and then relevant single nucleotide polymorphisms (SNPs). Finally, we adjusted them for the meta-analysis. To maximize our chances of analysis, we introduced proxy SNPs during the first stage. To minimize publication bias, no significant SNPs and solitary SNPs without pairs were combined to be reconsidered during the third stage. Additionally, two SNPs were newly genotyped. Finally, we conducted a meta-analysis of 37 published studies in 50 SNPs located at 22 loci corresponding to the total number of 4,853 Crohn's disease (CD), 5,612 ulcerative colitis (UC) patients, and 14,239 healthy controls. RESULTS We confirmed that the NKX2-3 polymorphism is associated with common susceptibility to IBD and that HLA-DRB1*0450 alleles increase susceptibility to CD but reduce risk for UC while HLA-DRB1*1502 alleles increase susceptibility to UC but reduce CD risk. Moreover, we found individual disease risk loci: TNFSF15 and TNFα to CD and HLA-B*5201, and NFKBIL1 to UC. The genetic risk of HLA was substantially high (odds ratios ranged from 1.54 to 2.69) while that of common susceptibility loci to IBD was modest (odds ratio ranged from 1.13 to 1.24). CONCLUSIONS Results indicate that Japanese IBD susceptibility loci identified by the meta-analysis are closely associated with the HLA regions.
Collapse
|
|
6
|
Kobashigawa T, Nanke Y, Takazoe M, Iihara K, Yamanaka H, Kotake S. A Case of Human Leukocyte Antigen (HLA) B27-Positive Intestinal Behçet's Disease with Crohn's Disease-Like Anal Fistulas. CLINICAL MEDICINE INSIGHTS-CASE REPORTS 2014; 7:13-9. [PMID: 24855400 PMCID: PMC4011670 DOI: 10.4137/ccrep.s11807] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
A 49-year-old male was admitted to our hospital with complaints of perianal pain, bloody stool, and high-grade fever due to perianal abscess. Drainage was carried out; however, the patient’s complaints worsened, and biopsy findings of colonoscopy showed ulcerative colitis-like lesions. The patient was diagnosed as having Behçet’s disease with intestinal involvement, did not have HLA-B51, but did have HLA-B27. We describe a case of Behcet’s disease with colitis, making a differential diagnosis of inflammatory bowel disease difficult.
Collapse
Affiliation(s)
- Tsuyoshi Kobashigawa
- Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan. ; Inflammatory Bowel Disease Center, Department of Internal Medicine, Social Insurance Chuo General Hospital, Tokyo, Japan
| | - Yuki Nanke
- Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan
| | - Masakazu Takazoe
- Inflammatory Bowel Disease Center, Department of Internal Medicine, Social Insurance Chuo General Hospital, Tokyo, Japan
| | - Kuniko Iihara
- Department of Pathology, Social Insurance Chuo General Hospital, Tokyo, Japan
| | - Hisashi Yamanaka
- Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan
| | - Shigeru Kotake
- Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan
| |
Collapse
|
|
7
|
Gravano DM, Hoyer KK. Promotion and prevention of autoimmune disease by CD8+ T cells. J Autoimmun 2013; 45:68-79. [PMID: 23871638 DOI: 10.1016/j.jaut.2013.06.004] [Citation(s) in RCA: 117] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2013] [Accepted: 06/10/2013] [Indexed: 11/25/2022]
Abstract
Until recently, little was known about the importance of CD8+ T effectors in promoting and preventing autoimmune disease development. CD8+ T cells can oppose or promote autoimmune disease through activities as suppressor cells and as cytotoxic effectors. Studies in several distinct autoimmune models and data from patient samples are beginning to establish the importance of CD8+ T cells in these diseases and to define the mechanisms by which these cells influence autoimmunity. CD8+ effectors can promote disease via dysregulated secretion of inflammatory cytokines, skewed differentiation profiles and inappropriate apoptosis induction of target cells, and work to block disease by eliminating self-reactive cells and self-antigen sources, or as regulatory T cells. Defining the often major contribution of CD8+ T cells to autoimmune disease and identifying the mechanisms by which they alter the pathogenesis of disease is a rapidly expanding area of study and will add valuable information to our understanding of the kinetics, pathology and biology of autoimmune disease.
Collapse
Affiliation(s)
- David M Gravano
- Department of Molecular Cell Biology, Health Sciences Research Institute, University of California, Merced, CA, USA
| | | |
Collapse
|
|
8
|
Kamoun A, Bouzid D, Mahfoudh N, Amouri A, Gaddour L, Hakim F, Tahri N, Masmoudi H, Makni H. Association study of MICA-TM polymorphism with inflammatory bowel disease in the South Tunisian population. Genet Test Mol Biomarkers 2013; 17:615-9. [PMID: 23822824 DOI: 10.1089/gtmb.2012.0423] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders of the gastro-intestinal tract with unknown etiology. Both environmental and genetic factors are involved in the pathogenesis of these inflammatory bowel diseases (IBD). AIM The purpose of the present study was to determine the association between the polymorphism of the transmembrane region of MICA (MICA-TM), and the genetic susceptibility in Tunisian patients with IBD. PATIENTS AND METHODS A total of 102 Tunisian patients (66 with UC, 36 with CD) and 123 healthy controls were enrolled in our study. MICA-TM was genotyped by a semiautomatic fluorescent-labelled PCR method, amplicons were analysed on an ABI Prism 310 genotyper. Comparisons of allele frequencies between patients and controls, and between patients' subgroups were performed using SPSS 13.0. RESULTS No MICA allele was significantly increased in both groups of IBD compared to controls. The MICA-A5.1 allele was significantly decreased in CD patients (p=0.006, pc=0.03). In UC, MICA-A6 was associated with the presence of extraintestinal manifestations (p=0.04, pc=0.2), whereas MICA-A5 was associated with late age of onset (p=0.04). In CD, MICA-A6 was significantly increased in active disease patients when compared to moderately active or inactive disease (p=0.03, pc=0.15). CONCLUSION Some clinical features of CD and UC may be influenced by specific MICA-TM alleles. In our South Tunisian population, MICA plays a disease modifying role, rather than being an important gene in the susceptibility for developing IBD.
Collapse
Affiliation(s)
- Arwa Kamoun
- Immunology Department, Hédi Chaker Hospital, Sfax 3029, Tunisia.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
9
|
Al-Mamari F, Al-Shirawi A, Banodkar D, Al-Hashmi S, Al-Yahyaae F, Varghese M, Raeburn J. HLA Antigens in Omani Psoriasis Vulgaris Patients. Oman Med J 2012; 24:27-9. [PMID: 22303505 DOI: 10.5001/omj.2009.7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2008] [Accepted: 11/21/2008] [Indexed: 11/03/2022] Open
Abstract
OBJECTIVES To determine the frequency of different HLA-antigens in patients with plaque psoriasis in the Omani Arab population. METHODS Fifty four Omani patients clinically diagnosed with plaque psoriasis attending the dermatology outpatient clinic in Al-Nahdah Hospital (the tertiary dermatology centre in Oman) were selected for HLA studies. RESULTS HLA-B52 was present in 20.4% of patients 11/54 and in 5% of controls without psoriasis 5/100. For the association p was <0.004 and the relative risk (RR) was 4.86. CONCLUSION Psoriasis does not appear to be associated universally with the same HLA antigens. The association of HLA-B52 with plaque psoriasis in Omani patients compares with the HLA-Cw6, -Bw57 and -DR7 preponderance in most other ethnic groups.
Collapse
|
|
10
|
Asakura H. HLA-Cw*1202-B*5201-DRB1*1502 haplotype increases risk for ulcerative colitis but reduces risk for Crohn's disease. Gastroenterology 2012; 142:e27-8; author reply e28-9. [PMID: 22281265 DOI: 10.1053/j.gastro.2011.10.044] [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] [Received: 10/11/2011] [Accepted: 10/31/2011] [Indexed: 12/02/2022]
|
|
11
|
Yamamoto-Furusho JK. Genetic Susceptibility in Inflammatory Bowel Disease. Clin Rev Bone Miner Metab 2010. [DOI: 10.1007/s12018-009-9068-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
|
|
12
|
Li Y, Xia B, Lü M, Ge L, Zhang X. MICB0106 gene polymorphism is associated with ulcerative colitis in central China. Int J Colorectal Dis 2010; 25:153-9. [PMID: 19662431 PMCID: PMC2803256 DOI: 10.1007/s00384-009-0787-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/22/2009] [Indexed: 02/04/2023]
Abstract
BACKGROUND The highly polymorphic nonclassical MHC class I chain-related genes A and B (MICA and MICB) encode stress-inducible glycoproteins expressed on various epithelial cells including intestinal epithelial cells. MICA and MICB gene polymorphisms and expressions are associated with autoimmune diseases but not known in ulcerative colitis (UC). AIMS To investigate the association of MICB exon 2-4 polymorphisms and soluble MICA (sMICA) expression with the susceptibility of UC in central China. MATERIALS AND METHODS Genomic DNA was isolated from peripheral blood. The allele frequencies of MICB exon 2-4 were genotyped in 105 UC patients and 213 healthy controls by PCR single-stranded conformation polymorphism method. Thirty-two patients and 32 controls were selected for determining serum sMICA expression by ELISA. RESULTS Allele frequency of MICB0106 was significantly higher in UC patients than in healthy controls (19.0% vs. 8.9%, corrected P (Pc) = 0.0006), especially in patients with extensive colitis (24.4% vs. 8.9%, Pc = 0.0006), moderate and severe disease (24.1% vs. 8.9%, Pc = 0.0006), extraintestinal manifestations (20.5% vs. 8.9%, Pc = 0.012), male patients (22.1% vs. 8.0%, Pc = 0.006), and patients over the age of 40 years (28.8% vs. 8.3%, Pc = 0.0006). The sMICA level was significantly higher in UC than in healthy controls (604.41 +/- 480.43 pg/ml vs. 175.37 +/- 28.31 pg/ml, P = 0.0001) but not associated with the MICB0106 genotypes. CONCLUSIONS Overall, MICB0106 allele was positively associated with UC in the Han Chinese in central China. sMICA was highly expressed in UC but not associated with the MICB0106 genotype.
Collapse
Affiliation(s)
- Yi Li
- Department of Gastroenterology and Research Center of Digestive Diseases, Zhongnan Hospital, Wuhan University School of Medicine, Wuhan, People’s Republic of China ,Clinical Research Center for Intestinal and Colorectal Diseases and Key Laboratory of Allergy and Immune-related Diseases of Hubei Province, Wuhan, People’s Republic of China ,Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Bing Xia
- Department of Gastroenterology and Research Center of Digestive Diseases, Zhongnan Hospital, Wuhan University School of Medicine, Wuhan, People’s Republic of China ,Clinical Research Center for Intestinal and Colorectal Diseases and Key Laboratory of Allergy and Immune-related Diseases of Hubei Province, Wuhan, People’s Republic of China ,Department of Gastroenterology, Wuhan University Zhongnan Hospital, Donghu Road 169, Wuhan, 430071, Hubei Province People’s Republic of China
| | - Min Lü
- Department of Gastroenterology and Research Center of Digestive Diseases, Zhongnan Hospital, Wuhan University School of Medicine, Wuhan, People’s Republic of China ,Clinical Research Center for Intestinal and Colorectal Diseases and Key Laboratory of Allergy and Immune-related Diseases of Hubei Province, Wuhan, People’s Republic of China
| | - Liuqing Ge
- Department of Gastroenterology and Research Center of Digestive Diseases, Zhongnan Hospital, Wuhan University School of Medicine, Wuhan, People’s Republic of China ,Clinical Research Center for Intestinal and Colorectal Diseases and Key Laboratory of Allergy and Immune-related Diseases of Hubei Province, Wuhan, People’s Republic of China
| | - Xiaolian Zhang
- Clinical Research Center for Intestinal and Colorectal Diseases and Key Laboratory of Allergy and Immune-related Diseases of Hubei Province, Wuhan, People’s Republic of China
| |
Collapse
|
|
13
|
Abstract
The mechanism of inflammatory bowel disease (IBD) is partially understood, but it is certain that a genetic predisposition, through the inheritance of a number of contributory genetic polymorphisms, contributes to the pathogenesis of IBD. These variant forms of genes may be associated with an abnormal response to normal luminal bacteria. Those genes that have been consistently associated with IBD thus far primarily fall into one of three classes: those affecting bacterial recognition, those affecting immune response, and a third group affecting mucosal transport polarity or mucosal transporter function. This article reviews the IBD related genes mentioned above.
Collapse
|
|
14
|
Aizawa H, Kinouchi Y, Negoro K, Nomura E, Imai G, Takahashi S, Takagi S, Kakuta Y, Tosa M, Mochida A, Matsumura Y, Endo K, Shimosegawa T. HLA-Bis the best candidate of susceptibility genes inHLAfor Japanese ulcerative colitis. ACTA ACUST UNITED AC 2009; 73:569-74. [DOI: 10.1111/j.1399-0039.2009.01241.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
|
|
15
|
Cassinotti A, Birindelli S, Clerici M, Trabattoni D, Lazzaroni M, Ardizzone S, Colombo R, Rossi E, Porro GB. HLA and autoimmune digestive disease: a clinically oriented review for gastroenterologists. Am J Gastroenterol 2009; 104:195-217; quiz 194, 218. [PMID: 19098870 DOI: 10.1038/ajg.2008.10] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES The human leukocyte antigen (HLA) system includes genes involved in graft-vs-host rejection and in immune response. The discovery that HLAs are associated with several diseases led to appealing developments both in basic biomedical research and in clinical medicine, and offered the opportunity to improve the understanding of pathogenesis and classification of diseases, as well as to provide diagnostic and prognostic indicators. The aim of this article is to review the association between HLA alleles and autoimmune digestive disease and its current relationship with modern HLA nomenclature and clinical practice. METHODS Articles dealing with the association between HLAs and autoimmune digestive disease (including celiac disease, inflammatory bowel disease, autoimmune hepatitis, sclerosing cholangitis and primary biliary cirrhosis) were searched for using Pubmed and SCOPUS databases from earliest records to January 2008. RESULTS The review has provided two sections. In the first, we explain the basic principles of HLA structure, function, and nomenclature, as an introduction to the second section, which describes current associations between HLA alleles and digestive diseases. The clinical implications of each HLA association are critically discussed. Actually, a clinical role for HLA typing is suggested for only a few conditions, e.g., celiac disease. CONCLUSIONS The knowledge of current HLA nomenclature and of its association with some digestive diseases such as celiac disease can be useful in clinical practice for diagnostic and prognostic purposes. This can avoid improper HLA typing as well as stressing the need for further studies on other possible clinical applications.
Collapse
Affiliation(s)
- Andrea Cassinotti
- Department of Clinical Science, Division of Gastroenterology, L. Sacco University Hospital, via G.B.Grassi 74, Milan, Italy.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
16
|
Hancock L, Beckly J, Geremia A, Cooney R, Cummings F, Pathan S, Guo C, Warren BF, Mortensen N, Ahmad T, Jewell D. Clinical and molecular characteristics of isolated colonic Crohn's disease. Inflamm Bowel Dis 2008; 14:1667-77. [PMID: 18521924 DOI: 10.1002/ibd.20517] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Clinical, serological, and molecular data support the existence of discrete subsets of Crohn's disease (CD) defined by location of disease. Little is known about the epidemiology and natural history of isolated CD of the colon (Montreal Classification L2) because most studies have not accurately distinguished it from ileocolonic disease. Our objectives were to describe the clinical features and natural history of isolated colonic CD in a rigorously characterized patient cohort and to investigate the association of polymorphisms in a number of genes with colonic location of disease and disease behavior. METHODS Patients with L2 disease were identified from a database of 675 CD patients. Only patients with a normal small bowel enema (70%), ileoscopy alone (30%), or both (20%) were included. Genotyping was performed using PCR-SSP or the iPLEX platform. RESULTS In all, 135 patients were classified with L2 disease. L2 disease was more common in women (74.0% versus 58.0%; P = 0.0004; odds ratio [OR] = 2.11, 95% confidence interval [CI] 1.36-3.26) and in never smokers (48.9% versus 36.9%; P = 0.008; OR = 1.64, 95% CI 1.09-2.45); 20.7% underwent colonic resection for severe disease. We confirmed that carriage of the HLA-DRB1*0103 allele is strongly associated with isolated colonic CD (14.9% versus 4.0%; P = 0.000016; OR 4.6, 95% CI 2.25-9.47) and report the novel association of this allele with time to first surgical event (log rank P = 0.001). There was no association with any of the known CD susceptibility loci (NOD2, IBD5, NOD1, IL23R, ATG16L1) and isolated colonic CD. A nonsynonymous polymorphism in MEKK1 (rs832582) was associated with CD susceptibility overall (15% versus 19%; P = 0.0083; OR = 1.28, 95% CI 1.07-1.54). The association was strongest in those patients not carrying a NOD2 mutation and had no effect on disease location. CONCLUSIONS This study describes the clinical features of isolated colonic CD and demonstrates the importance of the HLA region in determining the molecular basis of colonic inflammation.
Collapse
Affiliation(s)
- Laura Hancock
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
17
|
Lü M, Xia B, Ge L, Li Y, Zhao J, Chen F, Zhou F, Zhang X, Tan J. Role of major histocompatibility complex class I-related molecules A*A5.1 allele in ulcerative colitis in Chinese patients. Immunology 2008; 128:e230-6. [PMID: 19016911 DOI: 10.1111/j.1365-2567.2008.02953.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The major histocompatibility complex (MHC) class I-related molecules A (MICA) is a stress-inducible cell surface antigen that is recognized by intestinal epithelial Vdelta1 gammadelta T cells, natural killer (NK) cells and CD8(+) T cells with NKG2D receptor participating in the immunological reaction in the intestinal mucosa. The present study aimed to investigate the functions of the MICA*A5.1 allele in the development of ulcerative colitis (UC) in the Chinese population. The microsatellite polymorphisms of MICA were genotyped in 124 unrelated Chinese patients with UC and 172 ethnically matched healthy controls using a semiautomatic fluorescently labelled polymerase chain reaction. MICA*A5.1-expressing Raji cells were generated by gene transfection. Cytotoxicity of NK cells to Raji cells expressing different MICA molecules was detected using the lactate dehydrogenase method. Soluble MICA in the culture supernatant was detected by enzyme-linked immunosorbent assay. The frequency of MICA*A5.1 was significantly higher in UC patients compared with the healthy controls (29.0% versus 17.4%, P = 0.001, corrected P = 0.005, OR = 1.936, 95% CI 1.310-2.863) and the frequency of a MICA*A5.1/A5.1 homozygous genotype was increased in UC patients (18.5% versus 7% in healthy controls, P = 0.0032, corrected P = 0.048, OR = 3.036, 95% CI 1.447-6.372). Raji cells with MICA*A5.1 expression produced more soluble MICA (t = 5.75, P < 0.01) than Raji cells with full-length MICA expression in culture supernatant. Raji cells with MICA*A5.1 expression were more resistant to killing by NK cells than Raji cells with full-length MICA expression. The MICA*A5.1 allele and MICA*A5.1/A5.1 genotype are significantly associated with Chinese UC patients in central China. MICA*A5.1 may play a role in the development of UC by producing more soluble MICA and resistance to NK cells.
Collapse
Affiliation(s)
- Min Lü
- Internal Medicine Department, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing, China
| | | | | | | | | | | | | | | | | |
Collapse
|
|
18
|
Matsumura Y, Kinouchi Y, Nomura E, Negoro K, Kakuta Y, Endo K, Aizawa H, Takagi S, Takahashi S, Shimosegawa T. HLA-DRB1 alleles influence clinical phenotypes in Japanese patients with ulcerative colitis. ACTA ACUST UNITED AC 2008; 71:447-52. [PMID: 18416774 DOI: 10.1111/j.1399-0039.2008.01031.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The human leukocyte antigen (HLA) region has been implicated in the disease susceptibility of inflammatory bowel disease by several linkage and association studies. In Caucasians, HLA-DRB1 has been reported to determine the clinical phenotypes of ulcerative colitis (UC). Others and we previously reported that HLA-DRB1*1502 was strongly associated with UC in the Japanese population. However, the contribution of HLA-DRB1 to the clinical phenotypes in Japanese UC has not been elucidated yet. The aim of this study was to determine whether HLA-DRB1 alleles were associated with the clinical phenotypes in Japanese patients with UC. A total of 353 patients with UC were recruited. Patients were classified into subgroups by sex, age at diagnosis, disease extent, need for steroid therapy or need for surgical treatment. The allele frequency of HLA-DRB1*08 was significantly higher in patients whose disease extended beyond the rectum (left-sided and extensive UC) than in those with proctitis [odds ratio (OR)=2.20, Pc=0.043). The allele frequency of HLA-DRB1*09 was significantly higher in patients with UC diagnosed at the age of 40 years or older than in those with UC diagnosed before the age of 40 years (OR=2.31, Pc=0.022). Besides these positive associations, no significant differences were found in the allele frequencies between the other subgroups. We conclude that HLA-DRB1*09 is associated with the age at diagnosis and HLA-DRB1*08 is associated with the disease extent of UC in Japanese. These results indicate that HLA-DRB1 is not only associated with the overall UC susceptibility but also associated with the clinical phenotypes in Japanese.
Collapse
Affiliation(s)
- Y Matsumura
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
19
|
Fernando MMA, Stevens CR, Walsh EC, De Jager PL, Goyette P, Plenge RM, Vyse TJ, Rioux JD. Defining the role of the MHC in autoimmunity: a review and pooled analysis. PLoS Genet 2008; 4:e1000024. [PMID: 18437207 PMCID: PMC2291482 DOI: 10.1371/journal.pgen.1000024] [Citation(s) in RCA: 387] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The major histocompatibility complex (MHC) is one of the most extensively studied regions in the human genome because of the association of variants at this locus with autoimmune, infectious, and inflammatory diseases. However, identification of causal variants within the MHC for the majority of these diseases has remained difficult due to the great variability and extensive linkage disequilibrium (LD) that exists among alleles throughout this locus, coupled with inadequate study design whereby only a limited subset of about 20 from a total of approximately 250 genes have been studied in small cohorts of predominantly European origin. We have performed a review and pooled analysis of the past 30 years of research on the role of the MHC in six genetically complex disease traits - multiple sclerosis (MS), type 1 diabetes (T1D), systemic lupus erythematosus (SLE), ulcerative colitis (UC), Crohn's disease (CD), and rheumatoid arthritis (RA) - in order to consolidate and evaluate the current literature regarding MHC genetics in these common autoimmune and inflammatory diseases. We corroborate established MHC disease associations and identify predisposing variants that previously have not been appreciated. Furthermore, we find a number of interesting commonalities and differences across diseases that implicate both general and disease-specific pathogenetic mechanisms in autoimmunity.
Collapse
Affiliation(s)
- Michelle M. A. Fernando
- Section of Molecular Genetics and Rheumatology, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Christine R. Stevens
- Program in Medical and Population Genetics, Broad Institute, Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, United States of America
| | - Emily C. Walsh
- Program in Medical and Population Genetics, Broad Institute, Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, United States of America
| | - Philip L. De Jager
- Program in Medical and Population Genetics, Broad Institute, Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, United States of America
- Department of Neurology, Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America
- Harvard Medical School/Partners Healthcare Center for Genetics and Genomics, Boston, Massachusetts, United States of America
| | - Philippe Goyette
- Université de Montréal, Montréal Heart Institute, Montréal, Québec, Canada
| | - Robert M. Plenge
- Program in Medical and Population Genetics, Broad Institute, Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, United States of America
- Harvard Medical School, Division of Rheumatology, Allergy and Immunology, Boston, Massachusetts, United States of America
| | - Timothy J. Vyse
- Section of Molecular Genetics and Rheumatology, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - John D. Rioux
- Program in Medical and Population Genetics, Broad Institute, Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, United States of America
- Université de Montréal, Montréal Heart Institute, Montréal, Québec, Canada
| |
Collapse
|
|
20
|
Rodríguez-Bores L, Fonseca GC, Villeda MA, Yamamoto-Furusho JK. Novel genetic markers in inflammatory bowel disease. World J Gastroenterol 2007; 13:5560-70. [PMID: 17948929 PMCID: PMC4172734 DOI: 10.3748/wjg.v13.i42.5560] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Genetic factors play a significant role in determining inflammatory bowel disease (IBD) susceptibility. Epidemiologic data support genetic contribution to the pathogenesis of IBD, which include familial aggregation, twin studies, racial and ethnic differences in disease prevalence. Linkage studies have identified several susceptibility genes contained in different genomic regions named IBD1 to IBD9. Nucleotide oligomerization domain (NOD2) and human leukocyte antigen (HLA) genes are the most extensively studied genetic regions (IBD1 and IBD3 respectively) in IBD. Mutations of the NOD2 gene are associated with Crohn's disease (CD) and several HLA genes are associated with ulcerative colitis (UC) and CD. Toll like receptors (TLRs) have an important role in the innate immune response against infections by mediating recognition of pathogen-associated microbial patterns. Studying single-nucleotide polymorphisms (SNPs) in molecules involved in bacterial recognition seems to be essential to define genetic backgrounds at risk of IBD. Recently, numerous new genes have been identified to be involved in the genetic susceptibility to IBD: NOD1/Caspase-activation recruitment domains 4 (CARD4), Chemokine ligand 20 (CCL20), IL-11, and IL-18 among others. The characterization of these novel genes potentially will lead to the identification of therapeutic agents and clinical assessment of phenotype and prognosis in patients with IBD.
Collapse
|
|
21
|
Mochida A, Kinouchi Y, Negoro K, Takahashi S, Takagi S, Nomura E, Kakuta Y, Tosa M, Shimosegawa T. Butyrophilin-like 2 gene is associated with ulcerative colitis in the Japanese under strong linkage disequilibrium with HLA-DRB1*1502. ACTA ACUST UNITED AC 2007; 70:128-35. [PMID: 17610417 DOI: 10.1111/j.1399-0039.2007.00866.x] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
The human leukocyte antigen (HLA) region has been implicated in the pathogenesis of inflammatory bowel disease (IBD), which is classified into Crohn's disease (CD) and ulcerative colitis (UC). Recently, an association between sarcoidosis and the butyrophilin-like 2 (BTNL2) gene was reported. BTNL2 is located in the HLA region and its messenger RNA is expressed most abundantly in the intestine. In this study, we performed a case-control association study of BTNL2 in the Japanese patients with IBD and performed linkage disequilibrium (LD) analysis between BTNL2 and HLA-DRB1. We analyzed eight polymorphisms selected after direct sequencing and found that none of the polymorphisms were associated with the Japanese CD cohort. In contrast, five polymorphisms were significantly associated with UC, especially three single nucleotide polymorphisms (BTNL2_19, BTNL2_22 and BTNL2_23) were associated as a haplotype. The most frequent haplotype (GGC haplotype) was a low-risk haplotype (P= 0.000052), whereas the other TCT haplotype was a high-risk haplotype (P= 0.0000085). Among the eight polymorphisms, the strongest association with UC was found in BTNL2_19 (OR = 1.92, P= 0.0000035). As expected, the BTNL2_19-T allele showed strong LD with DRB1*1502 (D'= 0.92). When BTNL2_19 was tested as conditional on the DRB1*1502 carrier status, the significant association disappeared, suggesting that the association was because of its strong LD with DRB1*1502. We conclude that BTNL2 does not contribute to the susceptibility to Japanese CD but is associated with Japanese UC because of the strong LD with HLA-DRB1*1502. The strong LD between BTNL2 and HLA-DRB1 raises another issue about the potential role of BTNL2 in other diseases associated with HLA-DRB1.
Collapse
Affiliation(s)
- A Mochida
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
22
|
Ferguson LR, Shelling AN, Browning BL, Huebner C, Petermann I. Genes, diet and inflammatory bowel disease. Mutat Res 2007; 622:70-83. [PMID: 17628615 DOI: 10.1016/j.mrfmmm.2007.05.011] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2006] [Revised: 04/30/2007] [Accepted: 05/23/2007] [Indexed: 02/06/2023]
Abstract
Inflammatory bowel disease (IBD) arises in part from a genetic predisposition, through the inheritance of a number of contributory genetic polymorphisms. These variant forms of genes may be associated with an abnormal response to normal luminal bacteria. A consistent observation across most populations is that any of three polymorphisms of the Caspase-activated recruitment domain (CARD15) gene are more prevalent in IBD patients as compared with unaffected controls. Similar aberrant responses to bacteria are associated with variants in Autophagy-related 16-like 1 (ATG16L1) and human defensin (HBD-2, -3 and -4) genes. The defective bacterial signal in turn leads to an excessive immune response, presenting as chronic gut inflammation in susceptible individuals. Inconsistent population reports implicate the major histocompatability complex (MHC), that encodes a number of human leukocyte antigens (HLA), MHC class I chain-related gene A (MICA) or cytokines, such as tumour necrosis factor-alpha (TNF-alpha). Toll-like receptors encoded by the TLR4 or TLR9 genes may also play a role. Recent whole genome scans suggest that a rare variant in the interleukin-23 receptor (IL23R) gene may actually protect against IBD. Other implicated genes may affect mucosal cell polarity (Drosophila discs large homologue 5, DLG5) or mucosal transporter function (sodium dependent organic cation transporters, SLC22A4 and SLC22A5). A variant in ABCB1 (ATP-binding cassette subfamily B member 1) may be especially associated with increased risk of UC. While pharmacogenetics is increasingly being used to predict and optimise clinical response to therapy, nutrigenetics may have even greater potential. In many cases, IBD can be controlled through prescribing an elemental diet, which appears to act through modulating cytokine response and changing the gut microbiota. More generally, no single group of dietary items is beneficial or detrimental to all patients, and elimination diets have been used to individualise dietary requirements. However, recognising the nature of the genes involved may suggest a more strategic approach. Pro- or prebiotics will directly influence the microbial flora, while immunonutrition, including omega-3 fatty acids and certain polyphenols, may reduce the symptoms of gut inflammation. The expression of gut transporters may be modulated through various herbal remedies including green tea polyphenols. Such approaches would require that the gene of interest is functioning normally, other than its expression being up or down-regulated. However, new approaches are being developed to overcome the effects of polymorphisms that affect the function of a gene. A combination of human correlation studies with experimental models could provide a rational strategy for optimising nutrigenetic approaches to IBD.
Collapse
Affiliation(s)
- Lynnette R Ferguson
- Discipline of Nutrition, Faculty of Medical & Health Science, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
| | | | | | | | | |
Collapse
|
|
23
|
Abstract
The human leucocyte antigen (HLA) complex on chromosome 6p21.3 is the most extensively studied genetic region in Inflammatory bowel disease (IBD). Consistent evidence of linkage to IBD3 (6p21.1-23), an area which encompasses the HLA complex, has been demonstrated for both Crohn’s disease and ulcerative colitis, and a number of replicated associations with disease susceptibility and phenotype have recently emerged. However, despite these efforts the HLA susceptibility gene (s) for IBD remain elusive, a consequence of strong linkage disequilibrium, extensive polymorphism and high gene density across this region. This article reviews current knowledge of the role of HLA complex genes in IBD susceptibility and phenotype, and discusses the factors currently limiting the translation of this knowledge to clinical practice.
Collapse
Affiliation(s)
- Tariq Ahmad
- Gastroenterology Unit, University of Oxford, Gibson Laboratories, Radcliffe Infirmary, UK.
| | | | | |
Collapse
|
|
24
|
Lü M, Xia B, Li J, Ye M, Zhang X, Tan Q. MICB microsatellite polymorphism is associated with ulcerative colitis in Chinese population. Clin Immunol 2006; 120:199-204. [PMID: 16679067 DOI: 10.1016/j.clim.2006.03.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2005] [Revised: 02/27/2006] [Accepted: 03/08/2006] [Indexed: 12/12/2022]
Abstract
The MHC class I-related molecules A and B (MICA and MICB) are stress-inducible cell surface antigens that are recognized by immunocytes bearing the receptor NKG2D, including intestinal epithelial Vdelta1 gammadelta T cells, which may play a role in immunological reaction in intestinal mucosa. The present study was aimed to investigate the association of the microsatellite polymorphisms in the intron 1 of MICB and the MICA-MICB haplotype with the susceptibility to ulcerative colitis (UC) in Chinese population. The microsatellite polymorphisms of MICB were genotyped in unrelated 127 Chinese patients with UC and 193 ethnically matched healthy controls by a semiautomatic fluorescently labeled PCR method. All the subjects were the Chinese with Han nationality. The frequency of MICB-CA18 was significantly higher in UC patients compared with the healthy controls (14.0% vs. 5.8%, P = 0.0016, Pc = 0.024, OR = 2.637, 95%CI: 1.443-4.820) and was increased in the female patients compared with the female healthy controls (18.3% vs. 4.1%, P = 0.0006, Pc = 0.0080, OR = 5.224, 95%CI: 1.940-14.069). Thus, MICB-CA18 is positively associated with UC and female UC patients in Chinese population.
Collapse
Affiliation(s)
- Min Lü
- Department of Internal Medicine and Geriatrics, and Research Center of Digestive Diseases, Zhongnan Hospital, PR China
| | | | | | | | | | | |
Collapse
|
|
25
|
Ding Y, Xia B, Lü M, Zhang Y, Li J, Ye M, Luo H, Yu J, Zhang X, Tan J. MHC class I chain-related gene A-A5.1 allele is associated with ulcerative colitis in Chinese population. Clin Exp Immunol 2005; 142:193-8. [PMID: 16178876 PMCID: PMC1809485 DOI: 10.1111/j.1365-2249.2005.02907.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
The human MHC class I chain-related gene A (MICA) plays a role in regulating protective responses by intestinal epithelial Vdelta1 gamma delta T cells and the polymorphism of MICA were reported to be related to several autoimmune diseases. The present study aimed to investigate the association of the microsatellite polymorphisms of TM region of MICA gene with the susceptibility to ulcerative colitis (UC) in Chinese population. The microsatellite polymorphisms of the MICA were genotyped in unrelated 86 Chinese patients with UC and 172 ethnically matched healthy controls by a semiautomatic fluorenscently labelled PCR method. All the subjects were the Chinese with Han nationality. The frequency of MICA-A5.1 homozygous genotype and A5.1 allele were significantly increased in UC patients compared with healthy controls (22.1%versus 7%, P = 0.0009, Pc = 0.0126, OR = 3.781, 95%CI: 1.738-8.225 and 30.2%versus 17.4%, P = 0.0014, Pc = 0.007, OR = 2.051, 95%CI: 1.336-3.148, respectively). Adjusted the effects of gender and age at onset, MICA-A5.1 homozygous genotype and A5.1 allele were also increased in the UC patients. Moreover MICA-A5.1 allele was significantly increased in frequency in the female UC patients (38.2%versus 21.0%, P = 0.0095, Pc = 0.0475, OR = 2.326, 95%CI: 1.234-4.382). Logistic regression analysis also revealed that gender was independently associated with UC patients carried MICA-A5.1 allele (P = 0.046, OR (male) = 0.511, 95% CI: 0.264-0.987). Although the UC patients with extensive colitis (32.5%versus 17.4% in the healthy controls, P = 0.005, Pc = 0.025) and the UC patients with extraintestinal manifestations (36%versus 17.4% in the healthy controls, P = 0.0039, Pc = 0.0195) were more likely to carry the MICA-A5.1 allele, EIMs was associated with extent of disease (P < 0.0001, OR (with EIMs) = 3.511, 95% CI 1.747-7.056) and MICA-A5.1 allele was not associated with UC patients with extensive colitis or with EIMs in the logistic regression analysis. Therefore, the MICA-A5.1 homozygous genotype and A5.1 allele were closely associated with UC and the MICA-A5.1 allele was positively associated with the female UC patients in Chinese population.
Collapse
Affiliation(s)
- Yijuan Ding
- Department of Gastroenterology, Renmin Hospital, Wuhan University School of MedicineWuhan
| | - Bing Xia
- Department of Internal Medicine & Geriatrics, Research Centre of Digestive Diseases of Zhongnan HospitalPeoples Republic of China
- Department of Key Laboratory of Allergy and Immune Related Diseases, Wuhan University School of MedicineWuhan
| | - Min Lü
- Department of Internal Medicine & Geriatrics, Research Centre of Digestive Diseases of Zhongnan HospitalPeoples Republic of China
| | - Yan Zhang
- Department of Internal Medicine & Geriatrics, Research Centre of Digestive Diseases of Zhongnan HospitalPeoples Republic of China
| | - Jin Li
- Department of Internal Medicine & Geriatrics, Research Centre of Digestive Diseases of Zhongnan HospitalPeoples Republic of China
| | - Mei Ye
- Department of Internal Medicine & Geriatrics, Research Centre of Digestive Diseases of Zhongnan HospitalPeoples Republic of China
| | - Hesheng Luo
- Department of Gastroenterology, Renmin Hospital, Wuhan University School of MedicineWuhan
| | - Jieping Yu
- Department of Gastroenterology, Renmin Hospital, Wuhan University School of MedicineWuhan
| | - Xiaolian Zhang
- Department of Internal Medicine & Geriatrics, Research Centre of Digestive Diseases of Zhongnan HospitalPeoples Republic of China
| | - Jingquan Tan
- Department of Internal Medicine & Geriatrics, Research Centre of Digestive Diseases of Zhongnan HospitalPeoples Republic of China
| |
Collapse
|
|
26
|
Shao W, Tang J, Dorak MT, Song W, Lobashevsky E, Cobbs CS, Wrensch MR, Kaslow RA. Molecular typing of human leukocyte antigen and related polymorphisms following whole genome amplification. ACTA ACUST UNITED AC 2005; 64:286-92. [PMID: 15304010 DOI: 10.1111/j.0001-2815.2004.00295.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Reliable, high-resolution genotyping of human leukocyte antigen (HLA) polymorphisms is often compromised by DNA samples of suboptimal quality or limited quantity. We tested the feasibility of molecular typing for variants at HLA and neighboring loci using whole genome amplification (WGA) strategy facilitated by the Phi29 DNA polymerase. With little (5-100 ng) starting genomic DNA of varying quality and source materials, WGA was deemed successful in 167 of 169 DNA from 47 cell lines, 100 European Americans, and 22 native Africans. The Phi29-processed DNA provided adequate templates for polymerase chain reaction (PCR)-based analyses of several HLA (A, B, C, DRB1, and DQB1) and related loci (HFE, MICA, and 10 microsatellites) in the 6p24.3-6p21.3 region, with PCR amplicons ranging from 92 to 2200 bp. Five different genotyping techniques resolved and confirmed 364 genotypes when both original and Phi29-processed DNA worked in PCRs. General population genetic analyses provided additional evidence that WGA may represent a reliable and simple approach to securing ample genomic DNA for typing HLA, MICA, and related variants.
Collapse
Affiliation(s)
- W Shao
- Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA
| | | | | | | | | | | | | | | |
Collapse
|
|
27
|
Romphruk AV, Romphruk A, Choonhakarn C, Puapairoj C, Inoko H, Leelayuwat C. Major histocompatibility complex class I chain-related gene A in Thai psoriasis patients: MICA association as a part of human leukocyte antigen-B-Cw haplotypes. ACTA ACUST UNITED AC 2005; 63:547-54. [PMID: 15140030 DOI: 10.1111/j.0001-2815.2004.00238.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Psoriasis is a chronic inflammatory skin disorder. Although the aetiology and pathogenesis of psoriasis are unproven, it is hypothesised that the major histocompatibility complex (MHC) gene/haplotype contributes to the susceptibility of psoriasis in many populations. MHC class I chain-related gene A (MICA), located 46-kb centromeric of HLA-B, is expressed on keratinocytes and fibroblasts. MICA is in linkage disequilibrium with HLA-B and is involved in natural killer-cell functions. To investigate the relative contribution of the MICA gene in the pathogenesis of psoriasis, extracellular polymorphisms of MICA were studied by polymerase chain reaction-sequence specific primers in 128 Thai psoriasis patients (87 and 41 were Types I and II, respectively) from Srinagarind Hospital, Faculty of Medicine, Khon Kaen University. The control group included 255 healthy, unrelated Northeast Thais. We observed 11 MICA alleles (or groups of alleles) in the patients. A comparison of the psoriasis patients and the control group revealed that MICA*010 and MICA*017 were associated with Type I psoriasis whereas only MICA*010 was associated with Type II. The haplotype analysis revealed that MICA*008-HLA-B*13-Cw*0602 and MICA*010-HLA-B*4601-Cw*01 were significantly increased in both Types I and II, whereas MICA*002-HLA-B*38-Cw*07 (01-03) and MICA*017-HLA-B*57-Cw*0602 were elevated only in Type I. MICA*010 was in strong linkage with Cw*01. Analysis of independent association of MICA*010 in individuals lacking Cw*01 failed to maintain an association. Our results suggest that a significant increase of the MICA alleles in the patient group is a part of HLA-B-Cw haplotypes. It is conceivable that an unknown susceptibility gene, on certain HLA-B-Cw haplotypes, is responsible for the development of psoriasis.
Collapse
Affiliation(s)
- A V Romphruk
- Blood Transfusion Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | | | | | | | | | | |
Collapse
|
|
28
|
Ahmad T, Armuzzi A, Neville M, Bunce M, Ling KL, Welsh KI, Marshall SE, Jewell DP. The contribution of human leucocyte antigen complex genes to disease phenotype in ulcerative colitis. ACTA ACUST UNITED AC 2004; 62:527-35. [PMID: 14617036 DOI: 10.1046/j.1399-0039.2003.00129.x] [Citation(s) in RCA: 76] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Linkage and association studies implicate the human leucocyte antigen (HLA) region in genetic susceptibility to ulcerative colitis (UC). However, associations with specific variants have been inconsistent, even within defined ethnic groups. A genetic basis for the disease heterogeneity of UC may account for these discrepant findings from studies in unselected populations. Here, we examine the contribution of the HLA region to the clinical phenotype of UC. We studied 321 accurately phenotyped patients recruited from a single UK centre, with a median follow-up time of 15 years. Individuals were genotyped for 340 polymorphisms constructed into 25 gene-specific allelic haplotypes between HLA-A and Tapasin. Data were analysed with respect to age of onset, disease extent and severity. Strongest association with overall susceptibility was identified with HLA-DRB1 alleles replicating previous studies (DRB1*0103, DRB1*1502 and DRB1*0401). We report a novel association with homozygosity of a tumour necrosis factor (TNF) promoter haplotype (TNF-1031T, -863C, -857C, -380G, -308G and -238G) and distal disease extent that does not extend with time (distal vs total 40.9 vs 25.7%; RR = 2.0; 95% CI 1.23-3.24). We confirm the association of DRB1*0103 with total disease and/or disease requiring colectomy and further demonstrate that DRB1*0103 is associated with shorter time to surgery. Genes in the HLA play a role in modifying disease phenotype. Further studies are required to dissect how these genes functionally interact with each other and with environmental factors to determine clinical patterns of disease
Collapse
Affiliation(s)
- T Ahmad
- Gastroenterology Unit, University of Oxford, Gibson Laboratories, Radcliffe Infirmary, Woodstock Road, Oxford, UK.
| | | | | | | | | | | | | | | |
Collapse
|
|
29
|
Yap LM, Ahmad T, Jewell DP. The contribution of HLA genes to IBD susceptibility and phenotype. Best Pract Res Clin Gastroenterol 2004; 18:577-96. [PMID: 15157829 DOI: 10.1016/j.bpg.2004.01.003] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The human leukocyte antigen (HLA) region located on chromosome 6p encodes the highly polymorphic, classical class I and II genes essential for normal lymphocyte function; it also encodes a further 224 genes. Many early studies investigating this region were limited by small sample size, poor statistical methodology, population stratification and variable disease definition. Although more recent studies have improved study design, investigators are still challenged by the complex patterns of linkage disequilibrium across this gene-dense region, and by the disease heterogeneity characteristic of all genetically complex disorders. However, a number of important observations have emerged from recent studies: (1) the HLA harbours gene(s) that determine susceptibility to colonic inflammation in both ulcerative colitis (UC) and Crohn's disease (CD); (2) most of the specific associations with UC and CD appear to differ; (3) associations between different ethnic groups differ; (4) markers in the HLA might predict the course of disease and the development of complications, notably the extraintestinal manifestations of disease.
Collapse
Affiliation(s)
- Lee Min Yap
- Gastroenterology Unit, Gibson Laboratories, University of Oxford, Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE, UK.
| | | | | |
Collapse
|
|
30
|
Grubić Z, Perić P, Eeèuk-Jelicić E, Zunec R, Stingl K, Curković B, Kerhin-Brkljacić V. The MICA-A4 triplet repeats polymorphism in the transmembrane region confers additional risk for development of psoriatic arthritis in the Croatian population. ACTA ACUST UNITED AC 2004; 31:93-8. [PMID: 15086350 DOI: 10.1111/j.1365-2370.2004.00452.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The aim of this study was to investigate possible differences in the frequencies of alleles at the HLA loci and at microsatellite loci within the HLA region among patients suffering from psoriatic arthritis (PsA) and healthy controls. Fifty-eight Croatian PsA patients (28 male and 30 female) and 157 healthy unrelated controls were typed for HLA alleles (A, B, Cw and DRB1) by the polymerase chain reaction-sequence-specific primers (PCR-SSP) method, while microsatellite alleles (D6S265, D6S273, MHC class I chain-related gene (MICA) and MIB) were analysed by electrophoresis in an ALFexpress sequencer (Pharmacia Biotech, Uppsala, Sweden). The findings from this study were: (1) the frequencies of B*39 and B*57 were significantly increased in PsA patients; (2) differences in the frequencies of B*13 and B*27 were not statistically significant after correction; (3) the B*0702, B*18, and B*38 alleles were decreased in patients only before correction; (4) none of the alleles at other HLA loci tested were associated with PsA in Croatia; (5) polymorphism at D6S265, D6S273, and MIB microsatellites in patients did not show any statistically significant differences when compared to controls; (6) the increase in the MICA-A4 allele frequency in PsA patients was independent of the B*39 and B*57 alleles.
Collapse
Affiliation(s)
- Z Grubić
- National Referral Organ Transplantation and Tissue Typing Centre, University Hospital Centre Zagreb, Zagreb, Croatia.
| | | | | | | | | | | | | |
Collapse
|
|
31
|
Kobashigawa T, Okamoto H, Kato J, Shindo H, Imamura T, Iizuka BE, Tanaka M, Uesato M, Ohta SJ, Terai C, Hara M, Kamatani N. Ulcerative colitis followed by the development of Behçet's disease. Intern Med 2004; 43:243-7. [PMID: 15098609 DOI: 10.2169/internalmedicine.43.243] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
A 34-year-old man who had a history of ulcerative colitis (UC) was admitted to our hospital with complaints of arthralgia, erythema nodosum, recurrent oral aphthous ulcers and bloody stools. A colonoscopy revealed multiple aphthous ulcers on his cecum and colon and also revealed a transmural ulcer on his rectum consistent with a diagnosis of UC. The patient was HLA-B51 positive. Based on clinical evidence [recurrent oral ulcers, skin lesions (erythema nodosum), positivity for pathergy test] this patient was diagnosed as having Behçet's disease with gastrointestinal involvement. We describe this rare case of Behçet's disease with colitis and discuss the difficulties in making a differential diagnosis between Behçet's disease and the inflammatory bowel diseases.
Collapse
|
|
32
|
|
|
33
|
Lo FS, Lee YJ, Huang CY, Lin CH, Chang SC, Dang CW, Liu HF. Polymorphism in the transmembrane region of the major histocompatibility complex class I chain-related gene A: association of five GCT repetitions with Graves' disease in children. Thyroid 2003; 13:839-43. [PMID: 14588097 DOI: 10.1089/105072503322401023] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Graves' disease is an autoimmune disease involving a complex interplay of multiple genetic and environmental influences. An association between the disorder and the major histocompatibility complex (MHC; human leukocyte antigen [HLA]) region has long been reported. The major histocompatibility complex class I chain-related gene A (MICA) has a triplet repeat polymorphism in the transmembrane region consisting of six alleles. For this study, the polymorphism in question was analyzed for 129 unrelated children with Graves' disease (97 girls and 32 boys, 10.0 +/- 3.0 years of age) and 396 randomly selected, unrelated subjects (205 females, 191 males, 8.4 +/- 13.5 years of age). The frequencies of genotype A5/A5 and A5/A5.1 were significantly higher in patients than in controls (relative risk [RR] = 2.49, 95% confidence interval [CI] 1.52-4.10, p = 0.00024, pc = 0.0035 and RR = 2.13, 95% CI 1.31-3.47, p = 0.0020, pc = 0.030; respectively). The frequency of genotype A5.1/A5.1 was significantly lower in patients than in controls (RR = 0.09, 95% CI 0.01-0.66, p = 0.0030, pc = 0.044). Allele frequency for allele A5 was significantly higher for children with Graves' disease compared to controls (RR = 2.12; 95% CI = 1.59-2.82; p = 1.9 x 10(-7); pc = 9.5 x 10(-7)). This study demonstrates that MICA allele A5 confers the risk for Graves' disease.
Collapse
Affiliation(s)
- Fu-Sung Lo
- Department of Pediatrics, Chang Gung Children's Hospital, Tao-Yuang, Taiwan
| | | | | | | | | | | | | |
Collapse
|
|
34
|
Cottone M, Marrone C, Casà A, Oliva L, Orlando A, Calabrese E, Martorana G, Pagliaro L. Familial occurrence of inflammatory bowel disease in celiac disease. Inflamm Bowel Dis 2003; 9:321-3. [PMID: 14555916 DOI: 10.1097/00054725-200309000-00006] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND The authors have previously reported a possible increased risk of the familial occurrence of Crohn's disease in patients with celiac disease. AIM The aim of the current study was to evaluate in a case-control study the familial occurrence of inflammatory bowel disease (IBD) in first-degree relatives of patients with celiac disease. METHODS One hundred eleven consecutive patients with biopsy-proven celiac disease were interviewed to ascertain whether IBD was present in first-degree relatives. The number of relatives, their ages, and possible IBD status were collected in a questionnaire. When a diagnosis of familial IBD was reported, the diagnosis was checked in the hospital records. Two hundred twenty-two controls matched for age and sex (111 from the general population and 111 from orthopedic wards) were also interviewed regarding the possible occurrence of IBD in first-degree relatives. The chi2 test was used to evaluate the difference in proportion of familial occurrence of IBD among individuals with celiac disease and controls. RESULTS Among 600 first-degree relatives of patients with celiac disease, 10 cases of IBD were identified among first-degree relatives (7 cases of ulcerative colitis and 3 cases of Crohn's disease), whereas only 1 case of IBD was identified among the 1,196 first-degree relatives of control patients (p < 0.01). When ulcerative colitis and Crohn's disease were analyzed separately, only the prevalence of ulcerative colitis was statistically significant (p </= 0.02). CONCLUSIONS This case-control study shows that there is a significantly increased prevalence of familial ulcerative colitis in patients with celiac disease. There was no significant increase in the prevalence of Crohn's disease in patients with celiac disease. The possible role of this association is discussed.
Collapse
Affiliation(s)
- Mario Cottone
- Clinica Medica R, University of Palermo, Ospedale V. Cervello, Palermo, Italy.
| | | | | | | | | | | | | | | |
Collapse
|
|
35
|
Zheng CQ, Hu GZ, Zeng ZS, Lin LJ, Gu GG. Progress in searching for susceptibility gene for inflammatory bowel disease by positional cloning. World J Gastroenterol 2003; 9:1646-56. [PMID: 12918095 PMCID: PMC4611518 DOI: 10.3748/wjg.v9.i8.1646] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) includes two clinical subtypes: Crohn disease (CD) and ulcerative colitis (UC). The general prevalence is about 1.0%-2.0% in Western countries. It is predominantly regarded as a multifactorial disorder involving environmental factors and polygenic defects. The view was confirmed by a lot of evidences from clinical attributions and animal models, especially from epidemiological investigations. So the etiological study of IBD has been focused on searching for susceptibility genes by positional cloning, which consists of two steps: linkage analysis and association analysis. Linkage analysis has been an important method of searching for susceptibility genes to polygenic diseases as well as single-gene disorders. IBD, as a polygenic disease, has been widely investigated by linkage analysis for susceptibility gene since 1996. The paper reviewed 38 articles, which covered almost all original researches in relation to IBD and linkage analysis. So far, several loci, such as 16q, 12q, 6p and 3p, have been identified by the studies. The most striking is 16q12 (IBD1), which linked only with CD not UC in the majority of studies. Association analysis, as one essential step for positional cloning, is usually carried out by genotyping candidate genes selected by means of linkage analysis or other methods, for figuring out the frequencies of alleles and comparing the frequencies between IBD group and healthy control group to identify the specific allele. It has been established that IBD is implicated in immune disorder. So the studies were centered on the genes of NOD2/CARD15, HLA-II, cytokine, cytokine receptor and adhesion molecule. This paper reviewed 14 original articles on association between NOD2 and IBD that have been published since 2001. All results, with the exception of one report from a Japanese group, provide evidences that the three kinds of variants of NOD2 are susceptibility factors for IBD. This article also comprehensively analyzed 18 original researches of HLA gene polymorphism in IBD. We found extensive discrepancy among the conclusions and a novel hypothesis was put forward to explain the discordance. Most studies published recently on association between IBD and cytokine gene polymorphism were reviewed.
Collapse
Affiliation(s)
- Chang-Qing Zheng
- Department of Gastroenterology, the Second Affiliated Clinical College of China Medical University, Shenyang 110001, Liaoning Province, China.
| | | | | | | | | |
Collapse
|
|
36
|
Fdez-Morera JL, Rodrigo L, López-Vázquez A, Rodero SR, Martínez-Borra J, Niño P, González S, López-Larrea C. MHC class I chain-related gene A transmembrane polymorphism modulates the extension of ulcerative colitis. Hum Immunol 2003; 64:816-22. [PMID: 12878361 DOI: 10.1016/s0198-8859(03)00121-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Recent evidence from several studies has suggested a genetic predisposition in the pathogenesis of ulcerative colitis (UC), which is especially related with major histocompatibility complex (MHC) genes. The aim of this study was to investigate the possible association of human leukocyte antigen (HLA-B, HLA-DR) and MHC class I chain-related-transmembrane (MICA-TM) polymorphism with the behavior and extension of UC. We selected 121 unrelated patients with UC. These were divided into two groups according to the extension of the disease: 31 patients with distal UC and 90 with wide extension UC; 116 blood donors were also selected as healthy controls, all of whom were typed for HLA-B, HLA-DR, and MICA-TM alleles. HLA-B7 was found to be overrepresented in distal UC patients compared with those with extensive UC (p(c) = 0.007, OR = 5.33) and healthy controls (p(c) = 0.03, OR = 4.09). The MICA-A5.1 allele was also increased in distal UC (p(c) = 0.015, OR = 3.82) when compared with extensive forms. These alleles are in strong linkage disequilibrium in our population. The MICA-A5 allele was significantly increased in extensive forms when compared with healthy controls(p(c) = 0.02, OR = 2.4). According to our results, MICA-A5.1 allele seems to be protective against extensive forms of UC, and MICA-A5 may condition a worse progression of the disease. These results are in agreement with other studies that suggest a similar role of such alleles in other diseases, such as insulin-dependent diabetes mellitus and celiac disease.
Collapse
|
|
37
|
Herbon N, Werner M, Braig C, Gohlke H, Dütsch G, Illig T, Altmüller J, Hampe J, Lantermann A, Schreiber S, Bonifacio E, Ziegler A, Schwab S, Wildenauer D, van den Boom D, Braun A, Knapp M, Reitmeir P, Wjst M. High-resolution SNP scan of chromosome 6p21 in pooled samples from patients with complex diseases. Genomics 2003; 81:510-8. [PMID: 12706109 DOI: 10.1016/s0888-7543(02)00035-6] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
We apply a high-throughput protocol of chip-based mass spectrometry (matrix-assisted laser desorption/ionization time-of-flight; MALDI-TOF) as a method of screening for differences in single-nucleotide polymorphism (SNP) allele frequencies. Using pooled DNA from individuals with asthma, Crohn's disease (CD), schizophrenia, type 1 diabetes (T1D), and controls, we selected 534 SNPs from an initial set of 1435 SNPs spanning a 25-Mb region on chromosome 6p21. The standard deviations of measurements of time of flight at different dots, from different PCRs, and from different pools indicate reliable results on each analysis step. In 90% of the disease-control comparisons we found allelic differences of <10%. Of the T1D samples, which served as a positive control, 10 SNPs with significant differences were observed after taking into account multiple testing. Of these 10 SNPs, 5 are located between DQB1 and DRB1, confirming the known association with the DR3 and DR4 haplotypes whereas two additional SNPs also reproduced known associations of T1D with DOB and LTA. In the CD pool also, two earlier described associations were found with SNPs close to DRB1 and MICA. Additional associations were found in the schizophrenia and asthma pools. They should be confirmed in individual samples or can be used to develop further quality criteria for accepting true differences between pools. The determination of SNP allele frequencies in pooled DNA appears to be of value in assigning further genotyping priorities also in large linkage regions.
Collapse
Affiliation(s)
- Nicole Herbon
- Institut für Epidemiologie, GSF Forschungszentrum für Umwelt und Gesundheit, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
38
|
Pyo CW, Hur SS, Kim YK, Choi HB, Kim TY, Kim TG. Distribution of MICA alleles and haplotypes associated with HLA in the Korean population. Hum Immunol 2003; 64:378-84. [PMID: 12590984 DOI: 10.1016/s0198-8859(02)00826-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
The MICA (MHC class I chain-related gene A) is a polymorphic gene located 46 kb centromeric of the HLA-B gene, and is preferentially expressed in epithelial cells and intestinal mucosa. The MICA gene, similar to human leukocyte antigen (HLA) class I, displays a high degree of genetic polymorphism in exons 2, 3, 4, and 5, amounting to 54 alleles. In this study, we investigated the polymorphisms at exons coding for extracellular domains (exons 2, 3, and 4), and the GCT repeat polymorphism at the transmembrane (exon 5) of MICA in 199 unrelated healthy Koreans. Eight alleles were observed in the Korean population, with allele frequencies for MICA*010, MICA*00201, MICA*027, MICA*004, MICA*012, MICA*00801, MICA*00901, and MICA*00701 being 18.3%, 17.8%, 13.6%, 12.3%, 11.1%, 10.8%, 10.6%, and 3.3%, respectively. Strong linkage disequilibria were also observed between the MICA and HLA-B gene-MICA*00201-B58, MICA*004-B44, MICA*00701-B27, MICA*00801-B60, MICA*00901-B51, MICA*010-B62, MICA*012-B54, and MICA*027-B61. In the analysis of the haplotypes of HLA class I genes (HLA-A, B, and C) and the MICA, the most common haplotype was MICA*004-A33-B44-Cw*07, followed by MICA*00201-A2-B58-Cw*0302 and MICA*012-A2-B54-Cw*0102. The MICA null haplotype might be identified in the HLA-B48 homozygous individual. These results will provide an understanding of the role of MICA in transplantation, disease association, and population analyses in Koreans.
Collapse
Affiliation(s)
- Chul-Woo Pyo
- Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | | | | | | | | | | |
Collapse
|
|
39
|
Ahmad T, Marshall SE, Mulcahy-Hawes K, Orchard T, Crawshaw J, Armuzzi A, Neville M, van Heel D, Barnardo M, Welsh KI, Jewell DP, Bunce M. High resolution MIC genotyping: design and application to the investigation of inflammatory bowel disease susceptibility. TISSUE ANTIGENS 2002; 60:164-79. [PMID: 12392511 DOI: 10.1034/j.1399-0039.2002.600207.x] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The highly polymorphic nonclassical MHC class I chain-related (MIC) genes MICA and MICB encode stress inducible glycoproteins expressed on a variety of epithelial cells including intestinal cells. Interaction with the receptor NKG2D is likely to provide an important costimulatory signal for activation and proliferation of NK cells, activated macrophages and CD8 alphabeta and gammadelta T cells. Fifty-four MICA and 17 MICB alleles have been described to date. Although the functional significance of this polymorphism is not known, the high degree of nonconservative substitution, concentration to the putative ligand-binding site and recent observation that different MICA alleles bind to NKG2D with varying affinity has generated much interest. The MIC genes are attractive functional and positional candidate genes for inflammatory bowel disease susceptibility as a consequence of their position in the HLA region and expression on the gastrointestinal epithelium. We developed a robust, high-resolution PCR-SSP genotyping method that can be incorporated into the standard 'Phototyping' system and which effectively identifies 46 of 54 MICA alleles, and all 17 MICB alleles. We applied this system in combination with microsatellite genotyping of the exon 5 variable number of tandem repeats (VNTR) to the investigation of genetic susceptibility to the inflammatory bowel diseases, ulcerative colitis and Crohn's disease. We studied 248 patients with Crohn's disease, 329 with ulcerative colitis and 354 ethnically matched controls. Linkage disequilibrium patterns between HLA-B, MICA and MICB are presented. Analysis by individual allele or by multilocus haplotype failed to identify any significant disease associations.
Collapse
Affiliation(s)
- T Ahmad
- Gastroenterology Unit, University of Oxford, Gibson Laboratories, Radcliffe Infirmary, UK.
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
40
|
Martin TM, Smith JR, Rosenbaum JT. Anterior uveitis: current concepts of pathogenesis and interactions with the spondyloarthropathies. Curr Opin Rheumatol 2002; 14:337-41. [PMID: 12118164 DOI: 10.1097/00002281-200207000-00001] [Citation(s) in RCA: 62] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Anterior uveitis describes inflammation that involves the iris or ciliary body. Anterior uveitis may be part of a systemic illness such as a spondyloarthropathy. It may also arise from an infection such as herpes simplex; be part of an ocular syndrome, such as Fuchs' heterochromic iridocyclitis; be part of trauma, as in cataract surgery; or result from an idiopathic eye disease with a presumed immune pathogenesis. During 2001, progress has been made understanding uveitis in general, as well as specifically, in association with spondyloarthropathy. Here, we review recent insights into anterior uveitis with regard to clinical presentation, immune mechanisms, genetics, and anti-tumor necrosis factor therapy.
Collapse
Affiliation(s)
- Tammy M Martin
- Oregon Health & Science University, Casey Eye Institute, Portland, Oregon 97201, USA.
| | | | | |
Collapse
|