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Song J, Li Y, Bowlus CL, Yang G, Leung PSC, Gershwin ME. Cholangiocarcinoma in Patients with Primary Sclerosing Cholangitis (PSC): a Comprehensive Review. Clin Rev Allergy Immunol 2020; 58:134-149. [PMID: 31463807 DOI: 10.1007/s12016-019-08764-7] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Cholangiocarcinoma (CCA) is the most common malignancy in patients with primary sclerosing cholangitis (PSC) and carries a high rate of mortality. Although the pathogenesis of CCA in PSC is largely unknown, inflammation-driven carcinogenesis concomitant with various genetic and epigenetic abnormalities are underlying factors. The majority of CCA cases develop from a dominant stricture (DS), which is defined as a stricture with a diameter < 1.5 mm in the common bile duct or < 1.0 mm in the hepatic duct. In PSC patients presenting with an abrupt aggravation of jaundice, pain, fatigue, pruritus, weight loss, or worsening liver biochemistries, CCA should be suspected and evaluated utilizing a variety of diagnostic modalities. However, early recognition of CCA in PSC remains a major challenge. Importantly, 30-50% of CCA in PSC patients are observed within the first year following the diagnosis of PSC followed by an annual incidence ranging from 0.5 to 1.5 per 100 persons, which is nearly 10 to 1000 times higher than that in the general population. Cumulative 5-year, 10-year, and lifetime incidences are 7%, 8-11%, and 9-20%, respectively. When PSC-associated CCA is diagnosed, most tumors are unresectable, and no effective medications are available. Given the poor therapeutic outcome, the surveillance and management of PSC patients who are at an increased risk of developing CCA are of importance. Such patients include older males with large-duct PSC and possibly concurrent ulcerative colitis. Thus, more attention should be paid to patients with these clinical features, in particular within the first year after PSC diagnosis. In contrast, CCA is less frequently observed in pediatric or female PSC patients or in those with small-duct PSC or concurrent Crohn's disease. Recently, new biomarkers such as antibodies to glycoprotein 2 have been found to be associated with an increased risk of developing CCA in PSC. Herein, we review the literature on the pathogenesis, incidence, clinical features, and risk factors, with a focus on various diagnostic modalities of PSC-associated CCA.
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Affiliation(s)
- Junmin Song
- Department of Gastroenterology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, People's Republic of China.,Division of Rheumatology, Allergy and Clinical Immunology, University of California, 451 Health Science Drive, Suite 6510, Davis, CA, 95616, USA
| | - Yang Li
- Department of Intensive Care Unit (ICU), Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, Liaoning, 110004, People's Republic of China
| | - Christopher L Bowlus
- Division of Gastroenterology and Hepatology, University of California, 451 Health Sciences Drive, Suite 6510, Davis, CA, 95616, USA
| | - GuoXiang Yang
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, 451 Health Science Drive, Suite 6510, Davis, CA, 95616, USA
| | - Patrick S C Leung
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, 451 Health Science Drive, Suite 6510, Davis, CA, 95616, USA.
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, 451 Health Science Drive, Suite 6510, Davis, CA, 95616, USA.
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Matrix metalloproteinases in inflammatory bowel disease: an update. Mediators Inflamm 2015; 2015:964131. [PMID: 25948887 PMCID: PMC4408746 DOI: 10.1155/2015/964131] [Citation(s) in RCA: 98] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2014] [Accepted: 09/07/2014] [Indexed: 02/07/2023] Open
Abstract
Matrix metalloproteinases (MMPs) are known to be upregulated in inflammatory bowel disease (IBD) and other inflammatory conditions, but while their involvement is clear, their role in many settings has yet to be determined. Studies of the involvement of MMPs in IBD since 2006 have revealed an array of immune and stromal cells which release the proteases in response to inflammatory cytokines and growth factors. Through digestion of the extracellular matrix and cleavage of bioactive proteins, a huge diversity of roles have been revealed for the MMPs in IBD, where they have been shown to regulate epithelial barrier function, immune response, angiogenesis, fibrosis, and wound healing. For this reason, MMPs have been recognised as potential biomarkers for disease activity in IBD and inhibition remains a huge area of interest. This review describes new roles of MMPs in the pathophysiology of IBD and suggests future directions for the development of treatment strategies in this condition.
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Lepetsos P, Pampanos A, Kanavakis E, Tzetis M, Korres D, Papavassiliou AG, Efstathopoulos N. Association of MMP-1 -1607 1G/2G (rs1799750) polymorphism with primary knee osteoarthritis in the Greek population. J Orthop Res 2014; 32:1155-60. [PMID: 24838892 DOI: 10.1002/jor.22647] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2014] [Accepted: 04/24/2014] [Indexed: 02/04/2023]
Abstract
Osteoarthritis is the most common form of arthritis with still unknown pathogenic etiology and considerable contribution of genetic factors. One of the mechanisms of cartilage degradation in osteoarthritis is enzymatic proteolysis of the extracellular matrix by metalloproteinases. MMP-1, produced by chondrocytes and synovial cells, is a major proteinase of the MMPs family. The present study aims at evaluating the association of MMP1 gene -1607 1G/2G (rs1799750) polymorphism with primary knee osteoarthritis in the Greek population. One hundred fifty five patients with primary symptomatic knee osteoarthritis participated in the study along with 139 controls. Genotypes were determined using PCR-RLFP technique. Allelic and genotypic frequencies were compared between both study groups. There was no significant association between MMP1 -1607 1G/2G polymorphism and knee osteoarthritis, in crude analysis; however, after multiple logistic regression analysis, 1G/2G was associated with reduced odds of knee osteoarthritis by 75% in males, compared to genotypes 1G/1G + 2G/2G, adjusting for age and BMI (adjusted OR: 0.25, 95% CI: 0.069, 0.910, p = 0.035). The present study shows that MMP1 -1607 1G/2G (rs1799750) polymorphism might be a risk factor for knee osteoarthritis susceptibility in the Greek population. Further investigations are needed to confirm this association in the pathogenesis of osteoarthritis.
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Affiliation(s)
- Panagiotis Lepetsos
- 2nd Department of Trauma and Orthopaedics, University of Athens Medical School, "Agia Olga" Hospital, 3-5 Ag. Olgas Street, 14233, Nea Ionia, Athens, Greece; Department of Medical Genetics, University of Athens Medical School, "Agia Sophia" Children's Hospital, Thivon and Levadias Str., 11527, Athens, Greece
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Næss S, Shiryaev A, Hov JR, Franke A, Karlsen TH. Genetics in primary sclerosing cholangitis. Clin Res Hepatol Gastroenterol 2012; 36:325-33. [PMID: 22554879 DOI: 10.1016/j.clinre.2012.02.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2012] [Accepted: 02/24/2012] [Indexed: 02/04/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic cholestatic disorder with a progressive course. PSC is strongly associated with inflammatory bowel disease and is often complicated by cholangiocarcinoma development. Etiology and pathogenesis remain obscure, but the diverse clinical manifestation of the disease might, to some extent, indicate different genetic susceptibility in subgroups of patients. In recent years, genome-wide association studies performed in PSC have identified a number of genetic susceptibility loci. In this mini-review, we suggest that the genetic associations established can be grouped according to four pathogenic aspects relating to inflammation, cholangiocyte function, fibrosis and carcinogenesis. Subclassification of PSC patients according to their genetic predisposition could be a valuable tool in future functional and clinical studies.
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Affiliation(s)
- Sigrid Næss
- Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, 0027 Oslo, Norway
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Krones E, Graziadei I, Trauner M, Fickert P. Evolving concepts in primary sclerosing cholangitis. Liver Int 2012; 32:352-69. [PMID: 22097926 DOI: 10.1111/j.1478-3231.2011.02607.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2011] [Accepted: 06/27/2011] [Indexed: 02/13/2023]
Abstract
Patients suffering from primary sclerosing cholangitis (PSC) show considerable differences regarding clinical manifestations (i.e. large duct versus small-duct PSC, presence or absence of concomitant inflammatory bowel disease), disease progression, risk for malignancy and response to therapy, raising the question whether PSC may represent a mixed bag of diseases of different aetiologies. The growing list of secondary causes and diseases 'mimicking' or even overlapping with PSC (e.g. IgG4-associated sclerosing cholangitis), which frequently causes problems in clear-cut discrimination from classic PSC and the emerging knowledge about potential disease modifier genes (e.g. variants of CFTR, TGR5 and MDR3) support such a conceptual view. In addition, PSC in children differs significantly from PSC in adults in several aspects resulting in distinct therapeutic concepts. From a clinical perspective, appropriate categorization and careful differential diagnosis are essential for the management of concerned patients. Therefore, the aim of the current review is to summarize current and evolving pathophysiological concepts and to provide up-to-date perspectives including future treatment strategies for PSC.
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Affiliation(s)
- Elisabeth Krones
- Department of Internal Medicine, Medical University of Graz, Graz, Austria
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Pollheimer MJ, Halilbasic E, Fickert P, Trauner M. Pathogenesis of primary sclerosing cholangitis. Best Pract Res Clin Gastroenterol 2011; 25:727-39. [PMID: 22117638 PMCID: PMC3236286 DOI: 10.1016/j.bpg.2011.10.009] [Citation(s) in RCA: 94] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2011] [Accepted: 10/25/2011] [Indexed: 01/31/2023]
Abstract
Primary sclerosing cholangitis (PSC) represents a chronic cholestatic liver disease with fibroobliterative sclerosis of intra- and/or extrahepatic bile ducts, eventually leading to biliary cirrhosis. The association with human leukocyte antigen (HLA) and non-HLA haplotypes and the presence of autoantibodies in sera of PSC patients support a crucial role for immune-mediated mechanisms in the initiation and progression of PSC. The strong clinical association between PSC and inflammatory bowel diseases led to intriguing pathogenetic concepts, in which the inflamed gut with translocation of bacterial products and homing of gut-primed memory T lymphocytes via aberrantly expressed adhesion molecules plays a fundamental role. Genetically or chemically modified bile composition was shown to induce sclerosing cholangitis and liver fibrosis in a number of animal models ("toxic bile concept"). The potential role of vascular injury with ischemia of bile duct epithelium cells in the development of sclerosing cholangitis is supported by animal models of endothelial cell injury showing close morphological similarities with human PSC.
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Affiliation(s)
- Marion J. Pollheimer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria
| | - Emina Halilbasic
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Peter Fickert
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria,Corresponding author. Tel.:+43 (0) 1 40400 4741; fax: +43 (0) 1 40400 4735.
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Juran BD, Atkinson EJ, Schlicht EM, Larson JJ, Ellinghaus D, Franke A, Lazaridis KN. Genetic polymorphisms of matrix metalloproteinase 3 in primary sclerosing cholangitis. Liver Int 2011; 31:785-91. [PMID: 21134112 PMCID: PMC3139245 DOI: 10.1111/j.1478-3231.2010.02420.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/05/2022]
Abstract
BACKGROUND The damaging cholestasis inherent to primary sclerosing cholangitis (PSC) results from bile duct stricturing because of progressive fibrosis. The matrix metalloproteinase 3 (MMP3) degrades a wide range of matrix components and is expressed by activated liver stellate cells, and so is a candidate for involvement with the fibrotic processes underlying PSC. Moreover, the MMP3 gene harbours polymorphisms associated with variation in its activity directly impacting clinical phenotypes. AIMS We aimed to examine the influence of MMP3 polymorphisms on PSC risk and progression. METHODS Nine single nucleotide polymorphisms (SNPs) tagging the common genetic variation of MMP3 were genotyped in 266 PSC patients and 407 controls. SNPs and inferred haplotypes were assessed for PSC association by logistic regression and score tests. The effect of SNPs on survival to liver transplant or death was analysed using Cox regression, and Kaplan-Meier curves were constructed. RESULTS No association of PSC with individual SNPs or haplotypes of MMP3 was detected. However, progression to death or liver transplant was significantly associated with homozygosity for minor alleles of rs522616, rs650108 and rs683878, particularly among PSC patients with concurrent ulcerative colitis (UC) (strongest in redundant SNPs rs650108/rs683878, hazard ratio=3.23, 95% confidence interval 1.45-7.25, P=0.004). CONCLUSIONS Genetic variation in MMP3 influences PSC progression, possibly in the context of coexisting UC. While the functional variants and specific mechanisms remain unknown, this finding implicates the turnover of the extracellular matrix as an important and variable component of PSC pathogenesis. Efforts to understand this process could form the basis for developing effective treatments, which are currently lacking for PSC.
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Affiliation(s)
- Brian D. Juran
- Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | | | - Erik M. Schlicht
- Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Joseph J. Larson
- Division of Biostatistics, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - David Ellinghaus
- Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, Kiel, Germany
| | - Andre Franke
- Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, Kiel, Germany
| | - Konstantinos N. Lazaridis
- Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
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Folseraas T, Karlsen TH. To MMP or not to MMP: a role for matrix metalloproteinase 3 in primary sclerosing cholangitis? Liver Int 2011; 31:751-4. [PMID: 21645205 DOI: 10.1111/j.1478-3231.2011.02471.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
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Langers AM, Verspaget HW, Hommes DW, Sier CF. Single-nucleotide polymorphisms of matrix metalloproteinases and their inhibitors in gastrointestinal cancer. World J Gastrointest Oncol 2011; 3:79-98. [PMID: 21731908 PMCID: PMC3124635 DOI: 10.4251/wjgo.v3.i6.79] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2011] [Revised: 05/27/2011] [Accepted: 06/03/2011] [Indexed: 02/05/2023] Open
Abstract
Matrix metalloproteinases (MMPs) are implicated in cancer development and progression and are associated with prognosis. Single-nucleotide polymorphisms (SNPs) of MMPs, most frequently located in the promoter region of the genes, have been shown to influence cancer susceptibility and/or progression. SNPs of MMP-1, -2, -3, -7, -8, -9, -12, -13 and -21 and of the tissue inhibitor of metalloproteinases (TIMPs) TIMP-1 and TIMP-2 have been studied in digestive tract tumors. The contribution of these polymorphisms to the cancer risk and prognosis of gastrointestinal tumors are reviewed in this paper.
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Affiliation(s)
- Alexandra Mj Langers
- Alexandra MJ Langers, Hein W Verspaget, Daniel W Hommes, Cornelis FM Sier, Department of Gastroenterology and Hepatology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands
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Samarasena JB, Hu KQ. Hepatobiliary manifestations of gastrointestinal and nutritional disorders. Clin Liver Dis 2011; 15:89-110. [PMID: 21111995 DOI: 10.1016/j.cld.2010.09.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatobiliary manifestations of gastrointestinal and nutritional disorders can occur as part of the clinical spectrum of the underlying disease or as a consequence of the treatment of the disease. This article reviews aspects of pathogenesis, diagnosis, and management of hepatobiliary manifestations associated with a selection of gastrointestinal and nutritional disorders including inflammatory bowel disease, celiac disease, Whipple's disease, and parenteral nutrition associated disorders.
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Affiliation(s)
- Jason B Samarasena
- Division of Gastroenterology, University of California Irvine Medical Center, 101 The City Drive, City Tower, Suite 400, Zot 4092, Orange, CA 92868, USA
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Malik N, Kumar R, Prasad KN, Kawal P, Srivastava A, Mahapatra AK. Association of matrix metalloproteinase-1 gene polymorphism with glioblastoma multiforme in a northern Indian population. J Neurooncol 2010; 102:347-52. [PMID: 20706772 DOI: 10.1007/s11060-010-0337-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2010] [Accepted: 07/27/2010] [Indexed: 11/25/2022]
Abstract
Matrix metalloproteinase-1 (MMP-1) is known to be involved in the pathogenesis of glioma. It damages the extra-cellular matrix to produce invasiveness in cancer tissue, and hence has a direct effect in cancer invasion. The study aims to explore the association of single nucleotide polymorphism of -1607 MMP-1 gene with susceptibility to glioblastoma multiforme (GBM) in northern Indian subjects. One hundred and ten GBM patients and 150 healthy controls were included in this study. 1607 MMP-1 gene was studied by PCR-RFLP; different genotypes being combinations of 1G and 2G allele (1G/1G, 1G/2G and 2G/2G). 2G/2G genotype was significantly associated with GBM patients (OR, 2.24; P = 0.016; 95% CI, 1.16-4.30) as compared to controls. Prevalence of the 2G allele of -1607 MMP-1 polymorphism was significantly greater in GBM patients as compared to controls (62.3 vs 48.3%, OR, 1.76; P = 0.002; 95% CI, 1.23-2.52). This study suggests that the 2G/2G genotype and 2G allele of -1607 MMP-1 polymorphism are associated with an increased susceptibility for developing GBM.
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Affiliation(s)
- Nitin Malik
- Department of Neurosurgery, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
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Yi YC, Chou PT, Chen LY, Kuo WH, Shih-Chu Ho E, Han CP, Yang SF. Matrix metalloproteinase-7 (MMP-7) polymorphism is a risk factor for endometrial cancer susceptibility. Clin Chem Lab Med 2010; 48:337-44. [DOI: 10.1515/cclm.2010.082] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Abstract
Matrix metalloproteinases (MMPs) are a family of zinc (Zn)-dependent endopeptidases that are collectively capable of cleaving virtually all extracellular matrix (ECM) substrates and play an important role in diverse physiological and pathological processes. The activity of MMPs is regulated at multiple levels. The transcriptional regulation of MMP appears to represent the key step in MMP regulation. There are diverse types of MMPs that differ structural and functionally. MMP-1 is the most ubiquitously expressed interstitial collagenase and has a prominent role in initial cleavage of the ECM. The level of MMP-1 expression can be influenced by different single-nucleotide polymorphisms (SNPs) in the promoter region. A functional polymorphism at position -1607 has been shown to alter the transcriptional activity of MMP-1 and was associated with diverse pathological processes. The aim of our review was to discuss some topics related to MMP in physiological and pathological processes, with a focus on MMP-1 polymorphism.
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Huang CD, Lin SM, Chang PJ, Liu WT, Wang CH, Liu CY, Lin HC, Hsieh LL, Kuo HP. Matrix metalloproteinase-1 polymorphism is associated with persistent airway obstruction in asthma in the Taiwanese population. J Asthma 2009; 46:41-6. [PMID: 19191136 DOI: 10.1080/02770900802252077] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
BACKGROUND AND OBJECTIVE Overexpression of matrix metalloproteinase (MMP)-1 has been demonstrated in asthma, and MMP polymorphisms are known to enhance disease susceptibility. We investigated whether MMP-1 polymorphism is associated with persistent airway obstruction in asthma in the Taiwanese population. METHODS A total of 131 unrelated Taiwanese subjects were enrolled, age-matched, and divided as follows: (1) those who had asthma with persistent airway obstruction with forced expiratory volume in 1 second (FEV(1)) and FEV(1)/forced vital capacity (FVC) values less than 75% predicted (n = 41); (2) those with asthma without airway obstruction with FEV(1) and FEV(1)/FVC values > or = 75% predicted (n = 47); and (3) normal control subjects (n = 43). All were genotyped for the 1G/2G polymorphism of MMP-1 promoter (-1607 bp). RESULTS 1G genotypes of MMP-1 containing at least one 1G allele were found in asthmatic patients with persistent airway obstruction (OR = 3.696, 95% CI: 1.489-9.173, p = 0.027), but not in asthmatic patients without airway obstruction (OR = 2.065, 95% CI: 0.890-4.790, p = 0.091) when compared with homozygous 2G (2G/2G). The heterozygous 1G genotype (1G/2G) was more associated with persistent airway obstruction than homozygous 2G (2G/2G) (OR: 4.727, 95% CI: 1.759-12.703, p = 0.012). The adjusted risk estimate of 1G genotypes for asthmatics with persistent airway obstruction was 4.416 (95% CI: 1.651-11.812, p = 0.003). CONCLUSION 1G genotypes of MMP-1 polymorphism are associated with asthma with persistent airway obstruction, and the heterozygous 1G genotype (1G/2G) poses the most susceptibility to persistent airway obstruction in asthma.
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Affiliation(s)
- Chien-Da Huang
- Department of Thoracic Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
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Barlas IÖ, Sezgin M, Erdal ME, Sahin G, Ankarali HC, Altintas ZM, Türkmen E. Association of (−1,607) 1G/2G polymorphism of matrix metalloproteinase-1 gene with knee osteoarthritis in the Turkish population (knee osteoarthritis and MMPs gene polymorphisms). Rheumatol Int 2008; 29:383-8. [DOI: 10.1007/s00296-008-0705-6] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2008] [Accepted: 09/07/2008] [Indexed: 11/21/2022]
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Abstract
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown etiology but lymphocytic portal tract infiltration is suggestive of an immune-mediated basis for this disease. Associations with inflammatory bowel disease (IBD) especially ulcerative colitis (UC), and with particular autoimmune diseases, as well as the genetic associations further suggest PSC may be an immune-mediated disease. The immunogenetics of PSC have been the subject of active research and several HLA and non-HLA associated genes have been implicated in the development of the disease. Lymphocytes derived from the inflamed gut may enter the liver via the enterohepatic circulation to cause hepatic disease. PSC may be triggered in genetically susceptible individuals by infections or toxins entering the portal circulation through a permeable colon and hence evoking an abnormal immune response.
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Genetics of biliary tract diseases: new insights into gallstone disease and biliary tract cancers. Curr Opin Gastroenterol 2008; 24:363-71. [PMID: 18408466 DOI: 10.1097/mog.0b013e3282f79b32] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
PURPOSE OF REVIEW Chronic biliary diseases are due to complex interactions between environmental and genetic factors. Here we summarize the current knowledge of genetic factors that contribute to common biliary diseases, focusing on gallstones and carcinogenesis, and review the recent association studies. RECENT FINDINGS Since most studies were based on small sample sizes, replication of the findings is mandatory. Recently a large twin study confirmed a genetic predisposition to gallstones and a genome-wide association scan identified the hepatocanalicular cholesterol transporter ABCG8 as the common susceptibility factor for gallstone disease. Genetic studies in patients with cholangiocarcinoma indicate that genes controlling the metabolism and transport of xenobiotics or modulating chronic inflammation may determine individual susceptibility. SUMMARY Genetic studies have identified the first susceptibility factors for gallstones and biliary tract cancers, but most results have yet to be replicated. In the future, genome-wide studies in different populations are likely to identify the entire set of genes contributing to chronic biliary diseases. Since the disease phenotypes result from the manifestation of susceptibility factors under the influence of environmental triggers, the discovery of these genes will open avenues to control environmental challenges and lead to novel strategies for risk assessment ('gene signatures') and prevention.
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Stickel F, Osterreicher CH, Halangk J, Berg T, Homann N, Hellerbrand C, Patsenker E, Schneider V, Kolb A, Friess H, Schuppan D, Puhl G, Seitz HK, Leathart JLB, Day CP. No role of matrixmetalloproteinase-3 genetic promoter polymorphism 1171 as a risk factor for cirrhosis in alcoholic liver disease. Alcohol Clin Exp Res 2008; 32:959-65. [PMID: 18445105 DOI: 10.1111/j.1530-0277.2008.00654.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND As only a minority of alcoholics develop cirrhosis, polymorphic genes, whose products are involved in fibrosis development were suggested to confer individual susceptibility. We tested whether a functional promoter polymorphism in the gene encoding matrix metalloproteinase-3 (MMP-3; 1171 5A/6A) was associated liver cirrhosis in alcoholics. METHODS Independent cohorts from the UK and Germany were studied. (i) UK cohort: 320 alcoholic cirrhotics and 183 heavy drinkers without liver damage and (ii) German cohort: 149 alcoholic cirrhotics, 220 alcoholic cirrhotics who underwent liver transplantation and 151 alcoholics without liver disease. Patients were genotyped for MMP-3 variants by restriction fragment length polymorphism, single strand confirmation polymorphism, and direct sequencing. In addition, MMP-3 transcript levels were correlated with MMP-3 genotype in normal liver tissues. RESULTS Matrix metalloproteinase-3 genotype and allele distribution in all 1023 alcoholic patients were in Hardy-Weinberg equilibrium. No significant differences in MMP-3 genotype and allele frequencies were observed either between alcoholics with or without cirrhosis. There were no differences in hepatic mRNA transcription levels according to MMP-3 genotype. CONCLUSIONS Matrix metalloproteinase-3 1171 promoter polymorphism plays no role in the genetic predisposition for liver cirrhosis in alcoholics. Stringently designed candidate gene association studies are required to exclude chance observations.
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Affiliation(s)
- Felix Stickel
- Institute of Clinical Pharmacology, University of Berne, Switzerland.
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Shin HP, Lee JI, Jung JH, Yim SV, Kim HJ, Cha JM, Park JB, Joo KR, Hwang JS, Jang BK. Matrix metalloproteinase (MMP)-3 polymorphism in patients with HBV related chronic liver disease. Dig Dis Sci 2008; 53:823-9. [PMID: 17763953 DOI: 10.1007/s10620-007-9937-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2007] [Accepted: 07/11/2007] [Indexed: 01/15/2023]
Abstract
A common and important problem in patients with chronic hepatitis B is the progression of liver fibrosis. Matrix metalloproteinases (MMPs) play an important role in the progression of liver fibrosis. Our aim of this study was to examine the association of MMP-3 polymorphism with liver cirrhosis in Korean patients with chronic hepatitis B. Genomic DNA was extracted from 127 patients with chronic hepatitis B (CHB), 92 patients with hepatitis B virus (HBV)-related liver cirrhosis (HBV-LC), and 146 healthy subjects. MMP-3 polymorphism was determined by polymerase-chain reaction-based assays, and the association with the progression of liver cirrhosis was investigated. With regard to MMP-3 polymorphism, there was no statistical difference in genotype distributions among the three groups. However, the peripheral platelet count of the 5A carriers was significantly lower than that of the 6A homozygotes in the HBV-LV group (85.0 +/- 36.9 vs. 109.8 +/- 47.0 x 10(9)/l; P = 0.02). With MMP-3 promoter polymorphism (rs3025058), a lower peripheral blood platelet count, which was related to advanced liver cirrhosis, was observed in 5A carriers. Therefore, more studies of MMP-3 gene polymorphism with larger populations should be conducted to further understand its role in the progression of liver cirrhosis.
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Affiliation(s)
- Hyun Phil Shin
- Department of Internal Medicine, East-West Neo Medical Center, Kyung Hee University College of Medicine, Gangdong-gu, Seoul 134-090, Korea
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Matrix metalloproteinase-1 polymorphism in Taiwanese patients with endobronchial tuberculosis. Tuberculosis (Edinb) 2007; 88:262-7. [PMID: 17996495 DOI: 10.1016/j.tube.2007.08.010] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2006] [Revised: 07/16/2007] [Accepted: 08/27/2007] [Indexed: 11/21/2022]
Abstract
Endobronchial tuberculosis (TB) often leads to some degree of tracheobronchial stenosis. Because matrix metalloproteinases (MMPs) play an essential role in tissue remodeling in the airways, we investigated the role of MMP-1 polymorphism in patients with endobronchial TB. One hundred and one cases of pulmonary TB in Taiwanese patients were genotyped for the 1G/2G polymorphism of MMP-1 promoter (-1607 bp). Bronchoscopic examination was performed to determine the presence of endobronchial involvement. Levels of MMP-1 in peripheral blood monocytes and in bronchial biopsies were also determined. 1G genotypes of MMP-1 polymorphism, containing at least one 1G allele, were associated with the presence of endobronchial TB. Using multivariate analysis, 1G genotypes and female gender were independent predictors of the development of endobronchial TB. Endobronchial TB patients with 1G genotypes had a 9.86-fold greater risk of developing tracheobronchial stenosis. IL-1beta increased levels of MMP-1 in peripheral blood monocytes of TB patients with 1G genotypes. MMP-1 activity was also present in the endobronchial TB granuloma from patients with 1G/1G genotype. 1G genotypes of MMP-1 polymorphism were associated with a greater risk of developing tracheobronchial stenosis through up-regulation of MMP-1 activity.
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Abstract
The aetiology of primary sclerosing cholangitis (PSC) is not known. A more than 80-fold increased risk of PSC among first-degree relatives emphasizes the importance of genetic factors. Genetic associations within the human leukocyte antigen (HLA) complex on chromosome 6p21 were detected in PSC 25 years ago. Subsequent studies have substantiated beyond doubt that one or more genetic variants located within this genetic region are important. The true identities of these variants, however, remain to be identified. Several candidate genes at other chromosomal loci have also been investigated. However, according to strict criteria for what may be denominated a susceptibility gene in complex diseases, no such gene exists for PSC today. This review summarises present knowledge on the genetic susceptibility to PSC, as well as genetic associations with disease progression and clinical subsets of particular interest (inflammatory bowel disease and cholangiocarcinoma).
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MESH Headings
- Bile Duct Neoplasms/genetics
- Bile Duct Neoplasms/immunology
- Bile Ducts, Intrahepatic/immunology
- Cholangiocarcinoma/genetics
- Cholangiocarcinoma/immunology
- Cholangitis, Sclerosing/complications
- Cholangitis, Sclerosing/epidemiology
- Cholangitis, Sclerosing/genetics
- Cholangitis, Sclerosing/immunology
- Chromosomes, Human, Pair 6
- Data Interpretation, Statistical
- Disease Progression
- Effect Modifier, Epidemiologic
- Genetic Predisposition to Disease
- HLA Antigens/genetics
- Humans
- Inflammatory Bowel Diseases/genetics
- Inflammatory Bowel Diseases/immunology
- Odds Ratio
- Pedigree
- Polymorphism, Genetic
- Risk Assessment
- Risk Factors
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Affiliation(s)
- Tom-H Karlsen
- Medical Department, Rikshospitalet-Radiumhospitalet Medical Center, N-0027 Oslo, Norway.
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Piccoli MF, Figueira M, Andreoni C, Marumo JT, Schor N, Bellini MH. Lack of association between matrix metalloproteinase-1 (MMP-1) promoter polymorphism and risk of renal cell carcinoma. Int Braz J Urol 2007; 33:622-9. [DOI: 10.1590/s1677-55382007000500003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/06/2007] [Indexed: 11/22/2022] Open
Affiliation(s)
| | | | | | | | | | - Maria H. Bellini
- Federal University of Sao Paulo, Brazil; Federal University of Sao Paulo, Brazil
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Meijer MJW, Mieremet-Ooms MAC, van Hogezand RA, Lamers CBHW, Hommes DW, Verspaget HW. Role of matrix metalloproteinase, tissue inhibitor of metalloproteinase and tumor necrosis factor-α single nucleotide gene polymorphisms in inflammatory bowel disease. World J Gastroenterol 2007; 13:2960-6. [PMID: 17589947 PMCID: PMC4171149 DOI: 10.3748/wjg.v13.i21.2960] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the (functional) relevance of single nucleotide polymorphisms (SNPs) in genes encoding matrix metalloproteinases (MMP)-1, -2, -3, -9, tissue inhibitors of metalloproteinases (TIMP)-1, -2 and tumor necrosis factor (TNF)-α in the etiopathogenesis of inflammatory bowel diseases (IBD), that may enhance susceptibility and/or disease severity.
METHODS: Genomic DNA from 134 Crohn’s disease (CD), 111 ulcerative colitis (UC) patients and 248 control subjects was isolated from resected intestinal tissue or blood. Allelic composition at SNP loci was determined by PCR-RFLP or tetra primer ARMS PCR.
RESULTS: The TIMP-1 genotype TT in women and T in men at SNP +372 T/C was found to increase CD susceptibility (39% vs 23.8%, P = 0.018 and 67.9% vs 51.6%, P = 0.055, respectively), while women with this genotype were less prone to development of fistulae during follow-up (41.4% vs 68.3%, P = 0.025). Male IBD or CD patients carrying the TIMP-1 +372 T-allele expressed lower levels of TIMP-1 in surgically resected macroscopically inflamed tissue (0.065 < P < 0.01). The 5T5T genotype at MMP-3 SNP -1613 5T/6T increased the chance of stenotic complications in CD during follow-up (91.2% vs 71.8%, P = 0.022) but seemed to protect against colonic involvement of this disease at first endoscopic/radiologic examination (35.3% vs 59.5%, P = 0.017).
CONCLUSION: Allelic composition at the examined SNPs in genes coding for TIMP-1 and MMP-3 affect CD susceptibility and/or phenotype, i.e., fistulizing disease, stricture pathogenesis and first disease localisation. These findings reinforce the important role of these proteins in IBD.
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Affiliation(s)
- Martin J W Meijer
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
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Spurkland A, Sollid LM. Mapping genes and pathways in autoimmune disease. Trends Immunol 2006; 27:336-42. [PMID: 16753344 DOI: 10.1016/j.it.2006.05.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2006] [Revised: 04/25/2006] [Accepted: 05/16/2006] [Indexed: 11/15/2022]
Abstract
Identifying novel genes and pathways controlling T-cell activation holds the promise of developing novel therapies for autoimmune disease and cancer. Recent advances in the human genome project have shown that it is timely for small groups searching for this Holy Grail to rethink their options. In this review, some alternative strategies employed in pursuing novel disease pathways in rodents and humans, including recent results, are presented. Examples include the murine Roquin and Ncf1 genes, and the PTPN22 gene identified in humans. The potential benefit of reducing the heterogeneity of clinically defined diseases by the careful phenotyping of patients, cells and lesions using advanced molecular biology and imaging techniques is highlighted.
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Affiliation(s)
- Anne Spurkland
- Institute of Basic Medical Sciences, University of Oslo, Rikshospitalet University Hospital, Oslo N-0317, Norway.
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Wiencke K, Boberg KM, Donaldson P, Harbo H, Ling V, Schrumpf E, Spurkland A. No major effect of the CD28/CTLA4/ICOS gene region on susceptibility to primary sclerosing cholangitis. Scand J Gastroenterol 2006; 41:586-91. [PMID: 16638702 DOI: 10.1080/00365520500377870] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Primary sclerosing cholangitis (PSC) is currently thought to be an immune-mediated disease, where both host genes and environmental factors interact. Some of the immunoregulatory genes responsible for individual susceptibility to PSC have been identified. The co-stimulatory receptor gene cluster on chromosome 2q33 encodes both the positive T-cell regulators CD28 and ICOS, and the negative regulator CTLA4. The CTLA4 gene has been implicated in several immune-mediated diseases, but it is not known whether PSC is associated with any of these genes. MATERIAL AND METHODS Polymerase chain reaction (PCR)-based genotyping was performed on 144 PSC patients and 285 controls. Two single nucleotide polymorphisms (SNPs) in the CTLA4 gene were investigated as well as six microsatellites covering approximately 262 kb of the flanking regions, including the ICOS and CD28 genes. RESULTS Overall, there were no statistically significant differences between PSC patients and controls in genotype and allele frequencies for the CTLA4 +49AG and CT60 SNPs or for the CD28-A, CD28-B, SARA43, SARA1, SARA31, and SARA47 microsatellite markers. Nor were any associations with clinical subgroups observed. CONCLUSIONS There are no major effects of the CD28/CTLA4/ICOS gene region on susceptibility to PSC, but minor contributions (OR <1.8) cannot be excluded.
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Affiliation(s)
- Kristine Wiencke
- Medical Department, Rikshospitalet University Hospital, Oslo, Norway.
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Worthington J, Cullen S, Chapman R. Immunopathogenesis of primary sclerosing cholangitis. Clin Rev Allergy Immunol 2006. [PMID: 15879616 DOI: 10.1385/criai: 28: 2: 093] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown etiology;however, lymphocytic portal tract infiltration is suggestive of an immune-mediated basis for PSC. Associations with inflammatory bowel disease--especially ulcerative colitis--and with other auto-immune diseases, together with genetic associations, further suggest that PSC may be an immune-mediated disease. The immunogenetics of PSC have been the subject of active research, and several human leukocyte antigen (HLA)- and non-HLA-associated genes have been implicated in the development of the disease. Lymphocytes derived from the inflamed gut may enter the liver via the enterohepatic circulation to cause hepatic disease.PSC may be triggered in genetically susceptible individuals by infections or toxins entering the portal circulation through a permeable colon and, therefore, evoking an abnormal immune response.
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Affiliation(s)
- Joy Worthington
- Department of Gastroenterology, John Radcliffe Hospital, Headington, Oxford, UK
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Henckaerts L, Fevery J, Van Steenbergen W, Verslype C, Yap P, Nevens F, Roskams T, Libbrecht L, Rutgeerts P, Vermeire S. CC-type chemokine receptor 5-Delta32 mutation protects against primary sclerosing cholangitis. Inflamm Bowel Dis 2006; 12:272-7. [PMID: 16633049 DOI: 10.1097/01.mib.0000209790.21737.28] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
BACKGROUND Primary sclerosing cholangitis (PSC) is commonly associated with inflammatory bowel disease (IBD) and characterized by fibrosing inflammatory destruction of biliary ducts. The pathogenesis of PSC remains unknown, but immunological, bacterial, viral, and toxic factors play a role in a genetically susceptible host. We hypothesized that CC-type chemokine receptor 5 (CCR5) would be an interesting candidate gene for susceptibility to PSC from its chromosomal location within the IBD susceptibility locus on 3p21, as well as from a functional perspective. We therefore investigated the role of the functional 32-bp deletion in this gene (CCR5-Delta32) with regard to susceptibility to PSC. METHODS A total of 110 patients with PSC, 56 with concomitant IBD (23 with Crohn's disease, 28 with ulcerative colitis, 5 with indeterminate colitis), were collected. All of the subjects were genotyped for CCR5-Delta32 with polymerase chain reaction amplification, followed by detection on ethidium bromide-stained agarose gel. Genotypes and allele frequencies were compared with a cohort of IBD patients without PSC (n = 400) and healthy control subjects (n = 362). RESULTS The frequency of the CCR5-Delta32 mutation in PSC (6.8%) was significantly lower compared with IBD (12.6%; P = 0.016) and healthy control subjects (12.2%, P = 0.026), suggesting a protective effect of this mutation on PSC. None of the PSC patients with severe disease necessitating liver transplantation (n = 17) carried CCR5-Delta32. CONCLUSIONS Because an intact CCR5 receptor is needed for internalization of specific pathogens and homing of memory T lymphocytes to the liver, we hypothesize that a deficient expression of this receptor resulting from the CCR5-Delta32 variant may protect against PSC.
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Affiliation(s)
- Liesbet Henckaerts
- Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium
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29
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Abstract
PURPOSE OF REVIEW Primary sclerosing cholangitis is a chronic cholestatic liver disease characterized by strictures of the biliary tree. It is immune mediated, although the precise cause remains unknown. Recent reports have shown a higher prevalence and burden of disease than was previously suspected. RECENT FINDINGS The research into the etiopathogenesis, epidemiology, diagnosis of cholangiocarcinoma, medical and surgical therapy, and timing and outcome of liver transplantation is discussed. SUMMARY Genetic heterogeneity among patients with primary sclerosing cholangitis is supported, and further gene polymorphisms associated with protection against primary sclerosing cholangitis have been elucidated. Bile duct injury seems to be a multistep process. Magnetic resonance cholangiopancreatography is a cost-effective and accurate way of diagnosing primary sclerosing cholangitis in comparison with endoscopic retrograde cholangiopancreatography. Ursodeoxycholic acid may have a role as a colorectal and hepatobiliary cancer chemopreventive agent. Liver transplantation remains the only treatment in end-stage disease. The 5-year and 10-year patient and graft survival rates are comparable with those in patients without primary sclerosing cholangitis, but there is a higher rate of retransplantation for primary sclerosing cholangitis in most centers. Hepatobiliary malignancy is found in a minority of patients at transplantation, although 5-year survival rates for these patients are still promising.
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Affiliation(s)
- George R MacFaul
- Department of Gastroenterology, John Radcliffe Hospital, Oxford, UK
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