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Tiniakos DG, Anstee QM, Brunt EM, Burt AD. Fatty Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:330-401. [DOI: 10.1016/b978-0-7020-8228-3.00005-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Miteva D, Peshevska-Sekulovska M, Snegarova V, Peruhova M, Vasilev GH, Vasilev GV, Sekulovski M, Lazova S, Gulinac M, Tomov L, Mihova A, Velikova T. Microbiome and Genetic Factors in the Pathogenesis of Liver Diseases. GASTROENTEROLOGY INSIGHTS 2023; 14:575-597. [DOI: 10.3390/gastroent14040041] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2024] Open
Abstract
Our genetic background has not changed over the past century, but chronic diseases are on the rise globally. In addition to the genetic component, among the critical factors for many diseases are inhabitants of our intestines (gut microbiota) as a crucial environmental factor. Dysbiosis has been described in liver diseases with different etiologies like non-alcoholic fatty liver disease (NAFLD), alcohol-related liver disease (ALD), viral hepatitis, autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), cirrhosis, hepatocellular carcinoma (HCC). On the other hand, new technologies have increased our understanding of liver disease genetics and treatment options. Genome-wide association studies (GWAS) identify unknown genetic risk factors, positional cloning of unknown genes associated with different diseases, gene tests for single nucleotide variations (SNVs), and next-generation sequencing (NGS) of selected genes or the complete genome. NGS also allowed studying the microbiome and its role in various liver diseases has begun. These genes have proven their effect on microbiome composition in host genome–microbiome association studies. We focus on altering the intestinal microbiota, and supplementing some bacterial metabolites could be considered a potential therapeutic strategy. The literature data promote probiotics/synbiotics role in reducing proinflammatory cytokines such as TNF-α and the interleukins (IL-1, IL-6, IL-8), therefore improving transaminase levels, hepatic steatosis, and NAFLD activity score. However, even though microbial therapy appears to be risk-free, evaluating side effects related to probiotics or synbiotics is imperative. In addition, safety profiles for long-term usage should be researched. Thus, this review focuses on the human microbiome and liver diseases, recent GWASs on liver disease, the gut-liver axis, and the associations with the microbiome and microbiome during/after liver disease therapy.
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Affiliation(s)
- Dimitrina Miteva
- Department of Genetics, Faculty of Biology, Sofia University St. Kliment Ohridski, 8 Dragan Tzankov Str., 1164 Sofia, Bulgaria
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str., 1407 Sofia, Bulgaria
| | - Monika Peshevska-Sekulovska
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str., 1407 Sofia, Bulgaria
- Department of Gastroenterology, University Hospital Lozenetz, Kozyak 1 Str., 1407 Sofia, Bulgaria
| | - Violeta Snegarova
- Clinic of Internal Diseases, Naval Hospital—Varna, Military Medical Academy, Medical Faculty, Medical University, Blvd. Hristo Smirnenski 3, 9000 Varna, Bulgaria
| | - Milena Peruhova
- Department of Gastroenterology, Heart and Brain Hospital, Zdrave 1 Str., 8000 Burgas, Bulgaria
| | - Georgi H. Vasilev
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str., 1407 Sofia, Bulgaria
- Laboratory of Hematopathology and Immunology, National Specialized Hospital for Active Treatment of Hematological Diseases, “Plovdivsko Pole” Str. 6, 1756 Sofia, Bulgaria
| | - Georgi V. Vasilev
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str., 1407 Sofia, Bulgaria
- Department of Emergency Medicine and Clinic of Neurology, University Hospital “Sv. Georgi”, Blvd. Peshtersko Shose 66, 4000 Plovdiv, Bulgaria
| | - Metodija Sekulovski
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str., 1407 Sofia, Bulgaria
- Department of Anesthesiology and Intensive Care, University Hospital Lozenetz, 1 Kozyak Str., 1407 Sofia, Bulgaria
| | - Snezhina Lazova
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str., 1407 Sofia, Bulgaria
- Pediatric Department, University Hospital “N. I. Pirogov”, 21 “General Eduard I. Totleben” Blvd, 1606 Sofia, Bulgaria
- Department of Healthcare, Faculty of Public Health, “Prof. Tsekomir Vodenicharov, MD, DSc”, Medical University of Sofia, Bialo More 8 Str., 1527 Sofia, Bulgaria
| | - Milena Gulinac
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str., 1407 Sofia, Bulgaria
- Department of General and Clinical Pathology, Medical University of Plovdiv, Bul. Vasil Aprilov 15A, 4000 Plovdiv, Bulgaria
| | - Latchezar Tomov
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str., 1407 Sofia, Bulgaria
- Department of Informatics, New Bulgarian University, Montevideo 21 Str., 1618 Sofia, Bulgaria
| | - Antoaneta Mihova
- SMDL Ramus, Department of Immunology, Blvd. Kap. Spisarevski 26, 1527 Sofia, Bulgaria
| | - Tsvetelina Velikova
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str., 1407 Sofia, Bulgaria
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Roy N, Nadda N, Kumar H, Prasad C, Kumar Jha J, Pandey HC, Vanamail P, Saraya A, Balhara YPS, Shalimar, Nayak B. Pattern recognition receptor CD14 gene polymorphisms in alcohol use disorder patients and its Influence on liver disease susceptibility. Front Immunol 2022; 13:975027. [PMID: 36238273 PMCID: PMC9551314 DOI: 10.3389/fimmu.2022.975027] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 08/15/2022] [Indexed: 11/13/2022] Open
Abstract
Background Alcohol use disorders (AUDs) leading to liver disease is major concern over other spectrum of disorder. Excessive alcohol consumption resulting in leaky gut syndrome is attributed to alcohol-induced liver injury through portal translocation of bacterial endotoxin. Susceptibility to alcoholic liver disease (ALD) in AUD patients could be dependent upon genes responsible for inflammation and alcohol metabolism. The pattern recognition receptor CD14 gene is a major player in endotoxin-mediated inflammation and susceptibility to ALD. This study investigated the genetic association of CD14 polymorphisms and other mechanisms relevant to altered inflammatory responses leading to ALD. Methods Patients with alcohol use disorder with ALD (n = 128) and without liver disease (ALC, n = 184) and controls without alcohol use disorder (NALC, n = 152) from North India were enrolled. The CD4 gene polymorphisms in the North Indian population were evaluated by RFLP and sequencing. Secretory CD14 (sCD14), LBP, TLR4, MD2, TNFα, IL1b, IFNγ, IL6, IL10, and IL4 levels in serum were measured by ELISA among groups. The influence of polymorphisms on CD14 gene promoter activity and circulatory bacterial DNA level was determined. Results The CD14 gene promoter and exonic region SNPs were found to be monomorphic, except for SNP rs2569190 for the North Indian population. The genetic association of SNP rs2569190(C/T) with the risk of developing ALD was found significant for TT genotype [ORTT, 95% CI = 2.19, 1.16–4.13 for ALD vs. ALC and OR, 2.09, 1.18–3.72 for ALD vs. NALC]. An increased sCD14 level was observed in AUD patients compared to NALC control. Increased levels of LBP, TLR4, TNFα, IL1β, IFNγ, and IL6 and reduced levels of MD2, IL10, and IL4 were observed among the ALD patients compared to the other two control groups. Elevated levels of pro-inflammatory and reduced levels of anti-inflammatory cytokines were observed in the risk genotype TT groups of ALD patients and the ALC group compared to NALC. Promoter activity was observed in the intronic region flanking SNPs and risk genotype can influence reporter activity, indicating CD14 gene expression. Conclusion Enhanced CD14 expression associated with inflammatory responses increases susceptibility to ALD in the TT genotype of AUD patients.
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Sungkar T, Putra A, Lindarto D, Sembiring RJ. Intravenous Umbilical Cord-derived Mesenchymal Stem Cells Transplantation Regulates Hyaluronic Acid and Interleukin-10 Secretion Producing Low-grade Liver Fibrosis in Experimental Rat. Med Arch 2021; 74:177-182. [PMID: 32801431 PMCID: PMC7405996 DOI: 10.5455/medarh.2020.74.177-182] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Introduction: Immunomodulation properties of mesenchymal stem cells have attracted tremendous attention that eventually could regress liver fibrosis process. Aim: The study aims to demonstrate the immunomodulation activities of Umbilical cord-derived Mesenchymal stem cells (UC-MSCs) affecting interleukin-10 (IL-10) and hyaluronic acid (HA) secretion post intraperitoneal injection of CCl4, potent hepatotoxin, induced liver fibrosis among experimental rats. Methods: There were 18 Sprague-Dawley (SD) rats divided into three treatment groups (G1 sham group, G2 untreated liver fibrosis group, and G3 UC-MSCs treated-group) and isolated in Stem Cell and Cancer Research Facility, Semarang, Indonesia. Blood examination was conducted after 3 and 14 days of UC-MSCs transplantation using sandwich based ELISA followed by the histopathological analysis of rat liver tissue. ANOVA and posthoc LSD tests were determined the significance against all groups based on their quantitative measurement. Results: UC-MSCs have been successfully extracted and isolated as well as positive with osteogenic differentiation (Alizarin dye). In further analysis, there were significant mean differences among all groups through the ANOVA test, both IL-10 and HA secretion, concurrent with low-grade liver fibrosis in G3. IL-10 elevates during the early phase of UC-MSCs transplantation, and HA significantly reduced on the 14th day of transplantation, it characterizes the liver fibrosis that has been attenuated. Conclusion: The transplantation of UC-MSCs has given an opportunity for the treatment of a wide range of chronic liver diseases through the immunomodulation properties via its paracrine effects that regulate specific cytokine to suppress fibrosis development.
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Affiliation(s)
- Taufik Sungkar
- Divison of Gastroenterol-hepatology, Department of Internal Medicine, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
| | - Agung Putra
- Stem Cell And Cancer Research (SCCR), Medical Faculty, Sultan Agung Islamic University (UNISSULA), Semarang, Indonesia.,Department of Pathology, Medical Faculty, Sultan Agung Islamic University (UNISSULA), Semarang, Indonesia
| | - Dharma Lindarto
- Division of Endocrine Metabolic, Department of Internal Medicine, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
| | - Rosita Juwita Sembiring
- Department of Clinical Pathology, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
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Impact of IL10, MTP, SOD2, and APOE Gene Polymorphisms on the Severity of Liver Fibrosis Induced by HCV Genotype 4. Viruses 2021; 13:v13040714. [PMID: 33924242 PMCID: PMC8074775 DOI: 10.3390/v13040714] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 04/11/2021] [Accepted: 04/14/2021] [Indexed: 12/13/2022] Open
Abstract
Complications of hepatitis C virus (HCV) chronic infection cause ~400,000 deaths worldwide annually. One complication, liver fibrosis, is influenced by host genetic factors. Genes influencing fibrosis include immune, metabolic, oxidative stress, and viral entry genes, such as interleukin 10 (IL10), microsomal triglyceride-transfer protein (MTP), superoxide dismutase-2 (SOD2), and apolipoprotein E (APOE)-encoding genes, respectively. Thus, correlating variations in these genes with HCV-induced fibrosis represents an attractive biomarker for the prognosis of fibrosis severity in chronically infected patients. Here, we aimed to test whether polymorphisms in IL10, MTP, SOD2, and APOE genes correlated with the severity of fibrosis induced by HCV genotype 4 (HCV-gt4) in a cohort of chronically infected Egyptian patients. Our results demonstrate a significant association between the severity of fibrosis and specific SNPs in IL-10, SOD2, and ApoE-encoding genes. Haplotype-combination analysis for IL10, MTP, SOD2, and APOE showed statistically significant associations between specific haplotype combinations and fibrosis severity. Identifying biomarkers correlating with the severity of HCV-gt4-induced fibrosis would significantly impact precision prophylaxis and treatment of patients at risk.
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Blázovics A. Alcoholic liver disease. INFLUENCE OF NUTRIENTS, BIOACTIVE COMPOUNDS, AND PLANT EXTRACTS IN LIVER DISEASES 2021:57-82. [DOI: 10.1016/b978-0-12-816488-4.00010-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Bhatt M, Kumar S, Garg N, Siddiqui MH, Mittal B. Influence of IL-1β, STAT3 & 5 and TLR-5 gene polymorphisms on rheumatic heart disease susceptibility in north Indian population. Int J Cardiol 2019; 291:89-95. [PMID: 30929974 DOI: 10.1016/j.ijcard.2019.03.035] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 03/06/2019] [Accepted: 03/18/2019] [Indexed: 12/24/2022]
Abstract
BACKGROUND Rheumatic heart disease (RHD) is the most serious complication of heart that comprises inflammatory reactions in heart valves. Many studies have demonstrated the contribution of host genetic factors in susceptibility to RHD and many cytokine gene variants have been linked with susceptibility to RHD. We sought to determine the role of genetic variants in IL-1β, STAT3, STAT5B and TLR5 genes in conferring risk of RHD in two cohorts of RHD patients. METHODS The study included 400 echocardiography confirmed RHD patients and 300 controls from North Indian Population. We categorized RHD patients into two sub-groups based on involvement of heart valves, mitral valve lesion alone (MVL), and combined valve lesions including mitral valve (CVL). Genotyping for all the polymorphisms was done using TaqMan /PCR-RFLP methods. RESULTS Our results showed that the genotypic frequencies of IL-1β, STAT3, STAT5B andTLR5 genes polymorphisms were significantly associated with RHD risk. To validate our results, we performed a replication study in additional 200 cases with similar clinical characteristics and results again confirmed consistent findings with RHD risk. In subgroup analysis, STAT3 polymorphism remained significant with MVL in RHD patients. CONCLUSION IL-1β, STAT3, STAT5B and TLR5 genes polymorphism may be useful markers for the identification of individuals with high risk of RHD in the susceptible population.
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Affiliation(s)
- Mansi Bhatt
- Department of Urology, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow, India; Department of Biosciences, Integral University, Lucknow, India
| | - Surendra Kumar
- Department of Cytogenetics/Anatomy, All Indian Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Naveen Garg
- Department of Cardiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow, India
| | | | - Balraj Mittal
- Department of Biotechnology, Babasaheb Bhimrao Ambedkar University (BBAU), Lucknow, India.
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Meroni M, Longo M, Rametta R, Dongiovanni P. Genetic and Epigenetic Modifiers of Alcoholic Liver Disease. Int J Mol Sci 2018; 19:E3857. [PMID: 30513996 PMCID: PMC6320903 DOI: 10.3390/ijms19123857] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 10/31/2018] [Accepted: 11/28/2018] [Indexed: 12/12/2022] Open
Abstract
Alcoholic liver disease (ALD), a disorder caused by excessive alcohol consumption is a global health issue. More than two billion people consume alcohol in the world and about 75 million are classified as having alcohol disorders. ALD embraces a wide spectrum of hepatic lesions including steatosis, alcoholic steatohepatitis (ASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). ALD is a complex disease where environmental, genetic, and epigenetic factors contribute to its pathogenesis and progression. The severity of alcohol-induced liver disease depends on the amount, method of usage and duration of alcohol consumption as well as on age, gender, presence of obesity, and genetic susceptibility. Genome-wide association studies and candidate gene studies have identified genetic modifiers of ALD that can be exploited as non-invasive biomarkers, but which do not completely explain the phenotypic variability. Indeed, ALD development and progression is also modulated by epigenetic factors. The premise of this review is to discuss the role of genetic variants and epigenetic modifications, with particular attention being paid to microRNAs, as pathogenic markers, risk predictors, and therapeutic targets in ALD.
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Affiliation(s)
- Marica Meroni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pad. Granelli, via F Sforza 35, 20122 Milan, Italy.
| | - Miriam Longo
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pad. Granelli, via F Sforza 35, 20122 Milan, Italy.
| | - Raffaela Rametta
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pad. Granelli, via F Sforza 35, 20122 Milan, Italy.
| | - Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pad. Granelli, via F Sforza 35, 20122 Milan, Italy.
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Chen Y, Ouyang X, Hoque R, Garcia-Martinez I, Yousaf MN, Tonack S, Offermanns S, Dubuquoy L, Louvet A, Mathurin P, Massey V, Schnabl B, Bataller RA, Mehal WZ. β-Hydroxybutyrate protects from alcohol-induced liver injury via a Hcar2-cAMP dependent pathway. J Hepatol 2018; 69:687-696. [PMID: 29705237 PMCID: PMC6098974 DOI: 10.1016/j.jhep.2018.04.004] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Revised: 04/03/2018] [Accepted: 04/04/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Sterile inflammation resulting in alcoholic hepatitis (AH) occurs unpredictably after many years of excess alcohol intake. The factors responsible for the development of AH are not known but mitochondrial damage with loss of mitochondrial function are common features. Hcar2 is a G-protein coupled receptor which is activated by β-hydroxybutyrate (BHB). We aimed to determine the relevance of the BHB-Hcar2 pathway in alcoholic liver disease. METHODS We tested if loss of BHB production can result in increased liver inflammation. We further tested if BHB supplementation is protective in AH through interaction with Hcar2, and analyzed the immune and cellular basis for protection. RESULTS Humans with AH have reduced hepatic BHB, and inhibition of BHB production in mice aggravated ethanol-induced AH, with higher plasma alanine aminotransferase levels, increased steatosis and greater neutrophil influx. Conversely supplementation of BHB had the opposite effects with reduced alanine aminotransferase levels, reduced steatosis and neutrophil influx. This therapeutic effect of BHB is dependent on the receptor Hcar2. BHB treatment increased liver Il10 transcripts, and promoted the M2 phenotype of intrahepatic macrophages. BHB also increased the transcriptional level of M2 related genes in vitro bone marrow derived macrophages. This skewing towards M2 related genes is dependent on lower mitochondrial membrane potential (Δψ) induced by BHB. CONCLUSIONS Collectively, our data shows that BHB production during excess alcohol consumption has an anti-inflammatory and hepatoprotective role through an Hcar2 dependent pathway. This introduces the concept of metabolite-based therapy for AH. LAY SUMMARY Alcoholic hepatitis is a life-threatening condition with no approved therapy that occurs unexpectedly in people who consume excess alcohol. The liver makes many metabolites, and we demonstrate that loss of one such metabolite β-hydroxybutyrate occurs in patients with alcoholic hepatitis. This loss can increase alcohol-induced liver injury, and β-hydroxybutyrate can protect from alcohol-induced liver injury via a receptor on liver macrophages. This opens the possibility of metabolite-based therapy for alcoholic hepatitis.
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Affiliation(s)
- Yonglin Chen
- Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Xinshou Ouyang
- Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Rafaz Hoque
- Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Irma Garcia-Martinez
- Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Muhammad Nadeem Yousaf
- Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Sarah Tonack
- Max-Planck-Institute for Heart and Lung Research, Department of Pharmacology, Ludwigstr. 43, 61231 Bad Nauheim, Germany; Medical Faculty, J.W. Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany
| | - Stefan Offermanns
- Max-Planck-Institute for Heart and Lung Research, Department of Pharmacology, Ludwigstr. 43, 61231 Bad Nauheim, Germany; Medical Faculty, J.W. Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany
| | | | - Alexandre Louvet
- Service des Maladies de l'appareil digestif, Hôpital Huriez, Lille, France; Unité INSERM 995, Faculté de Médecine, Lille, France
| | - Philippe Mathurin
- Service des Maladies de l'appareil digestif, Hôpital Huriez, Lille, France; Unité INSERM 995, Faculté de Médecine, Lille, France
| | - Veronica Massey
- School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Ramon Alberola Bataller
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Wajahat Zafar Mehal
- Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, USA; USA West Haven Veterans Medical Center, West Haven, CT 06516, USA.
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Abstract
Alcoholic liver disease (ALD) is a leading cause of chronic liver disease with a wide spectrum of manifestations including simple steatosis to steatohepatitis, cirrhosis, and hepatocellular carcinoma. Liver injury in ALD is caused by chronic inflammation, which has been actively investigated as a therapeutic target for the treatment of ALD for over the last four decades. In this review, we summarize a wide variety of inflammatory mediators that have been shown to contribute to the pathogenesis of ALD, and discuss the therapeutic potential of these mediators for the treatment of ALD.
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Ramaiah S, Rivera C, Arteel G. Early-Phase Alcoholic Liver Disease: An Update on Animal Models, Pathology, and Pathogenesis. Int J Toxicol 2016; 23:217-31. [PMID: 15371166 DOI: 10.1080/10915810490502069] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Alcoholic liver disease (ALD) remains to be one of the most common etiology of liver disease and is a major cause of morbidity and mortality worldwide. The pathologic stages of ALD comprises of steatosis, steatohepatitis, and fibrosis/cirrhosis. Steatosis and steatohepatitis represents the early phase of ALD and are precursor stages for fibrosis/cirrhosis. Numerous research efforts have been directed at recognizing cofactors interacting with alcohol in the pathogenesis of steatosis and steatohepatitis. This review will elucidate the constellation of complex pathogenesis, available animal models, and microscopic pathologic findings mostly in the early-phase of ALD. The role of endotoxin, reactive oxygen species, alcohol metabolism, and cytokines are discussed. Understanding the mechanisms of early-phase ALD should provide insight into the development of therapeutic strategies and thereby decrease the morbidity and mortality associated with ALD.
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Affiliation(s)
- Shashi Ramaiah
- Department of Pathobiology, Texas Veterinary Medical Center, College of Veterinary Medicine, Texas A and M University, College Station, TX 77843, USA
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Zhao YY, Xiao M, Zhang CL, Xie KQ, Zeng T. Associations between the tumor necrosis factor-α gene and interleukin-10 gene polymorphisms and risk of alcoholic liver disease: A meta-analysis. Clin Res Hepatol Gastroenterol 2016; 40:428-39. [PMID: 26656007 DOI: 10.1016/j.clinre.2015.10.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Revised: 10/15/2015] [Accepted: 10/28/2015] [Indexed: 02/04/2023]
Abstract
BACKGROUND The critical roles of tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) in the pathogenesis of alcoholic liver diseases (ALD) suggest that functional variations in the TNF-α (TNFA) and IL-10 genes may be related to individual susceptibility to ALD. As available studies examining the associations between TNFA or IL-10 polymorphisms and ALD risk have yielded conflicting results, a meta-analysis was conducted to clarify the potential relation between TNFA and IL-10 polymorphisms and the risk of ALD. METHODS A comprehensive literature search was conducted to identify relevant studies. Pooled odds ratios and 95% confidence intervals were calculated using a random-effects model. The heterogeneity between studies was assessed using the Cochran's Q statistic and the I(2) statistic. Publication bias was assessed using funnel plots and the Egger's regression test. RESULTS A total of 17studies and 12studies were identified and included in the meta-analysis of the associations between TNFA polymorphisms and ALD risk, and IL-10 polymorphisms and ALD risk, respectively. The pooled results showed that the "A" allele of the TNFA-238G>A polymorphism was significantly associated with an increased risk of ALD. Significant differences in the allele and genotype distributions of the IL-10-1082A>G polymorphism were detected in the comparison between ALD patients and healthy controls, but not when comparing ALD patients and alcohol dependent individuals without ALD. No significant associations between other polymorphic loci and ALD risks were detected. CONCLUSIONS The TNFA-238G>A polymorphism was significantly associated with ALD risk, while the TNFA-308G>A polymorphism and IL-10 polymorphisms (-1082A>G and -592C>A) may not be associated with the individual susceptibility to ALD. The impact of combined TNFA and IL-10 polymorphisms on individual susceptibility to ALD needs to be investigated in future studies.
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Affiliation(s)
- Yu-Ying Zhao
- Institute of Toxicology, School of Public Health, Shandong University, 44, Wenhua West Road, Jinan City, Shandong Province, 250012, PR China
| | - Mo Xiao
- Institute of Toxicology, School of Public Health, Shandong University, 44, Wenhua West Road, Jinan City, Shandong Province, 250012, PR China
| | - Cui-Li Zhang
- Institute of Toxicology, School of Public Health, Shandong University, 44, Wenhua West Road, Jinan City, Shandong Province, 250012, PR China
| | - Ke-Qin Xie
- Institute of Toxicology, School of Public Health, Shandong University, 44, Wenhua West Road, Jinan City, Shandong Province, 250012, PR China
| | - Tao Zeng
- Institute of Toxicology, School of Public Health, Shandong University, 44, Wenhua West Road, Jinan City, Shandong Province, 250012, PR China.
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Liangpunsakul S, Haber P, McCaughan G. Alcoholic Liver Disease in Asia, Europe, and North America. Gastroenterology 2016; 150:1786-97. [PMID: 26924091 PMCID: PMC4887319 DOI: 10.1053/j.gastro.2016.02.043] [Citation(s) in RCA: 123] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Revised: 02/05/2016] [Accepted: 02/09/2016] [Indexed: 12/16/2022]
Abstract
Alcoholic liver diseases comprise a spectrum of clinical disorders and changes in liver tissue that can be detected by pathology analysis. These range from steatosis to more severe signs and symptoms of liver disease associated with inflammation, such as those observed in patients with alcoholic hepatitis or cirrhosis. Although the relationship between alcohol consumption and liver disease is well established, severe alcohol-related morbidities develop in only a minority of people who consume alcohol in excess. Inter-individual differences in susceptibility to the toxic effects of alcohol have been studied extensively-they include pattern of alcohol consumption, sex, environmental factors (such as diet), and genetic factors, which vary widely among different parts of the world. Alcoholic liver disease is becoming more common in many parts of Asia, but is decreasing in Western Europe. Treatment approaches, including availability of medications, models of care, and approach to transplantation, differ among regions.
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Affiliation(s)
- Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Roudebush Veterans Administration Medical Center, Indianapolis, Indiana.
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Anstee QM, Seth D, Day CP. Genetic Factors That Affect Risk of Alcoholic and Nonalcoholic Fatty Liver Disease. Gastroenterology 2016; 150:1728-1744.e7. [PMID: 26873399 DOI: 10.1053/j.gastro.2016.01.037] [Citation(s) in RCA: 175] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2015] [Revised: 01/17/2016] [Accepted: 01/20/2016] [Indexed: 02/07/2023]
Abstract
Genome-wide association studies and candidate gene studies have informed our understanding of factors contributing to the well-recognized interindividual variation in the progression and outcomes of alcoholic liver disease and nonalcoholic fatty liver disease. We discuss the mounting evidence for shared modifiers and common pathophysiological processes that contribute to development of both diseases. We discuss the functions of proteins encoded by risk variants of genes including patatin-like phospholipase domain-containing 3 and transmembrane 6 superfamily member 2, as well as epigenetic factors that contribute to the pathogenesis of alcoholic liver disease and nonalcoholic fatty liver disease. We also discuss important areas of future genetic research and their potential to affect clinical management of patients.
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Affiliation(s)
- Quentin M Anstee
- Liver Research Group, Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle-upon-Tyne, United Kingdom.
| | - Devanshi Seth
- Centenary Institute of Cancer Medicine, Royal Prince Alfred Hospital, Camperdown, Australia; Drug Health Services, Royal Prince Alfred Hospital, Camperdown, Australia; Central Clinical School, The University of Sydney, Camperdown, Australia
| | - Christopher P Day
- Liver Research Group, Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle-upon-Tyne, United Kingdom
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16
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Rosen HR, Golden-Mason L, Daly AK, Yang I, Day CP. Variants in the LGALS9 Gene Are Associated With Development of Liver Disease in Heavy Consumers of Alcohol. Clin Gastroenterol Hepatol 2016; 14:762-8.e1. [PMID: 26598225 DOI: 10.1016/j.cgh.2015.11.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Revised: 10/13/2015] [Accepted: 11/09/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Alcohol consumption is a major cause of chronic liver disease and contributes to a large proportion of cirrhosis-related deaths worldwide. However, only a fraction of heavy consumers of alcohol develop advanced alcoholic liver disease (ALD), so there are likely to be other risk factors. We investigated whether polymorphisms in the gene encoding galectin-9 (LGALS9), previously shown to mediate liver injury, were associated with the development of ALD. METHODS We isolated DNA from peripheral blood mononuclear cells (PBMCs) of 575 individuals with at-risk alcohol consumption but no other risk factors for chronic liver disease; all subjects were white Europeans who had consumed more than 80 grams ethanol per day. Of the subjects, 388 had ALD (including, 268 with cirrhosis and 74 with alcoholic hepatitis; mean age, 49 y; 72% male) and 187 had normal liver function with no biochemical or clinical evidence of liver disease (controls; mean age, 42 y; 73% male). Select LGALS9 polymorphisms were genotyped using allelic discrimination. We also genotyped and measured expression of LGALS9 messenger RNA in PBMCs from individuals who were not heavy consumers of alcohol. RESULTS We used data from the HapMap project to identify 5 single-nucleotide polymorphisms (SNPs) that tag all the common haplotypes. When we looked for these SNPs in individuals with vs without liver disease, 4 (rs3751093, rs4239242, rs732222, and rs4794976) were associated with an increased risk of developing ALD. We found that levels of LGALS9 messenger RNA and protein expressed were associated with an allele carried by PBMCs. Multivariate analysis confirmed that rs4239242 and rs4794976 were associated with an increased risk of ALD. CONCLUSIONS In a genetic analysis of heavy consumers of alcohol, we associated 2 SNPS in LGALS9 with the development of ALD. Although larger studies are required, this information could be used to determine the risk of individuals developing ALD or to develop therapeutic agents.
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Affiliation(s)
- Hugo R Rosen
- Division of Gastroenterology/Hepatology, University of Colorado, Aurora, Colorado.
| | - Lucy Golden-Mason
- Division of Gastroenterology/Hepatology, University of Colorado, Aurora, Colorado
| | - Ann K Daly
- Institute of Cellular Medicine, Newcastle University Medical School, Newcastle upon Tyne, United Kingdom
| | - Ivana Yang
- Division of Pulmonary Medicine, University of Colorado, Aurora, Colorado
| | - Christopher P Day
- Institute of Cellular Medicine, Newcastle University Medical School, Newcastle upon Tyne, United Kingdom
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Mathew S, Abdel-Hafiz H, Raza A, Fatima K, Qadri I. Host nucleotide polymorphism in hepatitis B virus-associated hepatocellular carcinoma. World J Hepatol 2016; 8:485-498. [PMID: 27057306 PMCID: PMC4820640 DOI: 10.4254/wjh.v8.i10.485] [Citation(s) in RCA: 14] [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: 09/12/2015] [Revised: 12/04/2015] [Accepted: 03/07/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is etiologically linked with hepatitis B virus (HBV) and is the leading cause of death amongst 80% of HBV patients. Among HBV affected patients, genetic factors are also involved in modifying the risk factors of HCC. However, the genetic factors that regulate progression to HCC still remain to be determined. In this review, we discuss several single nucleotide polymorphisms (SNPs) which were reportedly associated with increased or reduced risk of HCC occurrence in patients with chronic HBV infection such as cyclooxygenase (COX)-2 expression specifically at COX-2 -1195G/A in Chinese, Turkish and Egyptian populations, tumor necrosis factor α and the three most commonly studied SNPs: PAT-/+, Lys939Gln (A33512C, rs2228001) and Ala499Val (C21151T, rs2228000). In genome-wide association studies, strong associations have also been found at loci 1p36.22, 11q22.3, 6p21 (rs1419881, rs3997872, rs7453920 and rs7768538), 8p12 (rs2275959 and rs37821974) and 22q11.21. The genes implicated in these studies include HLA-DQB2, HLA-DQA1, TCF19, HLA-C, UBE2L3, LTL, FDX1, MICA, UBE4B and PG. The SNPs found to be associated with the above-mentioned genes still require validation in association studies in order to be considered good prognostic candidates for HCC. Screening of these polymorphisms is very beneficial in clinical experiments to stratify the higher or lower risk for HCC and may help in designing effective and efficient HCC surveillance programs for chronic HBV-infected patients if further genetic vulnerabilities are detected.
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Affiliation(s)
- Shilu Mathew
- Shilu Mathew, Center of Excellence in Genomic Medicine Research, King Abdul Aziz University, Jeddah 21589, Saudi Arabia
| | - Hany Abdel-Hafiz
- Shilu Mathew, Center of Excellence in Genomic Medicine Research, King Abdul Aziz University, Jeddah 21589, Saudi Arabia
| | - Abbas Raza
- Shilu Mathew, Center of Excellence in Genomic Medicine Research, King Abdul Aziz University, Jeddah 21589, Saudi Arabia
| | - Kaneez Fatima
- Shilu Mathew, Center of Excellence in Genomic Medicine Research, King Abdul Aziz University, Jeddah 21589, Saudi Arabia
| | - Ishtiaq Qadri
- Shilu Mathew, Center of Excellence in Genomic Medicine Research, King Abdul Aziz University, Jeddah 21589, Saudi Arabia
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Ghaleh Baghi S, Alavian SM, Mehrnoush L, Salimi S. Impact of the IL-10 Promoter Gene Polymorphisms in the Severity of Chronic Hepatitis B Infection. HEPATITIS MONTHLY 2015; 15:e28287. [PMID: 26300930 PMCID: PMC4539734 DOI: 10.5812/hepatmon.28287v2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Revised: 05/22/2015] [Accepted: 06/20/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND Interleukin-10 (IL-10) is an important anti-inflammatory cytokine. The polymorphisms of its promoter gene have been considered to be related with the chronicity of hepatitis B infection. OBJECTIVES The aim of this study was to evaluate the polymorphisms at different positions in the IL-10 promoter gene in patients with chronic hepatitis B. PATIENTS AND METHODS Totally, 166 patients with chronic hepatitis B infection were enrolled. Genotypes at different positions (i.e. -819, - 592, and - 1082) in the IL-10 gene promoter were determined. RESULTS The C/A genotype at position -592, C/T genotype at position -819, and GCC/ATA haplotype of the IL-10 gene promoter were significantly more common in the patients with cirrhosis. The genotypes were significantly different between the hepatitis B e antigen (HBeAg)-negative and HBeAg-positive patients at position -592 (C/A and C/C), position -819 (C/C and C/T), and position -1082 (A/A and G/A). CONCLUSIONS Some IL-10 promoter gene polymorphisms predisposed the infected hepatitis B virus cases to cirrhosis in our study population.
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Affiliation(s)
- Sahand Ghaleh Baghi
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Tehran, IR Iran
- Department of Otolaryngology and Head and Neck Surgery, Rasool Akram Hospital, Tehran, IR Iran
- Corresponding Author: Sahand Ghaleh Baghi, Department of Otolaryngology and Head and Neck Surgery, Rasool Akram Hospital, Tehran, IR Iran. Tel: +98-9126079880, E-mail:
| | - Seyed Moayed Alavian
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Tehran, IR Iran
- Middle East Liver Disease Center (MELD), Tehran, IR Iran
| | - Leila Mehrnoush
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Tehran, IR Iran
| | - Shima Salimi
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Tehran, IR Iran
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Neuman MG, French SW, French BA, Seitz HK, Cohen LB, Mueller S, Osna NA, Kharbanda KK, Seth D, Bautista A, Thompson KJ, McKillop IH, Kirpich IA, McClain CJ, Bataller R, Nanau RM, Voiculescu M, Opris M, Shen H, Tillman B, Li J, Liu H, Thomes PG, Ganesan M, Malnick S. Alcoholic and non-alcoholic steatohepatitis. Exp Mol Pathol 2014; 97:492-510. [PMID: 25217800 PMCID: PMC4696068 DOI: 10.1016/j.yexmp.2014.09.005] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2014] [Accepted: 09/08/2014] [Indexed: 02/08/2023]
Abstract
This paper is based upon the "Charles Lieber Satellite Symposia" organized by Manuela G. Neuman at the Research Society on Alcoholism (RSA) Annual Meetings, 2013 and 2014. The present review includes pre-clinical, translational and clinical research that characterize alcoholic liver disease (ALD) and non-alcoholic steatohepatitis (NASH). In addition, a literature search in the discussed area was performed. Strong clinical and experimental evidence lead to recognition of the key toxic role of alcohol in the pathogenesis of ALD. The liver biopsy can confirm the etiology of NASH or alcoholic steatohepatitis (ASH) and assess structural alterations of cells, their organelles, as well as inflammatory activity. Three histological stages of ALD are simple steatosis, ASH, and chronic hepatitis with hepatic fibrosis or cirrhosis. These latter stages may also be associated with a number of cellular and histological changes, including the presence of Mallory's hyaline, megamitochondria, or perivenular and perisinusoidal fibrosis. Genetic polymorphisms of ethanol metabolizing enzymes such as cytochrome p450 (CYP) 2E1 activation may change the severity of ASH and NASH. Alcohol mediated hepatocarcinogenesis, immune response to alcohol in ASH, as well as the role of other risk factors such as its co-morbidities with chronic viral hepatitis in the presence or absence of human immunodeficiency virus are discussed. Dysregulation of hepatic methylation, as result of ethanol exposure, in hepatocytes transfected with hepatitis C virus (HCV), illustrates an impaired interferon signaling. The hepatotoxic effects of ethanol undermine the contribution of malnutrition to the liver injury. Dietary interventions such as micro and macronutrients, as well as changes to the microbiota are suggested. The clinical aspects of NASH, as part of metabolic syndrome in the aging population, are offered. The integrative symposia investigate different aspects of alcohol-induced liver damage and possible repair. We aim to (1) determine the immuno-pathology of alcohol-induced liver damage, (2) examine the role of genetics in the development of ASH, (3) propose diagnostic markers of ASH and NASH, (4) examine age differences, (5) develop common research tools to study alcohol-induced effects in clinical and pre-clinical studies, and (6) focus on factors that aggravate severity of organ-damage. The intention of these symposia is to advance the international profile of the biological research on alcoholism. We also wish to further our mission of leading the forum to progress the science and practice of translational research in alcoholism.
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Affiliation(s)
- Manuela G Neuman
- In Vitro Drug Safety and Biotechnology, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
| | | | | | - Helmut K Seitz
- Centre of Alcohol Research, University of Heidelberg and Department of Medicine (Gastroenterology and Hepatology), Salem Medical Centre, Heidelberg, Germany
| | - Lawrence B Cohen
- Division of Gastroenterology, Sunnybrook Health Sciences Centre, Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Sebastian Mueller
- Centre of Alcohol Research, University of Heidelberg and Department of Medicine (Gastroenterology and Hepatology), Salem Medical Centre, Heidelberg, Germany
| | - Natalia A Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Internal Medicine, Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Kusum K Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Internal Medicine, Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Devanshi Seth
- Drug Health Services, Royal Prince Alfred Hospital, Centenary Institute of Cancer Medicine and Cell Biology, Camperdown, NSW 2050, Australia; Faculty of Medicine, The University of Sydney, Sydney, NSW 2006, Australia
| | - Abraham Bautista
- Office of Extramural Activities, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD, USA
| | - Kyle J Thompson
- Department of Surgery, Carolinas Medical Center, Charlotte, NC, USA
| | - Iain H McKillop
- Department of Surgery, Carolinas Medical Center, Charlotte, NC, USA
| | - Irina A Kirpich
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine and Department of Pharmacology; Toxicology, University of Louisville School of Medicine, Louisville, KY, USA
| | - Craig J McClain
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine and Department of Pharmacology; Toxicology, University of Louisville School of Medicine, Louisville, KY, USA; Robley Rex Veterans Medical Center, Louisville, KY, USA
| | - Ramon Bataller
- Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Radu M Nanau
- In Vitro Drug Safety and Biotechnology, University of Toronto, Toronto, Ontario, Canada
| | - Mihai Voiculescu
- Division of Nephrology and Internal Medicine, Fundeni Clinical Institute and University of Medicine and Pharmacy, "Carol Davila", Bucharest, Romania
| | - Mihai Opris
- In Vitro Drug Safety and Biotechnology, University of Toronto, Toronto, Ontario, Canada; Family Medicine Clinic CAR, Bucharest, Romania
| | - Hong Shen
- Harbor-UCLA Medical Center, Torrance, CA, USA
| | | | - Jun Li
- Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Hui Liu
- Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Paul G Thomes
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Internal Medicine, Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Murali Ganesan
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Internal Medicine, Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Steve Malnick
- Department Internal Medicine, Kaplan Medical Centre and Hebrew University of Jerusalem, Rehovot, Israel
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Sepahi S, Pasdar A, Ahadi M, Gerayli S, Rostami S, Meshkat Z. Haplotype analysis of interleukin-10 gene promoter polymorphisms in chronic hepatitis C infection: a case control study. Viral Immunol 2014; 27:398-403. [PMID: 25119896 DOI: 10.1089/vim.2014.0024] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
High prevalence of hepatitis c virus (HCV) infection in some areas necessitates more investigations of the causative factors. Genetic factors that cause disruption in operation or secretion of interleukin 10 (IL-10), an anti-inflammatory cytokine, may play a role in the intensity of the disease. The aim of this study was to evaluate genetic variants of IL-10 gene polymorphisms in HCV patients and their relationship with HCV disease. Fifty HCV patients and the same number of healthy individuals who were referred to hepatitis clinic in Mashhad, northeast of Iran, were recruited. Genomic DNA was extracted from whole blood. Genotyping for IL-10 gene promoter polymorphisms in three positions (-1082 G>A, -819 C>T and -592 C>A) was conducted by amplification refractory mutation system-polymerase chain reaction. Haplotype analysis was performed using PHASE software. In a recessive analysis model of the -1082 position (GG vs. AA+AG), GG genotype was more common in patients (adjusted p = 0.02; OR = 4.66 [95% CI 1.31-16.35]). Also, ATA haplotype was more prevalent in HCV patients (adjusted p = 0.061; OR = 1.87 [95% CI 0.97-3.61]). Also, ATC/GCA diplotypes were more common in controls (adjusted p=0.002; adjusted OR = 0.27 [95% CI 0.11-0.63]). Although we found a possible association between IL-10 promoter polymorphisms and HCV infection, certain genotypes or diplotypes may confer a higher risk or susceptibility for developing HCV infection.
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Affiliation(s)
- Samaneh Sepahi
- 1 Department of Chemistry, Faculty of Sciences, Ferdowsi University of Mashhad , Mashhad, Iran
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21
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Tamandani DMK, Hashemi M, Shafiepour S. Analysis of cytotoxic T-lymphocyte-associated antigen-4 and MMP-9 genes' methylation and their expression profiles with risk of non-alcoholic fatty liver disease. INDIAN JOURNAL OF HUMAN GENETICS 2013; 19:144-9. [PMID: 24019613 PMCID: PMC3758718 DOI: 10.4103/0971-6866.116106] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE: To investigate the effect of promoter methylation of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) gene and matrix metalloproteinases (MMPs) on the risk of non-alcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS: CTLA-4 and MMP-9 promoter methylation were investigated using a methylation-specific polymerase chain reaction (MS-PCR) in blood samples taken from 80 NAFLD individuals and 95 healthy controls. The expression levels of CTLA-4 and MMP-9 were also assessed in 10 blood and 9 liver tissues mRNA samples from NAFLD patients. These cases were compared to the blood (n = 10) samples of healthy controls with real-time quantitative reverse transcriptase PCR. RESULTS: No significant relationship was found for methylation of CTLA-4 and MMP-9 between cases and controls. The relative expression of CTLA-4 and MMP-9 mRNA in NAFLD was not significantly different compared to healthy control samples. CONCLUSION: For the first time, our outcomes indicate that the methylation status of CTLA-4 and MMP-9 genes has no significant function on the process of NAFLD.
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22
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Nezi V, Deutsch M, Gazouli M, Alexopoulou A, Paparrigopoulos T, Liappas IA, Dourakis SP. Polymorphisms of the CD14 genes are associated with susceptibility to alcoholic liver disease in Greek patients. Alcohol Clin Exp Res 2013; 37:244-251. [PMID: 23009036 DOI: 10.1111/j.1530-0277.2012.01925.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2012] [Accepted: 07/06/2012] [Indexed: 12/14/2022]
Abstract
BACKGROUND The incidence and severity of alcoholic liver disease (ALD) in chronic drinkers has been found to correlate with some environmental factors and especially with the dose of alcohol consumption, but it is obvious that other parameters clearly contribute to individual alcohol susceptibility. Chronic ethanol exposure leads to continuous endotoxin-mediated Toll-like receptor-4 (TLR-4) and CD14 activation and subsequent cytokine release resulting in chronic inflammation with continued hepatocellular damage. Therefore, genetic studies of polymorphism in TLR-4 and CD14 genes seem to be appropriate in determining genetic susceptibility to ALD. Our aim is to evaluate in a series of Greek drinkers, the possible association of polymorphisms in the TLR-4 and CD14 genes with ALD. METHODS In 96 patients with ALD polymorphism of TLR-4 and CD14 genes were studied compared with 104 patients with cirrhosis of other etiology, 100 healthy subjects, and 50 patients with a history of alcohol abuse but without liver disease. RESULTS No association between ALD and the presence of the Asp299Gly and Thr399Ile polymorphisms in the TLR-4 gene could be documented in our patients. Regarding the CD14 -159 (C/T) genotypes, TT genotype and T allele were found to be overrepresented in alcoholic patients compared with patients with nonalcohol-induced liver disease and healthy controls. On the other side, when compared patients with ALD and patients with alcohol abuse and no liver disease, TT genotype was found to be significantly less frequent. There is no statistically significant association with the presence of the T allele and the severity of ALD, suggesting that CD14 polymorphism does not influence disease severity in advanced stages of the disease. CONCLUSIONS In our series in Greek patients with alcohol abuse and alcoholic cirrhosis, a significant negative association with the CD14 endotoxin receptor gene polymorphism (TT genotype) but not with the TLR-4 gene polymorphism was documented.
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Affiliation(s)
- Vasiliki Nezi
- Second Department of Internal Medicine , Hippokration General Hospital, University of Athens Medical School, Athens, Greece.
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Roy N, Mukhopadhyay I, Das K, Pandit P, Majumder PP, Santra A, Datta S, Banerjee S, Chowdhury A. Genetic variants of TNFα, IL10, IL1β, CTLA4 and TGFβ1 modulate the indices of alcohol-induced liver injury in East Indian population. Gene 2012; 509:178-88. [PMID: 22902304 DOI: 10.1016/j.gene.2012.07.077] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2012] [Accepted: 07/31/2012] [Indexed: 02/06/2023]
Abstract
Alcohol induced liver disease or alcoholic liver disease (ALD), a complex trait, encompasses a gamut of pathophysiological alterations in the liver due to continuous exposure to a toxic amount of alcohol (more than 80 g per day). Of all chronic heavy drinkers, only 15-20% develops hepatitis or cirrhosis concomitantly or in succession. Several studies revealed that inter-individual as well as inter-ethnic genetic variation is one of the major factors that predispose to ALD. The role of genetic factors in ALD has long been sought for in ethnically distinct population groups. ALD is fast emerging as an important cause of chronic liver disease in India; even in populations such as "Bengalis" who were "culturally immune" earlier. While the genetic involvement in the pathogenesis of ALD is being sought for in different races, the complex pathophysiology of ALD as well as the knowledge of population level diversity of the relevant alcohol metabolizing and inflammatory pathways mandates the need for well designed studies of genetic factors in ethnically distinct population groups. An array of cytokines plays a critical role as mediators of injury, inflammation, fibrosis and cirrhosis in ALD. We, therefore, studied the association of polymorphisms in five relevant cytokine genes with "clinically significant" ALD in an ethnic "Bengali" population in Eastern India. Compared with "alcoholic" controls without liver disease (n=110), TNFα -238AA genotype, IL1β -511CC genotype, TGFβ1 -509CC genotype and IL10 -592AA genotype were significantly overrepresented in ALD patients (n=181; OR=2.4 and 95% CI 1.2-5.5, P(genotype)=0.042, P(allelic)=0.008; OR=2.7 and 95% CI 1.2-5.9, P(genotype)=0.018, P(allelic)=0.023; OR=4.7 and 95% CI 1.7-13.1, P(genotype)=0.003, P(allelic)=0.014; and OR=2.2 and 95% CI 1.1-4.8, P(genotype)=0.04, P(allelic)=0.039 respectively). Moreover a cumulative genetic risk analysis revealed a significant trend for developing ALD with an increase in the number of risk alleles on IL10 and TGFβ1 loci among alcoholics. The risk genotype of IL1β and TGFβ1 also influences the total bilirubin, albumin and alanine aminotransferase levels among alcoholic "Bengalis". The present study is the first case-control study from Eastern India that comprehensively identified polymorphic markers in TNFα, IL10, IL1β and TGFβ1 genes to be associated with ALD in the Bengali population, accentuating the significance of genetic factors in clinical expressions of ALD.
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Affiliation(s)
- Neelanjana Roy
- Centre for Liver Research, Institute of Post Graduate Medical Education & Research, Kolkata, India.
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Abstract
OBJECTIVES The variable susceptibility to alcoholic liver disease (ALD) may be genetic in origin, but clear candidate genes have not yet emerged. This study aimed to assess familial clustering of ALD using a case-control strategy. METHODS We recruited two cohorts of heavy drinkers (>60 U/week for men or >40 U/week for women): 291 individuals with decompensated ALD (Child's grade B or C) and 208 controls with similar alcohol consumption but no evidence of liver disease. Data were collected, through a questionnaire and a follow-up telephone call, on drinking behaviour and the presence of liver disease in parents and siblings of cases and controls. The results in the relatives of cases were compared with those in the relatives of the controls. RESULTS The odds ratio (OR) of heavy drinking in the relatives of the cases compared with the controls was 0.91 [95% confidence interval (CI), 0.73-1.1]. OR in the relatives of the cases versus the controls was 1.27 for definite ALD (95% CI, 0.63-2.6), 1.09 for all ALD (95% CI, 0.58-2.0) and 1.0 for all liver diseases (95% CI, 0.60-1.7). Multiple subgroup analyses yielded similar OR values, not exceeding 1.5. CONCLUSION These data do not suggest a strong familial predisposition to the development of ALD and rather suggest that the main cofactors are environmental.
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25
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Brunt EM, Neuschwander-Tetri BA, Burt AD. Fatty liver disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2012:293-359. [DOI: 10.1016/b978-0-7020-3398-8.00006-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Sawhney R, Visvanathan K. Polymorphisms of toll-like receptors and their pathways in viral hepatitis. Antivir Ther 2011; 16:443-58. [PMID: 21685532 DOI: 10.3851/imp1820] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Toll-like receptors (TLRs) are an important part of the innate immune response to a variety of pathogens including hepatic viral infections. Activation of TLRs stimulates a complex intracellular signalling cascade that results in production of proinflammatory cytokines and interferons important for antiviral responses as well as induction of the adaptive arm of the immune system. There is substantial evidence for an important role for TLRs and TLR-mediated signalling in the pathogenesis and outcomes of hepatitis B and C in particular, but it might also influence responses to other viral hepatitis infections. Several single nucleotide polymorphisms (SNPs) of TLRs, relevant adaptor molecules and cytokines mediated by TLR signalling have been described that alter innate immune responses and have been implicated in a variety of human diseases including viral and other infections. There is now significant evidence that a number of TLR SNPs can affect various clinical outcomes in Caucasian patients with chronic HCV. However, the role of these polymorphisms in acute and other chronic hepatitis infections, including HBV as well as in non-Caucasian populations, has not been elucidated. In addition, results for SNPs downstream of TLR activation, such as in relevant cytokines, are inconsistent and their influence requires further investigation to determine the clinical significance of genetic variations in these mediators.
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Affiliation(s)
- Rohit Sawhney
- Innate Immunity Laboratory, Department of Medicine, Monash University, Melbourne, Australia
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Abstract
A large number of case-control association studies on genetic susceptibility to drug-induced liver injury, involving both candidate gene and genome-wide association approaches, have now been reported. The strongest associations have been observed for human leukocyte antigen (HLA) class I and II genes and N-acetyltransferase 2 (NAT2). The associations with HLA class I and II genes are drug specific, though some apparently unrelated compounds show genetic associations with the same alleles. The underlying mechanism for the HLA association is likely to involve T-cell responses to either drug-protein adducts or to drug alone, but needs further investigation. The NAT2 association relates to liver injury induced by isoniazid, with most published studies finding an increased risk of injury in slow acetylators lacking NAT2 enzyme activity, presumably because of the accumulation of toxic metabolites. Other associations with genes relevant to drug disposition, innate immunity, oxidative stress, and mitochondrial function have also been reported, though these still need to be confirmed by replication in independent cohorts.
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Affiliation(s)
- Ann K Daly
- Institute of Cellular Medicine, Newcastle University Medical School, Newcastle upon Tyne, United Kingdom.
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Miller AM, Wang H, Bertola A, Park O, Horiguchi N, Ki SH, Yin S, Lafdil F, Gao B. Inflammation-associated interleukin-6/signal transducer and activator of transcription 3 activation ameliorates alcoholic and nonalcoholic fatty liver diseases in interleukin-10-deficient mice. Hepatology 2011; 54:846-56. [PMID: 21725996 PMCID: PMC3197882 DOI: 10.1002/hep.24517] [Citation(s) in RCA: 141] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
UNLABELLED Alcoholic and nonalcoholic steatohepatitis are characterized by fatty liver plus inflammation. It is generally believed that steatosis promotes inflammation, whereas inflammation in turn aggregates steatosis. Thus, we hypothesized the deletion of interleukin (IL)-10, a key anti-inflammatory cytokine, exacerbates liver inflammation, steatosis, and hepatocellular damage in alcoholic and nonalcoholic fatty liver disease models that were achieved via feeding mice with a liquid diet containing 5% ethanol for 4 weeks or a high-fat diet (HFD) for 12 weeks, respectively. IL-10 knockout (IL-10(-/-)) mice and several other strains of genetically modified mice were generated and used. Compared with wild-type mice, IL-10(-/-) mice had greater liver inflammatory response with higher levels of IL-6 and hepatic signal transducer and activator of transcription 3 (STAT3) activation, but less steatosis and hepatocellular damage after alcohol or HFD feeding. An additional deletion of IL-6 or hepatic STAT3 restored steatosis and hepatocellular damage but further enhanced liver inflammatory response in IL-10(-/-) mice. In addition, the hepatic expression of sterol regulatory element-binding protein 1 and key downstream lipogenic proteins and enzymes in fatty acid synthesis were down-regulated in IL-10(-/-) mice. Conversely, IL-10(-/-) mice displayed enhanced levels of phosphorylated adenosine monophosphate-activated protein kinase and its downstream targets including phosphorylated acetyl-coenzyme A carboxylase and carnitine palmitoyltransferase 1 in the liver. Such dysregulations were corrected in IL-10(-/-) IL-6(-/-) or IL-10(-/-) STAT3(Hep-/-) double knockout mice. CONCLUSION IL-10(-/-) mice are prone to liver inflammatory response but are resistant to steatosis and hepatocellular damage induced by ethanol or HFD feeding. Resistance to steatosis in these mice is attributable to elevation of inflammation-associated hepatic IL-6/STAT3 activation that subsequently down-regulates lipogenic genes but up-regulates fatty acid oxidation-associated genes in the liver.
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Affiliation(s)
- Andrew M. Miller
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Hua Wang
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Adeline Bertola
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Ogyi Park
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Norio Horiguchi
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Gunma 371-8511, Japan
| | - Sung Hwan Ki
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
- Laboratory of Toxicology, College of Pharmacy, Chosun University, Gwangju 501-759, South Korea
| | - Shi Yin
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui 230032, China
| | - Fouad Lafdil
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
- INSERM, U955, Créteil, F-94000 France
- Université Paris-Est, Faculté de Médecine, UMR-S955, Créteil, F-94000 France
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
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Seth D, Haber PS, Syn WK, Diehl AM, Day CP. Pathogenesis of alcohol-induced liver disease: classical concepts and recent advances. J Gastroenterol Hepatol 2011; 26:1089-105. [PMID: 21545524 DOI: 10.1111/j.1440-1746.2011.06756.x] [Citation(s) in RCA: 112] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Alcoholic liver disease (ALD) is a primary consequence of heavy and prolonged drinking. ALD contributes to the bulk of liver disease burden worldwide. Progression of ALD is a multifactorial and multistep process that includes many genetic and environmental risk factors. The molecular pathogenesis of ALD involves alcohol metabolism and secondary mechanisms such as oxidative stress, endotoxin, cytokines and immune regulators. The histopathological manifestation of ALD occurs as an outcome of complex but controlled interactions between hepatic cell types. Hepatic stellate cells (HSCs) are the key drivers of fibrogenesis, but transformation of hepatocytes to myofibroblastoids also implicate parenchymal cells as playing an active role in hepatic fibrogenesis. Recent discoveries indicate that lipogenesis during the early stages of ALD is a risk for advancement to cirrhosis. Other recently identified novel molecules and physiological/cell signaling pathways include fibrinolysis, osteopontin, transforming growth factor-β-SMAD and hedgehog signaling, and involvement of novel cytokines in hepatic fibrogenesis. The observation that ALD and non-alcoholic steatohepatitis share common pathways and genetic polymorphisms suggests operation of parallel pathogenic mechanisms. Future research involving genomics, epigenomics, deep sequencing and non-coding regulatory elements holds promise to identify novel diagnostic and therapeutic targets for ALD. There is also a need for adequate animal models to study pathogenic mechanisms at the molecular level and targeted therapy.
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Affiliation(s)
- Devanshi Seth
- Drug Health Services, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
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Kebir O, Gorsane MA, Blecha L, Krebs MO, Reynaud M, Benyamina A. Association of inflammation genes with alcohol dependence/abuse: a systematic review and a meta-analysis. Eur Addict Res 2011; 17:146-53. [PMID: 21447951 DOI: 10.1159/000324849] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2010] [Accepted: 02/01/2011] [Indexed: 01/18/2023]
Abstract
The aim of the present work was to systematically review all association studies of inflammation genes with alcohol dependence/alcohol abuse (AD/AA) and to perform a meta-analysis. Odds ratios (ORs) were estimated by contrasting the ratio of counts of the 'high-risk' versus 'low-risk' alleles in AD/AA cases versus controls. Data reported in at least three published studies were available for four genetic polymorphisms [TNF-α-238 (rs361525, G/A); TNF-α-308 (rs1800629, G/A); IL-1RA (VNTR [86 bp]n); IL-10-592 (rs1800896, C/A)]. In total, nine meta-analyses were performed. Of these, only the TNF-α-238 polymorphism showed a significant association with AD/AA (OR=1.36, 95% CI: 1.05-1.76). This risk remained significant and increased slightly when we considered only patients with advanced alcohol-related liver disease (AALD) (OR=1.5, 95% CI: 1.13-1.98) but not when we considered only patients without AALD (OR=1.08, 95% CI: 0.5-2.35). Sensitivity analysis showed that this genetic association is derived from the AALD phenotype rather than from AD. Our approach is limited by our phenotype definition; some studies included chronic heavy drinkers (minimal daily consumption of 80 g for a minimal duration of 10 years) but without a standardized psychiatric assessment.
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Affiliation(s)
- Oussama Kebir
- INSERM, Laboratory of Pathophysiology of Psychiatric Diseases, Centre of Psychiatry and Neurosciences, U894, Paris, France
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Medici V, M.Peerson J, Stabler SP, French SW, Gregory JF, Virata MC, Albanese A, Bowlus CL, Devaraj S, Panacek EA, Rahim N, Richards JR, Rossaro L, Halsted CH. Impaired homocysteine transsulfuration is an indicator of alcoholic liver disease. J Hepatol 2010; 53:551-7. [PMID: 20561703 PMCID: PMC2923260 DOI: 10.1016/j.jhep.2010.03.029] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2010] [Revised: 03/17/2010] [Accepted: 03/24/2010] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Although abnormal hepatic methionine metabolism plays a central role in the pathogenesis of experimental alcoholic liver disease (ALD), its relationship to the risk and severity of clinical ALD is not known. The aim of this clinical study was to determine the relationship between serum levels of methionine metabolites in chronic alcoholics and the risk and pathological severity of ALD. METHODS Serum levels of liver function biochemical markers, vitamin B6, vitamin B12, folate, homocysteine, methionine, S-adenosylmethionine, S-adenosylhomocysteine, cystathionine, cysteine, alpha-aminobutyrate, glycine, serine, and dimethylglycine were measured in 40 ALD patients, of whom 24 had liver biopsies, 26 were active drinkers without liver disease, and 28 were healthy subjects. RESULTS Serum homocysteine was elevated in all alcoholics, whereas ALD patients had low vitamin B6 with elevated cystathionine and decreased alpha-aminobutyrate/cystathionine ratios, consistent with decreased activity of vitamin B6 dependent cystathionase. The alpha-aminobutyrate/cystathionine ratio predicted the presence of ALD, while cystathionine correlated with the stage of fibrosis in all ALD patients. CONCLUSIONS The predictive role of the alpha-aminobutyrate/cystathionine ratio for the presence of ALD and the correlation between cystathionine serum levels with the severity of fibrosis point to the importance of the homocysteine transsulfuration pathway in ALD and may have important diagnostic and therapeutic implications.
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Affiliation(s)
- Valentina Medici
- Department of Internal Medicine, University of California Davis, Sacramento, CA 95817, USA.
| | - Janet M.Peerson
- Department of Nutrition, University of California Davis, Sacramento, CA
| | - Sally P. Stabler
- Department of Medicine, University of Colorado Health Sciences Center, Denver, CO
| | - Samuel W. French
- Department of Pathology, UCLA/Harbor Medical Center, Torrance, CA
| | - Jesse F. Gregory
- Food Science and Human Nutrition Department, Institute of Food and Agricultural Sciences, University of Florida, Gainesville, FL
| | | | - Antony Albanese
- Gastroenterology Section, Sacramento Veterans Affairs Medical Center, Sacramento, CA
| | | | - Sridevi Devaraj
- Department of Pathology, University of California Davis, Sacramento, CA
| | - Edward A. Panacek
- Department of Emergency Medicine, University of California Davis, Sacramento, CA
| | - Nazir Rahim
- Department of Internal Medicine, University of California Davis, Sacramento, CA
| | - John R. Richards
- Department of Emergency Medicine, University of California Davis, Sacramento, CA
| | - Lorenzo Rossaro
- Department of Internal Medicine, University of California Davis, Sacramento, CA
| | - Charles H. Halsted
- Department of Internal Medicine, University of California Davis, Sacramento, CA,Department of Nutrition, University of California Davis, Sacramento, CA
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Polymorphisms in the interleukin-10 gene promoter and the risk of alcoholism and alcoholic liver disease in Caucasian Spaniard men. Alcohol 2010; 44:211-6. [PMID: 20570082 DOI: 10.1016/j.alcohol.2010.02.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2008] [Revised: 12/06/2009] [Accepted: 02/10/2010] [Indexed: 02/07/2023]
Abstract
Controversy surrounds the possible influence of the single nucleotide polymorphisms (SNPs) of the interleukin-10 (IL-10) gene promoter on the risk for alcoholic liver disease. Our aim was to determine whether the SNP of the IL-10 gene promoter are associated with an increased risk for alcoholism and for alcoholic liver disease in male Spaniards. The -627 C>A SNP of the IL-10 gene promoter was assessed in a cohort of 344 Caucasian Spanish men, 168 alcoholics, and 176 nonalcoholics. The alcoholic group comprised 79 individuals without liver histopathologic abnormalities and 89 patients with chronic alcoholic liver disease. The nonalcoholic group was made of 62 healthy controls and 114 patients with chronic nonalcoholic liver disease. Genotyping was performed using PCR and automatic sequencing analysis methods on white cell DNA. Genotype and allele frequencies were compared by using the chi(2) test. Overall, no differences in either genotype and allele distribution was observed when comparing the four patient categories defined (P=0.62 and P=0.33, respectively). Subset analyses showed no differences in the genotype and allele distributions between all alcoholic and all nonalcoholic subjects (P=0.55 and P=0.29, respectively). This study failed to detect significant associations of the IL-10 -627C>A SNP and alcoholism or alcoholic liver disease in a cohort of Caucasian male Spaniards.
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33
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Abstract
Cytokines are thought to play a role in acute and/or immune-mediated adverse drug reactions (ADRs) due to their ability to regulate the innate and adaptive immune systems. This role is highly complex owing to the pluripotent nature of cytokines, which enables the same cytokine to play multiple roles depending on target organ(s) involved. As a result, the discussion of cytokine involvement in ADRs is organized according to target organ(s); specifically, ADRs targeting skin and liver, as well as ADRs targeting multiple organs, such as drug-induced autoimmunity and infusion-related reactions. In addition to discussing the mechanism(s) by which cytokines contribute to the initiation, propagation, and resolution of ADRs, we also discuss the usefulness and limitations of current methodologies available to conduct such mechanistic studies. While animal models appear to hold the most promise for uncovering additional mechanisms, this field is plagued by a lack of good animal models and, as a result, the mechanism of cytokine involvement in ADRs is often studied using less informative in vitro studies. The recent formation of the Drug-Induced Liver Injury Network, whose goal is collect thousands of samples from drug-induced liver injury patients, has enormous potential to advance knowledge in this field, by enabling large-scale cytokine polymorphism studies. In conclusion, we discuss how further advances in this field could be of significant benefit to patients in terms of preventing, predicting, and treating ADRs.
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Hold GL, Untiveros P, Saunders KA, El-Omar EM. Role of host genetics in fibrosis. FIBROGENESIS & TISSUE REPAIR 2009; 2:6. [PMID: 19961576 PMCID: PMC2796989 DOI: 10.1186/1755-1536-2-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/22/2009] [Accepted: 12/04/2009] [Indexed: 01/18/2023]
Abstract
Fibrosis can occur in tissues in response to a variety of stimuli. Following tissue injury, cells undergo transformation or activation from a quiescent to an activated state resulting in tissue remodelling. The fibrogenic process creates a tissue environment that allows inflammatory and matrix-producing cells to invade and proliferate. While this process is important for normal wound healing, chronicity can lead to impaired tissue structure and function. This review examines the major factors involved in transforming or activating tissues towards fibrosis. The role of genetic variation within individuals affected by fibrosis has not been well described and it is in this context that we have examined the mediators of remodelling, including transforming growth factor-beta, T helper 2 cytokines and matrix metalloproteinases. Finally we examine the role of Toll-like receptors in fibrosis. The inflammatory phenotype that precedes fibrosis has been associated with Toll-like receptor activation. This is particularly important when considering gastrointestinal and hepatic disease, where inappropriate Toll-like receptor signalling, in response to the local microbe-rich environment, is thought to play an important role.
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Affiliation(s)
- Georgina L Hold
- Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
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36
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Mieli-Vergani G, Vergani D. Biliary atresia. Semin Immunopathol 2009; 31:371-81. [PMID: 19533128 DOI: 10.1007/s00281-009-0171-6] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2009] [Accepted: 06/01/2009] [Indexed: 12/17/2022]
Abstract
Biliary atresia (BA) is a condition unique to infancy. It results from inflammatory destruction of the intrahepatic and extrahepatic bile ducts. It is the most frequent surgically correctable liver disorder in infancy and the most frequent indication for liver transplantation in paediatric age. Clinical presentation is in the first few weeks of life with conjugated hyperbilirubinaemia (dark urine and pale stools); other manifestations of liver disease, such as failure to thrive, splenomegaly and ascites, appear only later, when surgery is unlikely to be successful. Hence, all infants with conjugated hyperbilirubinaemia must be urgently referred to specialised centres for appropriate treatment. Success of surgery depends on the age at which it is performed. With corrective surgery, followed, when necessary, by liver transplantation, the overall survival rate is approximately 90%. The cause of BA is unknown, but there is evidence for the involvement of infectious, genetic and immunologic mechanisms, which will be discussed in this review.
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Affiliation(s)
- Giorgina Mieli-Vergani
- Paediatric Liver Centre, Institute of Liver Studies, King's College London School of Medicine, King's College Hospital, Denmark Hill, London, SE5 9RS, UK.
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The immunopathogenesis of alcoholic and nonalcoholic steatohepatitis: two triggers for one disease? Semin Immunopathol 2009; 31:359-69. [DOI: 10.1007/s00281-009-0152-9] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2009] [Accepted: 04/28/2009] [Indexed: 02/08/2023]
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Gleeson D, Jones JS, McFarlane E, Francis R, Gellion C, Bradley MP, Peck RJ. Severity of alcohol dependence in decompensated alcoholic liver disease: comparison with heavy drinkers without liver disease and relationship to family drinking history. Alcohol Alcohol 2009; 44:392-7. [PMID: 19286679 DOI: 10.1093/alcalc/agp008] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
AIM The aim of this study was to compare alcohol dependence severity in patients with severe alcoholic liver disease (ALD) with that in heavy drinkers without liver disease. METHODS Short alcohol dependence data and lifetime alcohol questionnaires applied to unselected heavy alcohol drinkers (>60 units/week (M) or 40 units/week (F) for >5 years) with either (a) decompensated ALD (patients n = 136) or (b) no evidence of serious liver disease by clinical, biochemical and ultrasound evaluation ('controls' n = 148). RESULTS The SADD alcohol dependence severity score (range 0-42) in patients with ALD was >28 (severe dependence) in 36 cases (26%); slightly higher than that in heavy-drinking controls taken as a whole; similar to that in controls who were seeking healthcare but higher than that in controls who were not; and lower than that in controls who attended specialist alcohol services. In ALD patients and controls, the SADD score was higher in those with three or more heavy-drinking first-degree relatives than in those with none. In multiple regression analysis, the SADD score showed independent associations with young age, clinically manifest alcohol dependence, seeking healthcare and the presence of multiple heavy drinking relatives, but not with ALD. CONCLUSIONS Alcohol dependence severity in patients with ALD varies and tends to be lower than that in heavy drinkers seeking treatment at alcohol treatment centres but is not as low as implied in some previous studies. Alcohol dependence severity is associated with young age and family drinking history but is not specifically associated with the development of liver disease.
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Gleeson D, Bradley MP, Jones J, Peck RJ, Bond SK, Teare MD, Duff GW. Cytokine gene polymorphisms in heavy drinkers with and without decompensated liver disease: a case-control study. Am J Gastroenterol 2008; 103:3039-46. [PMID: 19086955 DOI: 10.1111/j.1572-0241.2008.02150.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Twin studies have suggested some genetic predisposition to alcoholic liver disease (ALD). Cytokines may be involved in ALD pathogenesis. Several cytokine genes contain functionally significant polymorphisms. Associations between ALD and polymorphisms on the interleukin-1 (IL-1), IL-10, and tumor necrosis factor-alpha (TNF-alpha) genes have been reported but not confirmed. OBJECTIVE Comparison of allelic frequencies of cytokine gene polymorphisms between 223 patients with decompensated ALD (a more severe phenotype than in previous studies) and 162 controls with similar lifetime alcohol consumption but without serious liver disease. METHODS Genotyping of polymorphisms of the genes for IL-1A (+4,845), IL-1B (+3,954 and -511), IL-1 receptor antagonist (+2,018), IL-6 (-174), IL-10 (-574 and -1,117), and TNF-alpha (-238 and -308). RESULTS There were increases with respect to IL-6 -174 (2 x 3 chi(2)P < 0.1, OR for G allele carriage 1.61[1.05-2.48]) and Il-10 -592 (2 x 3 chi(2) 7.90, P < 0.01, OR for AA genotype carriage 4.85[1.40-16.8]) polymorphisms in patients compared with heavy-drinking controls. Differences were greater with analysis confined to Child's C patients. Genotype distribution for the other seven polymorphisms did not differ significantly between patients and heavy-drinking controls. CONCLUSION These data are consistent with a modest role for IL-6 -174, and IL-10 -592 polymorphisms in genetic susceptibility to ALD.
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Affiliation(s)
- Dermot Gleeson
- Liver Unit Sheffield Teaching Hospitals, Royal Hallamshire Hospital, Sheffield, United Kingdom
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A new genetic variant involved in genetic susceptibility to alcoholic liver cirrhosis: -330T>G polymorphism of the interleukin-2 gene. Eur J Gastroenterol Hepatol 2008; 20:855-9. [PMID: 18794598 DOI: 10.1097/meg.0b013e3282fd0db1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
OBJECTIVE Genetic factors may determine susceptibility to develop alcoholic liver cirrhosis, although it remains uncertain why only a minority of alcoholics suffers from this disease. A decrease in serum levels of interleukin-2 (IL-2) is usually found in alcoholic cirrhotics. In this study we examined the relationship between the -330T>G IL-2 gene (IL2) polymorphism and alcoholic liver cirrhosis. METHODS Genotyping of the aforementioned polymorphism was done by polymerase chain reaction and digestion with restriction enzymes in 257 male alcoholics (161 without liver disease and 96 with alcoholic liver cirrhosis) and 101 healthy controls. A logistic regression analysis was performed to adjust for potential confounders and to analyze the model of inheritance. RESULTS We found an association between the -330T>G IL2 polymorphism and alcoholic liver cirrhosis: the frequency of the allele T carriers (genotype TT and GT) was significantly higher in alcoholics with cirrhosis (96.9%) than in those without liver disease (89.4%, P=0.043). CONCLUSION We report for the first time that the possession of the -330T allele of the IL2 is associated with a higher risk of developing alcoholic liver cirrhosis and this fact may favor the progression of alcoholic liver disease.
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Chan HLY, Tse AML, Chim AML, Wong VWS, Choi PCL, Yu J, Zhang M, Sung JJY. Association of cytokine gene polymorphisms and liver fibrosis in chronic hepatitis B. J Gastroenterol Hepatol 2008; 23:783-9. [PMID: 17645476 DOI: 10.1111/j.1440-1746.2007.05110.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM As liver fibrosis is the result of persistent necroinflammation in the liver, pro-inflammatory cytokines secreted in response to cell injury have a central role in the pathogenesis of liver fibrosis. We aimed to investigate the association of cytokine gene polymorphism and liver fibrosis among Chinese patients with chronic hepatitis B. METHODS Polymorphisms at interleukin-10 (IL-10-627, -1117), interleukin-1-beta (IL-1beta-511, -31, -3964), interleukin-1 receptor antagonist (IL-1RN), and tumor necrosis factor-alpha (TNF-alpha-308, -238) among Chinese chronic hepatitis B patients were determined. Severe liver fibrosis was defined as Ishak fibrosis score = 4 (of 6). RESULTS Fifty-nine of 273 (22%) patients had severe fibrosis. The distribution of genotypes for IL-10-627 was CC (11%), CA (41%), and AA (48%). The CC genotype at IL-10-627 was protective against severe fibrosis (odds ratio (OR) 0.11; 95% CI 0.014-0.82; P = 0.032). After adjusted for baseline variables, the adjusted OR of CC genotypes at IL-10-627 for severe fibrosis was 0.063 (95% CI 0.06-0.64; P = 0.063). Other gene polymorphisms at IL-1beta, IL-1RN, TNF-alpha, and IL-10 had no significant association with severe fibrosis. Weak linkage disequilibrium was observed between IL-10-627 and IL-10-1117 with linkage disequilibrium coefficient of 0.12 (P < 0.001). The distribution of haplotypes of IL-10-1117 and IL-10-627 was A-A (69%), A-C (26%), and G-C (5%). High and intermediate IL-10 production (A-C and G-C) haplotypes were protective against severe fibrosis (OR 0.62; 95% CI 0.39-0.99; P = 0.046). CONCLUSIONS High production genotype and haplotypes of IL-10 were associated with less severe liver fibrosis in chronic hepatitis B in Chinese.
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Affiliation(s)
- Henry L-Y Chan
- Institute of Digestive Disease and Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.
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Marcos M, Pastor I, González-Sarmiento R, Laso FJ. Interleukin-10 gene polymorphism is associated with alcoholism but not with alcoholic liver disease. Alcohol Alcohol 2008; 43:523-8. [PMID: 18436572 DOI: 10.1093/alcalc/agn026] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
AIMS To determine whether the functional polymorphism -592C>A of the interleukin (IL)-10 gene (IL10) influences the development of alcoholic liver disease or alcoholism in alcoholic Spanish subjects. METHODS The -592C>A IL10 polymorphism was analyzed by the polymerase chain reaction and digestion with restriction enzymes in 257 male alcoholics [161 without alcoholic liver disease and 96 with alcoholic liver cirrhosis (ALC)] and 100 male healthy controls. RESULTS We found no association between the -592C>A IL10 polymorphism and ALC. Meta-analysis combining this result and data from previous studies failed also to show any significant association between this polymorphism and alcoholic liver disease. However, the frequency of allele A carriers (CA and AA genotypes) was significantly higher in alcoholic patients (defined as patients with abuse or dependence of alcohol) than in healthy controls. CONCLUSION The -592C>A IL10 polymorphism is not related to the risk of ALC. Nevertheless, our study shows that alcoholism is associated with an excess of allele A carriers in alcoholic patients.
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Affiliation(s)
- Miguel Marcos
- Servicio de Medicina Interna II, Hospital Universitario de Salamanca, Paseo de San Vicente 58-182, 37007 Salamanca, Spain.
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Gressner OA, Weiskirchen R, Gressner AM. Biomarkers of hepatic fibrosis, fibrogenesis and genetic pre-disposition pending between fiction and reality. J Cell Mol Med 2008; 11:1031-51. [PMID: 17979881 PMCID: PMC4401271 DOI: 10.1111/j.1582-4934.2007.00092.x] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Fibrosis is a frequent, life-threatening complication of most chronic liver diseases. Despite major achievements in the understanding of its pathogenesis, the translation of this knowledge into clinical practice is still limited. In particular, non-invasive and reliable (serum-) biomarkers indicating the activity of fibrogenesis are scarce. Class I biomarkers are defined as serum components having a direct relation to the mechanism of fibrogenesis, either as secreted matrix-related components of activated hepatic stellate cells and fibroblasts or as mediators of extracellular matrix (ECM) synthesis or turnover. They reflect primarily the activity of the fibrogenic process. Many of them, however, proved to be disappointing with regard to sensitivity and speci-ficity. Up to now hyaluronan turned out to be the relative best type I serum marker. Class II biomarkers comprise in general rather simple standard laboratory tests, which are grouped into panels. They fulfil most criteria for detection and staging of fibrosis and to a lesser extent grading of fibrogenic activity. More than 20 scores are currently available, among which Fibrotest™ is the most popular one. However, the diagnostic use of many of these scores is still limited and standardization of the assays is only partially realized. Combining of panel markers in sequential algorithms might increase their diagnostic validity. The translation of genetic pre-disposition biomarkers into clinical practice has not yet started, but some polymorphisms indicate a link to progression and outcome of fibrogenesis. Parallel to serum markers non-invasive physical techniques, for example, transient elastography, are developed, which can be combined with serum tests and profiling of serum proteins and glycans.
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Affiliation(s)
- O A Gressner
- Institute of Clinical Chemistry and Pathobiochemistry, Central Laboratory, RWTH-University Hospital, Aachen, Germany.
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Association of interleukin-6, interleukin-12, and interleukin-10 gene polymorphisms with essential hypertension in Tatars from Russia. Biochem Genet 2007; 46:64-74. [PMID: 18163209 DOI: 10.1007/s10528-007-9130-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2006] [Accepted: 10/24/2007] [Indexed: 12/28/2022]
Abstract
Essential hypertension is a common disease with fatal clinical complications. Epidemiological and family studies have confirmed the role of genetic predisposition in its development. Hypertensive patients have been shown to have an altered profile of pro- and anti-inflammatory cytokines. The aim of our investigation was to reveal the association of interleukin-6, interleukin-12, and interleukin-10 gene polymorphisms with essential hypertension and its clinical complications in a Tatar ethnic group from Bashkortostan, Russia. The study involved 362 hypertensive patients and 244 healthy subjects from this Tatar ethnic group (Bashkortostan, Russia). DNA was isolated from whole venous blood using phenol-chloroform extraction by the standard method. IL6 -572 G/C, IL12B 1159 C/A, and IL10 -627 C/A genotypes were typed using polymerase chain reaction followed by restriction enzyme digestion. We found that the IL10 -627 *C/*C genotype was associated with decreased risk of hypertension (OR = 0.64, P = 0.035). IL6 genotypes and allele distribution did not differ significantly between subjects with and without hypertension, but the IL6 -572 *G/*G genotype frequency was found to be significantly higher among those patients who had stroke, compared with normotensive control subjects (P = 0.036). Carriers of the IL12B 1159 *A/*A genotype had a lower risk of stroke (OR = 0.38, P = 0.028). Our study has shown the association between IL10 -627 C/A polymorphism and essential hypertension in the Tatar ethnic group from Bashkortostan, Russia. The IL10 -627*C/*C genotype was found to be protective against hypertension. We also demonstrated that hypertensive patients with the IL12B *A/*A and IL6 *G/*G genotypes had increased risk of stroke. Our results suggest a role for cytokines in cardiovascular disease development in the Tatar ethnic group, but further investigation is needed.
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Li D, Zhu JY, Gao J, Wang X, Lou YQ, Zhang GL. Polymorphisms of tumor necrosis factor-alpha, interleukin-10, cytochrome P450 3A5 and ABCB1 in Chinese liver transplant patients treated with immunosuppressant tacrolimus. Clin Chim Acta 2007; 383:133-9. [PMID: 17568575 DOI: 10.1016/j.cca.2007.05.008] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2007] [Revised: 04/17/2007] [Accepted: 05/11/2007] [Indexed: 02/06/2023]
Abstract
BACKGROUND Cytokine production in the host immune response after transplantation may contribute to the variable CYP3A-dependent drug disposition. We investigated the effect of TNF-alpha, IL-10, CYP3A5 and ABCB1 polymorphisms on immunosuppressant tacrolimus pharmacokinetics in liver transplant patients. METHODS Genetic polymorphisms in TNF-alpha, IL-10, CYP3A5 and ABCB1 were studied in 70 liver transplant recipients and 70 donors. Tacrolimus dosage and blood concentration were investigated at 1, 2 and 3 weeks after transplantation. RESULTS The IL-10 G-1082A polymorphism in recipients was significantly associated with tacrolimus concentration/dose (C/D) ratios (IL-10-1082GG < GA < AA) within the first 3weeks posttransplantation (P < 0.05). Recipients with the capacity for low IL-10 production (-1082AA) carrying CYP3A5 non-expressor (CYP3A5()3/()3) liver had the highest C/D ratios (mean: 172.4, 161.7, 160.3 for 1, 2 and 3 weeks posttransplantation, respectively), whereas recipients with intermediate or high production of IL-10 (-1082GA or GG) engrafted with CYP3A5 expressor (CYP3A5()1 carrier) liver were found to have the lowest ratios (96.4, 78.0 and 75.4, respectively, P < 0.01). CONCLUSIONS The IL-10 G-1082A and CYP3A5()3 polymorphisms may influence the interindividual variability of tacrolimus pharmacokinetics in Chinese liver transplant patients. This finding provided a new interpretation for the variable immunosuprressant disposition after transplantation.
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Affiliation(s)
- Dan Li
- Department of Pharmacology, Basic Medical School, Beijing University, Beijing, China
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Jin HS, Kim HB, Kim BS, Lee JK, Seo EJ, Yoo HW, Park IS, Hong YM, Hong SJ. The IL-10 (-627 A/C) promoter polymorphism may be associated with coronary aneurysms and low serum albumin in Korean children with Kawasaki disease. Pediatr Res 2007; 61:584-7. [PMID: 17413867 DOI: 10.1203/pdr.0b013e3180459fb5] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Kawasaki disease (KD) is an acute febrile vasculitic syndrome of unknown etiology that preferentially affects the coronary artery. Interleukin-10 (IL-10) is a key proinflammatory cytokine, and a polymorphism near the major transcriptional start site of the IL-10 gene was shown to influence IL-10 production in vitro. This study investigated the association of the IL-10 promoter polymorphism with KD and its clinical parameters in Korean children. A total of 194 children with congenital heart disease (CHD) and 95 children with KD were included in this study. IL-10 (-627 A/C) polymorphism genotypes were determined using the single-base extension method. There was no difference in the allele frequencies of IL-10 (-627 A/C) polymorphism between CHD children and KD children. KD children with one or two copies of the IL-10 (-627C) allele showed significantly lower albumin levels (p = 0.020) and higher frequencies of early coronary artery aneurysm [62.22% versus 37.78%, adjusted odds ratio (aOR) = 3.50, 95% confidence interval (CI): 1.50-8.16] compared with KD children with the common IL-10 (-627A) allele. These findings suggest that the IL-10 (-627 A/C) promoter polymorphism might be a genetic marker for the risk of early coronary artery complication in KD.
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Affiliation(s)
- Hyun-Seung Jin
- Department of Pediatrics, College of Medicine, Ulsan University, Asian Medical Center, Seoul 138-736, Korea
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Danilko KV, Korytyna GF, Akhmadishina LZ, Yanbaeva DG, Zagidullin SZ, Victorova TV. Association of polymorphisms of cytokine genes (IL1B, IL1RN, TNFA, LTA, IL6, IL8, and IL10) with chronic obstructive pulmonary disease. Mol Biol 2007. [DOI: 10.1134/s0026893307010049] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Hagymási K, Tulassay Z. [Genetic background of multifactorial liver and bile duct diseases]. Orv Hetil 2007; 148:147-153. [PMID: 17344128 DOI: 10.1556/oh.2007.27987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The majority of liver diseases, are complex. They are the results of interactions between several genes and environmental factors. Familial aggregation and higher concordance rate of monozygotic twins compared to those of dizygotic twins provide evidence for the importance of genetic factors in the pathogenesis. There are only limited data in connection with the genetic background of multifactorial liver diseases. In the future, the genetic background may permit prevention, early, accurate diagnosis, prediction of disease course, complications, prognosis, as well as treatment response.
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Affiliation(s)
- Krisztina Hagymási
- Semmelweis Egyetem, Altalános Orvostudományi Kar II. Belgyógyászati Klinika Budapest Szentkirályi u. 46.
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Abstract
While the vast majority of heavy drinkers and individuals with obesity, insulin resistance, and the metabolic syndrome will have steatosis, only a minority will ever develop steatohepatitis, fibrosis, and cirrhosis. Genetic and environmental risk factors for advanced alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) seem likely to include factors that influence the severity of steatosis and oxidative stress, the cytokine milieu, the magnitude of the immune response, and/or the severity of fibrosis. For ALD, the dose and pattern of alcohol intake, along with obesity are the most important environmental factors determining disease risk. For NAFLD, dietary saturated fat and antioxidant intake and small bowel bacterial overgrowth may play a role. Family studies and interethnic variations in susceptibility suggest that genetic factors are important in determining disease risk. For ALD, functional polymorphisms in the alcohol dehydrogenases and aldehyde dehydrogenase alcohol metabolising genes play a role in determining susceptibility in Oriental populations. No genetic associations with advanced NAFLD have been replicated in large studies. Preliminary data suggest that polymorphisms in the genes encoding microsomal triglyceride transfer protein, superoxide dismutase 2, the CD14 endotoxin receptor, TNF-alpha, transforming growth factor-beta, and angiotensinogen may be associated with steatohepatitis and/or fibrosis.
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Affiliation(s)
- C P Day
- Institute of Cellular Medicine, University of Newcastle upon Tyne, UK.
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