|
1
|
Abstract
A single-nucleotide polymorphism occurring in the sequence of the human patatin-like phospholipase domain-containing 3 gene (PNPLA3), known as I148M variant, is one of the best characterized and deeply investigated variants in several clinical scenarios, because of its tight correlation with increased risk for developing hepatic steatosis and more aggressive part of the disease spectrum, such as nonalcoholic steatohepatitis, advanced fibrosis and cirrhosis. Further, the I148M variant is positively associated with alcoholic liver diseases, chronic hepatitis C-related cirrhosis and hepatocellular carcinoma. The native gene encodes for a protein that has not yet a fully defined role in liver lipid metabolism and, according to recent observations, seems to be divergently regulated among distinct liver cells type, such as hepatic stellate cells. Therefore, the aim of this review is to collect the latest data regarding PNPLA3 expression in human liver and to analyze the impact of its genetic variant in human hepatic pathologies. Moreover, a description of the current biochemical and metabolic data pertaining to PNPLA3 function in both animal models and in vitro studies is summarized to allow a better understanding of the relevant pathophysiological role of this enzyme in the progression of hepatic diseases.
Collapse
Affiliation(s)
- Francesca Virginia Bruschi
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Matteo Tardelli
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Thierry Claudel
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| |
Collapse
|
|
2
|
Recent Advances in the Pathogenesis of Hepatitis C Virus-Related Non-Alcoholic Fatty Liver Disease and Its Impact on Patients Cured of Hepatitis C. ACTA ACUST UNITED AC 2017. [DOI: 10.1007/s11901-017-0370-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
|
|
3
|
Abstract
Metabolic disorders are common in patients with chronic hepatitis C virus (HCV) infection. Epidemiologic and clinical data indicate an overprevalence of lipids abnormalite, steatosis, insuline resistance (IR) and diabetes mellitus in HCV patients, suggesting that HCV itself may interact with glucido-lipidic metabolism. HCV interacts with the host lipid metabolism by several mechanisms leading to hepatic steatosis and hypolipidemia which are reversible after viral eradication. Liver and peripheral IR are HCV genotype/viral load dependent and improved after viral eradication. This article examines examine the relationship between HCV, lipid abnormalities, steatosis, IR, and diabetes and the pathogenic mechanisms accounting for these events in HCV-infected patients.
Collapse
Affiliation(s)
- Lawrence Serfaty
- Hepatology Department, INSERM UMR_S 938, APHP, Saint-Antoine Hospital, UPMC Univ Paris 06, Paris, France.
| |
Collapse
|
|
4
|
Chang ML. Metabolic alterations and hepatitis C: From bench to bedside. World J Gastroenterol 2016; 22:1461-1476. [PMID: 26819514 PMCID: PMC4721980 DOI: 10.3748/wjg.v22.i4.1461] [Citation(s) in RCA: 93] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Revised: 08/14/2015] [Accepted: 10/26/2015] [Indexed: 02/06/2023] Open
Abstract
In addition to causing cirrhosis and hepatocellular carcinoma, hepatitis C virus (HCV) is thought to cause hypolipidemia, hepatic steatosis, insulin resistance, metabolic syndrome, and diabetes. The viral life cycle of HCV depends on cholesterol metabolism in host cells. HCV core protein and nonstructural protein 5A perturb crucial lipid and glucose pathways, such as the sterol regulatory element-binding protein pathway and the protein kinase B/mammalian target of rapamycin/S6 kinase 1 pathway. Although several lines of transgenic mice expressing core or full HCV proteins exhibit hepatic steatosis and/or dyslipidemia, whether they completely reflect the metabolic alterations in humans with HCV infection remains unknown. Many cross-sectional studies have demonstrated increased prevalences of metabolic alterations and cardiovascular events in patients with chronic hepatitis C (CHC); however, conflicting results exist, primarily due to unavoidable individual variations. Utilizing anti-HCV therapy, most longitudinal cohort studies of CHC patients have demonstrated the favorable effects of viral clearance in attenuating metabolic alterations and cardiovascular risks. To determine the risks of HCV-associated metabolic alterations and associated complications in patients with CHC, it is necessary to adjust for crucial confounders, such as HCV genotype and host baseline glucose metabolism, for a long follow-up period after anti-HCV treatment. Adipose tissue is an important endocrine organ due to its release of adipocytokines, which regulate lipid and glucose metabolism. However, most data on HCV infection and adipocytokine alteration are inconclusive. A comprehensive overview of HCV-associated metabolic and adipocytokine alterations, from bench to bedside, is presented in this topic highlight.
Collapse
|
|
5
|
Kahali B, Halligan B, Speliotes EK. Insights from Genome-Wide Association Analyses of Nonalcoholic Fatty Liver Disease. Semin Liver Dis 2015; 35:375-91. [PMID: 26676813 PMCID: PMC4941959 DOI: 10.1055/s-0035-1567870] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is caused by hepatic steatosis, which can progress to nonalcoholic steatohepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma in the absence of excessive alcohol consumption. Nonalcoholic fatty liver disease will become the number one cause of liver disease worldwide by 2020. Nonalcoholic fatty liver disease is correlated albeit imperfectly with obesity and other metabolic diseases such as diabetes, hyperlipidemia, and cardiovascular disease, but exactly how having one of these diseases contributes to the development of other metabolic diseases is only now being elucidated. Development of NAFLD and related metabolic diseases is genetically influenced in the population, and recent genome-wide association studies (GWASs) have discovered genetic variants that associate with these diseases. These GWAS-associated variants cannot only help us to identify individuals at high risk of developing NAFLD, but also to better understand its pathophysiology so that we can develop more effective treatments for this disease and related metabolic diseases in the future.
Collapse
Affiliation(s)
- Bratati Kahali
- Division of Gastroenterology, Department of Internal Medicine, Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan
| | - Brian Halligan
- Division of Gastroenterology, Department of Internal Medicine, Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan
| | - Elizabeth K. Speliotes
- Division of Gastroenterology, Department of Internal Medicine, Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan
| |
Collapse
|
|
6
|
Coppola N, Pisaturo M, Sagnelli C, Onorato L, Sagnelli E. Role of genetic polymorphisms in hepatitis C virus chronic infection. World J Clin Cases 2015; 3:807-822. [PMID: 26380828 PMCID: PMC4568530 DOI: 10.12998/wjcc.v3.i9.807] [Citation(s) in RCA: 16] [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: 07/27/2014] [Revised: 12/09/2014] [Accepted: 06/08/2015] [Indexed: 02/05/2023] Open
Abstract
AIM: To analyze the host genetics factors influencing the clinical course and the response to antiviral treatment in patients with chronic hepatitis C (CHC).
METHODS: We conducted an electronic search on the PubMed and MEDLINE (2000-2014) databases and Cochrane library (2000-2014). A total of 73 articles were retrieved and their data were extensively evaluated and discussed by the authors and then analyzed in this review article.
RESULTS: Several studies associated polymorphisms in the interleukin 28B gene on chromosome 19 (19q13.13) with a spontaneous viral clearance in acute hepatitis C and with the response to pegylated interferon (Peg-IFN)-based treatment in chronic hepatitis C patients. Other investigations demonstrated that inosine triphosphate pyrophosphatase genetic variants protect hepatitis C virus-genotype-1 CHC patients from ribavirin-induced anemia, and other studies that a polymorphism in the patatin-like phospholipase domain-containing protein 3 was associated with hepatic steatosis in CHC patients. Although not conclusive, some investigations suggested that the vitamin D-associated polymorphisms play an important role in the achievement of sustained virologic response in CHC patients treated with Peg-IFN-based antiviral therapy. Several other polymorphisms have been investigated to ascertain their possible impact on the natural history and on the response to treatment in patients with CHC, but the data are preliminary and warrant confirmation.
CONCLUSION: Several genetic polymorphisms seem to influence the clinical course and the response to antiviral treatment in patients with CHC, suggesting individualized follow up and treatment strategies.
Collapse
|
|
7
|
Simon TG, Butt AA. Lipid dysregulation in hepatitis C virus, and impact of statin therapy upon clinical outcomes. World J Gastroenterol 2015; 21:8293-8303. [PMID: 26217081 PMCID: PMC4507099 DOI: 10.3748/wjg.v21.i27.8293] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2015] [Revised: 04/17/2015] [Accepted: 06/10/2015] [Indexed: 02/06/2023] Open
Abstract
The hepatitis C virus (HCV) is one of the most common causes of chronic liver disease and the leading indication for liver transplantation worldwide. Every aspect of the HCV life cycle is closely tied to human lipid metabolism. The virus circulates as a lipid-rich particle, utilizing lipoprotein cell receptors to gain entry into the hepatocyte. It has also been shown to upregulate lipid biosynthesis and impair lipid degradation, resulting in significant intracellular lipid accumulation and circulating hypocholesterolemia. Patients with chronic hepatitis C (CHC) are at increased risk of hepatic steatosis, fibrosis, and cardiovascular disease including accelerated atherosclerosis. HMG CoA Reductase inhibitors, or statins, have been shown to play an important role in the modulation of hepatic steatosis and fibrosis, and recent attention has focused upon their potential therapeutic role in CHC. This article reviews the hepatitis C viral life cycle as it impacts host lipoproteins and lipid metabolism. It then describes the pathogenesis of HCV-related hepatic steatosis, hypocholesterolemia and atherosclerosis, and finally describes the promising anti-viral and anti-fibrotic effects of statins, for the treatment of CHC.
Collapse
|
|
8
|
Geng N, Xin YN, Xia HHX, Jiang M, Wang J, Liu Y, Chen LZ, Xuan SY. Association of PNPLA3 I148M Variant With Chronic Viral Hepatitis, Autoimmune Liver Diseases and Outcomes of Liver Transplantation. HEPATITIS MONTHLY 2015; 15:e26459. [PMID: 26034504 PMCID: PMC4449891 DOI: 10.5812/hepatmon.15(4)2015.26459] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/29/2014] [Revised: 02/15/2015] [Accepted: 03/01/2015] [Indexed: 02/07/2023]
Abstract
CONTEXT The PNPLA3 I148M variant has been recognized as a genetic determinant of liver fat content and a genetic risk factor of liver damage progression associated with steatohepatitis. The I148M variant is associated with many chronic liver diseases. However, its potential association with inflammatory and autoimmune liver diseases has not been established. EVIDENCE ACQUISITION We systemically reviewed the potential associations of I148M variant with chronic viral hepatitis, autoimmune liver diseases and the outcome of liver transplantation, explored the underlying molecular mechanisms and tried to translate them into more individualized decision-making and personalized medicine. RESULTS There were associations between I148M variant and chronic viral hepatitis and autoimmune liver diseases and differential associations of I148M variant in donors and recipients with post-liver transplant outcomes. I148M variant may activate the development of steatosis caused by host metabolic disorders in chronic viral hepatitis, but few researches were found to illustrate the mechanisms in autoimmune liver diseases. The peripherally mediated mechanism (via extrahepatic adipose tissue) may play a principal role in triglyceride accumulation regardless of adiponutrin activity in the graft liver. CONCLUSIONS Evidences have shown the associations between I148M variant and mentioned diseases. I148M variant induced steatosis may be involved in the mechanism of chronic viral hepatitis and genetic considered personalized therapies, especially for PSC male patients. It is also crucial to pay attention to this parameter in donor selection and prognosis estimation in liver transplantation.
Collapse
Affiliation(s)
- Ning Geng
- Qingdao Municipal Hospital, Medical College, Qingdao University, Qingdao, P. R. China
| | - Yong-Ning Xin
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, P. R. China
- Corresponding Authors: Yong-Ning Xin, Department of Gastroenterology, Qingdao Municipal Hospital, P. O. Box: 266021, Qingdao, P. R. China. E-mail: ; Shi-Ying Xuan, Department of Gastroenterology, Qingdao Municipal Hospital, P. O. Box: 266021, Qingdao, P. R. China. Tel: +86-53288905508, Fax: +86-53282031522, E-mail:
| | | | - Man Jiang
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, P. R. China
| | - Jian Wang
- Qingdao Municipal Hospital, Medical College, Qingdao University, Qingdao, P. R. China
| | - Yang Liu
- Qingdao Municipal Hospital, Medical College, Qingdao University, Qingdao, P. R. China
| | - Li-Zhen Chen
- Qingdao Municipal Hospital, Medical College, Qingdao University, Qingdao, P. R. China
| | - Shi-Ying Xuan
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, P. R. China
- Corresponding Authors: Yong-Ning Xin, Department of Gastroenterology, Qingdao Municipal Hospital, P. O. Box: 266021, Qingdao, P. R. China. E-mail: ; Shi-Ying Xuan, Department of Gastroenterology, Qingdao Municipal Hospital, P. O. Box: 266021, Qingdao, P. R. China. Tel: +86-53288905508, Fax: +86-53282031522, E-mail:
| |
Collapse
|
|
9
|
Nakaoka K, Hashimoto S, Kawabe N, Nitta Y, Murao M, Nakano T, Shimazaki H, Kan T, Takagawa Y, Ohki M, Kurashita T, Takamura T, Nishikawa T, Ichino N, Osakabe K, Yoshioka K. PNPLA3 I148M associations with liver carcinogenesis in Japanese chronic hepatitis C patients. SPRINGERPLUS 2015; 4:83. [PMID: 25713769 PMCID: PMC4334918 DOI: 10.1186/s40064-015-0870-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Accepted: 02/03/2015] [Indexed: 12/15/2022]
Abstract
AIM To investigate associations between patatin-like phospholipase domain-containing 3 (PNPLA3) genotypes and fibrosis and hepatocarcinogenesis in Japanese chronic hepatitis C (CHC) patients. METHODS Two hundred and thirty-one patients with CHC were examined for PNPLA3 genotypes, liver stiffness measurements (LSM), and hepatocellular carcinoma (HCC) from May 2010 to October 2012 at Fujita Health University Hospital. The rs738409 single nucleotide polymorphism (SNP) encoding for a functional PNPLA3 I148M protein variant was genotyped using a TaqMan predesigned SNP genotyping assay. LSM was determined as the velocity of a shear wave (Vs) with an acoustic radiation force impulse. Vs cut-off values for cirrhosis were set at 1.55 m/s. We excluded CHC patients with a sustained virological response or relapse after interferon treatment. RESULTS PNPLA3 genotypes were CC, CG, and GG for 118, 72, and 41 patients, respectively. Multivariable logistic regression analysis selected older age (OR = 1.06; 95% CI: 1.03-1.09; p < 0.0001), higher body mass index (BMI) (OR= 1.12; 95% CI: 1.03-1.22; p = 0.0082), and PNPLA3 genotype GG (OR = 2.07; 95% CI: 0.97-4.42; p = 0.0599) as the factors independently associated with cirrhosis. When 137 patients without past history of interferon treatment were separately assessed, multivariable logistic regression analysis selected older age (OR = 1.05; 95% CI: 1.02-1.09; p = 0.0034), and PNPLA3 genotype GG (OR = 3.35; 95% CI: 1.13-9.91; p = 0.0291) as the factors independently associated with cirrhosis. Multivariable logistic regression analysis selected older age (OR = 1.12; 95% CI: 1.07-1.17; p < 0.0001), PNPLA3 genotype GG (OR = 2.62; 95% CI: 1.15-5.96; p = 0.0218), and male gender (OR = 1.83; 95% CI: 0.90-3.71); p = 0.0936) as the factors independently associated with HCC. CONCLUSION PNPLA3 genotype I148M is one of risk factors for developing HCC in Japanese CHC patients, and is one of risk factors for progress to cirrhosis in the patients without past history of interferon treatment.
Collapse
Affiliation(s)
- Kazunori Nakaoka
- />Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi 470-1192 Japan
| | - Senju Hashimoto
- />Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi 470-1192 Japan
| | - Naoto Kawabe
- />Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi 470-1192 Japan
| | - Yoshifumi Nitta
- />Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi 470-1192 Japan
| | - Michihito Murao
- />Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi 470-1192 Japan
| | - Takuji Nakano
- />Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi 470-1192 Japan
| | - Hiroaki Shimazaki
- />Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi 470-1192 Japan
| | - Toshiki Kan
- />Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi 470-1192 Japan
| | - Yuka Takagawa
- />Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi 470-1192 Japan
| | - Masashi Ohki
- />Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi 470-1192 Japan
| | - Takamitsu Kurashita
- />Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi 470-1192 Japan
| | - Tomoki Takamura
- />Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi 470-1192 Japan
| | - Toru Nishikawa
- />Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi 470-1192 Japan
| | - Naohiro Ichino
- />Faculty of Medical Technology, School of Health Sciences, Fujita Health University, Toyoake, Aichi 470-1192 Japan
| | - Keisuke Osakabe
- />Faculty of Medical Technology, School of Health Sciences, Fujita Health University, Toyoake, Aichi 470-1192 Japan
| | - Kentaro Yoshioka
- />Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi 470-1192 Japan
| |
Collapse
|
|
10
|
Zimmer V, Lammert F. Role of genetics in diagnosis and therapy of acquired liver disease. Mol Aspects Med 2014; 37:15-34. [DOI: 10.1016/j.mam.2013.10.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2013] [Revised: 10/07/2013] [Accepted: 10/15/2013] [Indexed: 02/08/2023]
|
|
11
|
Shaker M, Tabbaa A, Albeldawi M, Alkhouri N. Liver transplantation for nonalcoholic fatty liver disease: New challenges and new opportunities. World J Gastroenterol 2014; 20:5320-5330. [PMID: 24833862 PMCID: PMC4017047 DOI: 10.3748/wjg.v20.i18.5320] [Citation(s) in RCA: 91] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Revised: 01/10/2014] [Accepted: 01/20/2014] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is becoming rapidly one of the most common indications for orthotopic liver transplantation in the world. Development of graft steatosis is a significant problem during the post-transplant course, which may happen as a recurrence of pre-existing disease or de novo NAFLD. There are different risk factors that might play a role in development of graft steatosis including post-transplant metabolic syndrome, immune-suppressive medications, genetics and others. There are few studies that assessed the effects of NAFLD on graft and patient survival; most of them were limited by the duration of follow up or by the number of patients. With this review article we will try to shed light on post-liver transplantation NAFLD, significance of the disease, how it develops, risk factors, clinical course and treatment options.
Collapse
|
|
12
|
Jiménez-Sousa MA, Berenguer J, Fernández-Rodríguez A, Micheloud D, Guzmán-Fulgencio M, Miralles P, Pineda-Tenor D, García-Álvarez M, López JC, Aldámiz-Echevarria T, Carrero A, Resino S. IL28RA polymorphism (rs10903035) is associated with insulin resistance in HIV/HCV-coinfected patients. J Viral Hepat 2014; 21:189-97. [PMID: 24438680 DOI: 10.1111/jvh.12130] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2013] [Accepted: 05/01/2013] [Indexed: 12/18/2022]
Abstract
Hepatitis C virus (HCV) infection is associated with insulin resistance (IR), although mechanisms leading to IR in these patients are not completely understood. The aim of this study was to evaluate the association of interleukin 28B (IL28B) and interleukin 28 receptor alpha (IL28RA) polymorphisms with IR among human immunodeficiency virus (HIV)/HCV-coinfected patients. We carried out a cross-sectional study on 203 patients. IL28B (rs8099917) and IL28RA (rs10903035) polymorphisms were genotyped by GoldenGate(®) assay. IR was defined as homeostatic model assessment (HOMA) values ≥3.00. Univariate and multivariate generalized linear models (GLM) were used to compare HOMA values and the percentage of patients with IR according to IL28B and IL28RA genotypes. In total, 32% (n = 65/203) of the patients had IR. IL28B rs8099917 TT was not significantly associated with HOMA values and IR. In contrast, rs10903035 AA was significantly associated with high HOMA values taking into account all patients (P = 0.024), as well as the subgroups of patients with significant fibrosis (P = 0.047) and infected with HCV genotype 3 (P = 0.024). Additionally, rs10903035 AA was significantly associated with IR (HOMA ≥3.00) in all patients (adjusted odds ratio (aOR) = 2.02; P = 0.034), in patients with significant fibrosis (aOR = 2.86; P = 0.039) and HCV genotype 3 patients (aOR = 4.89; P = 0.031). In conclusions, IL28RA polymorphism (rs10903035) seems to be implicated in the glucose homeostasis because AA genotype increases the likelihood of IR, but this association was different depending on hepatic fibrosis and HCV genotype.
Collapse
Affiliation(s)
- M A Jiménez-Sousa
- Unit of Viral Infection and Immunity, National Centre of Microbiology, Instituto de Salud Carlos III, Majadahonda, Spain
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
13
|
Singal AG, Manjunath H, Yopp AC, Beg MS, Marrero JA, Gopal P, Waljee AK. The effect of PNPLA3 on fibrosis progression and development of hepatocellular carcinoma: a meta-analysis. Am J Gastroenterol 2014; 109:325-34. [PMID: 24445574 PMCID: PMC5610907 DOI: 10.1038/ajg.2013.476] [Citation(s) in RCA: 274] [Impact Index Per Article: 24.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2013] [Accepted: 12/05/2013] [Indexed: 02/07/2023]
Abstract
OBJECTIVES The PNPLA3 rs738409 single-nucleotide polymorphism is known to promote nonalcoholic steatohepatitis (NASH), but its association with fibrosis severity and hepatocellular carcinoma (HCC) risk is less well-defined. The objectives of this study were to determine the association between PNPLA3 and liver fibrosis severity, HCC risk, and HCC prognosis among patients with liver disease. METHODS We performed a systematic literature review using the Medline, PubMed, Scopus, and Embase databases through May 2013 and a manual search of national meeting abstracts from 2010 to 2012. Two investigators independently extracted data on patient populations, study methods, and results using standardized forms. Pooled odds ratios (ORs), according to PNPLA3 genotype, were calculated using the DerSimonian and Laird method for a random effects model. RESULTS Among 24 studies, with 9,915 patients, PNPLA3 was associated with fibrosis severity (OR 1.32, 95% confidence interval (CI) 1.20-1.45), with a consistent increased risk across liver disease etiologies. Among nine studies, with 2,937 patients, PNPLA3 was associated with increased risk of HCC in patients with cirrhosis (OR 1.40, 95% CI 1.12-1.75). On subgroup analysis, increased risk of HCC was demonstrated in patients with NASH or alcohol-related cirrhosis (OR 1.67, 95% CI 1.27-2.21) but not in those with other etiologies of cirrhosis (OR 1.33, 95% CI 0.96-1.82). Three studies, with 463 patients, do not support an association between PNPLA3 and HCC prognosis but are limited by heterogeneous outcome measures. For all outcomes, most studies were conducted in homogenous Caucasian populations, and studies among racially diverse cohorts are needed. CONCLUSIONS PNPLA3 is associated with an increased risk of advanced fibrosis among patients with a variety of liver diseases and is an independent risk factor for HCC among patients with nonalcoholic steatohepatitis or alcohol-related cirrhosis.
Collapse
Affiliation(s)
- Amit G. Singal
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
- Harold C. Simmons Cancer Center, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Hema Manjunath
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Adam C. Yopp
- Harold C. Simmons Cancer Center, UT Southwestern Medical Center, Dallas, Texas, USA
- Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Muhammad S. Beg
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Jorge A. Marrero
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
- Harold C. Simmons Cancer Center, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Purva Gopal
- Department of Pathology, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Akbar K. Waljee
- Veterans Affairs Center for Clinical Management Research, Ann Arbor, Michigan, USA
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| |
Collapse
|
|
14
|
Moritou Y, Ikeda F, Iwasaki Y, Baba N, Takaguchi K, Senoh T, Nagano T, Takeuchi Y, Yasunaka T, Ohnishi H, Miyake Y, Takaki A, Nouso K, Yamamoto K. Predictive impact of polymorphism of PNPLA3 on HCC development after interferon therapy in Japanese patients with chronic hepatitis C. SPRINGERPLUS 2013; 2:251. [PMID: 23772356 PMCID: PMC3682107 DOI: 10.1186/2193-1801-2-251] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/19/2013] [Accepted: 05/28/2013] [Indexed: 12/28/2022]
Abstract
The impact of single-nucleotide polymorphisms (SNP) of patatin-like phospholipase domain-containing protein 3 (PNPLA3) on development of hepatocellular carcinoma (HCC) is not clarified for Japanese patients with chronic hepatitis C. The present study investigated the associations of rs738409 PNPLA3 with HCC development after the antiviral therapy with peg-interferon and ribavirin for Japanese patients with hepatitis C virus serotype 1 and high viral load. Of the 271 patients enrolled in the study, 20 patients developed HCC, during a median follow-up period of 4.6 years. Multivariate analysis in the proportional hazards models revealed that sex, body mass index, platelet counts, and alpha feroprotein (AFP) had significant associations with HCC development (p = 0.011, 0.029, 0.0002, and 0.046, respectively). Multivariate regression analysis revealed that PNPLA3 148 M was significantly associated with serum AFP level (p = 0.032), other than body mass index, platelet count, and alanine aminotransferase (p = 0.0006, 0.0002, and 0.037, respectively), and that serum AFP level was significantly associated with PNPLA3 148 M (p = 0.017). Serum AFP level is an important factor in predicting HCC development after the antiviral therapy for Japanese patients with chronic hepatitis C, the mechanism of which might involve its significant associations with the SNP genotype of PNPLA3.
Collapse
Affiliation(s)
- Yuki Moritou
- />Department of Internal Medicine, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Fusao Ikeda
- />Department of Internal Medicine, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Yoshiaki Iwasaki
- />Department of Internal Medicine, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Nobuyuki Baba
- />Department of Internal Medicine, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Kouichi Takaguchi
- />Department of Internal Medicine, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Tomonori Senoh
- />Department of Internal Medicine, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Takuya Nagano
- />Department of Internal Medicine, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Yasuto Takeuchi
- />Department of Internal Medicine, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Tetsuya Yasunaka
- />Department of Internal Medicine, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Hideki Ohnishi
- />Department of Internal Medicine, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Yasuhiro Miyake
- />Department of Internal Medicine, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Akinobu Takaki
- />Department of Internal Medicine, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Kazuhiro Nouso
- />Department of Internal Medicine, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Kazuhide Yamamoto
- />Department of Internal Medicine, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| |
Collapse
|
|
15
|
Taliani G, Spaziante M, Biliotti E, Borro M, Palazzo D, Grieco S, Franchi C, Iaiani G, Furlan C, Gallinaro V, Simmaco M. IL28B gene polymorphisms and US liver fatty changes in patients who spontaneously cleared hepatitis C virus infection. PLoS One 2013; 8:e67301. [PMID: 23936294 PMCID: PMC3731327 DOI: 10.1371/journal.pone.0067301] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2013] [Accepted: 05/16/2013] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Recent clinical studies have shown that the presence of CC genotype in the rs12979860 region of IL28B gene is associated with an increase in the probability of spontaneous clearance of hepatitis C virus (HCV). Moreover, IL28B polymorphism seems to influence the probability of developing liver steatosis in chronic HCV patients. AIMS The aims of our clinical study were 1) to verify the distribution of IL28B genotypes (CC, CT or TT) among subjects with spontaneous clearance of HCV infection and 2) to examine the correlation between IL28B polymorphism and hepatic steatosis among these subjects. METHODS AND PATIENTS We enrolled 41 subjects with spontaneous resolution of HCV infection (detectable serum anti-HCV but undetectable HCV-RNA) and 134 healthy controls from the same geographical area. The IL28B single-nucleotide polymorphism (SNP) rs12979860 was genotyped by using a Pyrosequencing™ technique. The presence of steatosis was assessed by liver biopsy or ultrasound examination in the 41 study subjects. RESULTS CC, CT and TT-genotypes of the SNP rs1979860 were found in 66%, 24% and 10% of the subjects who spontaneously cleared HCV and in 31%, 54% and 15% of controls, respectively (p = 0.0003). Among the study subjects, females with CC-genotype were significantly more represented (p = 0.02). Hepatic steatosis did not correlate with IL28B genotype (p = 0,14) but only with a high body mass index (BMI) value (p = 0.03). CONCLUSIONS Female subjects carrying IL28B CC-genotype are significantly more represented among Italian patients who spontaneously cleared HCV infection. In addition, among these subjects, the presence of liver steatosis does not correlate with IL28B genotype but is solely related to the occurrence of high BMI. Thus, the association between IL28B polymorphism and steatosis in chronic HCV patients requires the presence of active HCV replication to occur, while in subjects who have cleared the infection, the mechanism(s) inducing liver steatosis are independent from IL28B profile.
Collapse
Affiliation(s)
- Gloria Taliani
- Clinica Malattie Infettive e Tropicali, Department of Clinical Medicine, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
16
|
Chen LJ, Wen XY, Niu JQ. Role of PNPLA3 polymorphism in pathogenesis of liver diseases. Shijie Huaren Xiaohua Zazhi 2013; 21:667-672. [DOI: 10.11569/wcjd.v21.i8.667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatic fat accumulation, a common phenomenon in nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD), is associated with liver inflammation development and disease progression. Besides, hepatic fat accumulation is also seen in HCV-infected patients, which influences the response to anti-HCV therapy. Although the causes of fatty accumulation in the above three diseases are different, hereditary factors causing fatty accumulation have attracted more and more attention. PNPLA3, a member of patatin-like phospholipase family, has the activity of triglyceride hydrolase and can influence the liver fatty metabolism. In recent years, PNPLA3 polymorphism has become a hot topic in research of NAFLD, ALD, and HCV, and important results have been achieved. This article describes the expression of PNPLA3 in human tissues and review recent progress in understanding the role of PNPLA3 polymorphism in the pathogenesis of the above three liver diseases.
Collapse
|
|
17
|
Guzmán-Fulgencio M, Berenguer J, García-Álvarez M, Fernández-Rodríguez A, Jiménez-Sousa MA, Alvarez E, Micheloud D, López JC, Miralles P, Cosín J, Catalán P, Resino S. IL28B polymorphisms are associated with severity of liver disease in human immunodeficiency virus (HIV) patients coinfected with hepatitis C virus. J Infect 2013; 66:170-8. [PMID: 23103287 DOI: 10.1016/j.jinf.2012.10.025] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2012] [Revised: 09/13/2012] [Accepted: 10/21/2012] [Indexed: 12/17/2022]
Abstract
OBJECTIVE To evaluate the association of IL28B polymorphisms and severity of liver disease among human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfected patients. METHODS We carried out a cross-sectional study on 223 patients. Liver biopsies were evaluated according to Metavir score. IL28B polymorphisms (rs12980275, rs8099917, rs7248668, and rs11881222) were genotyped using GoldenGate(®) assay. RESULTS IL28B polymorphisms were in strong linkage disequilibrium, especially the couples rs12980275/rs11881222 and rs8099917/rs7248668. For all patients, the rs12980275 A allele increased the odds for significant fibrosis (F ≥ 2) odds ratio (OR) = 1.68; p = 0.018) and more rapid fibrosis progression (FPR ≥ 0.075 fibrosis units/year) (OR = 1.64; p = 0.035), and decreased the odds for liver steatosis (OR = 0.61; p = 0.046). Furthermore, the rs8099917 T allele increased the odds for F ≥ 2 (OR = 1.93; p = 0.020), FPR ≥ 0.075 (OR = 2.08; p = 0.021), and elevated ALT (≥80 IU/l) (OR = 1.78; p = 0.048). For HCV-genotype 1 patients, rs12980275 A and rs8099917 T alleles decreased the odds for liver steatosis (OR = 0.22; p < 0.001 and OR = 0.39; p = 0.048; respectively). For HCV-genotype 3 patients, the rs12980275 A allele increased the odds for F ≥ 2 ((OR = 6.30; p = 0.012), FPR ≥ 0.075 (OR = 6.40; p = 0.025), and elevated ALT (OR = 4.12; p = 0.037); and the rs8099917 T allele also increased the odds for F ≥ 2 (OR = 7.56; p = 0.027), FPR ≥ 0.075 (OR = 50.8; p = 0.012), and elevated ALT (OR = 5.39; p = 0.043). However, we did not find significant trends in patients infected with HCV-genotype 4. CONCLUSION The major alleles of IL28B (rs12980275 A, rs11881222 A, rs8099917 T, and rs7248668 G) are associated with increased odds of liver disease severity in HIV patients infected with HCV-genotype 3. In contrast, HCV-genotype 1 patients carrying the major alleles of IL28B polymorphisms had lower odds for liver steatosis.
Collapse
Affiliation(s)
- María Guzmán-Fulgencio
- Unit of HIV/Hepatitis coinfection, National Centre of Microbiology, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
18
|
Dubuquoy C, Burnol AF, Moldes M. PNPLA3, a genetic marker of progressive liver disease, still hiding its metabolic function? Clin Res Hepatol Gastroenterol 2013; 37:30-5. [PMID: 22884299 DOI: 10.1016/j.clinre.2012.06.014] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2012] [Revised: 06/14/2012] [Accepted: 06/20/2012] [Indexed: 02/04/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is an emerging epidemic disease. It represents a large spectrum of liver diseases, and affects both adults and children. The etiology of NAFLD is multifactorial. Indeed, several events such as caloric imbalance including sedentary lifestyle, obesity and/or a predisposing genetic background are key players in the increasing risk for NAFLD development and its progression. Recently, a sequence variation within the gene encoding for patatin-like phospholipase containing 3 (PNPLA3, rs738409) was found to modulate steatosis, inflammation and fibrosis in NAFLD. It was also demonstrated as a novel genetic marker associated with progressive ALD (alcoholic liver disease). In this mini-review, we summarize the current knowledge on (i) PNPLA3 variant(s) in the pathogenesis of liver diseases, and (ii) PNPLA3 gene regulation and potential function in liver.
Collapse
|
|
19
|
IL28B rs12979860 is not associated with histologic features of NAFLD in a cohort of Caucasian North American patients. J Hepatol 2013; 58:402-3. [PMID: 23063570 PMCID: PMC3601946 DOI: 10.1016/j.jhep.2012.09.035] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2012] [Accepted: 09/29/2012] [Indexed: 01/10/2023]
|
|
20
|
Ezzikouri S, Alaoui R, Rebbani K, Brahim I, Fakhir FZ, Nadir S, Diepolder H, Khakoo SI, Thursz M, Benjelloun S. Genetic variation in the interleukin-28B gene is associated with spontaneous clearance and progression of hepatitis C virus in Moroccan patients. PLoS One 2013; 8:e54793. [PMID: 23358556 PMCID: PMC3554614 DOI: 10.1371/journal.pone.0054793] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2012] [Accepted: 12/14/2012] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Genetic variation in the IL28B gene has been strongly associated with treatment outcomes, spontaneous clearance and progression of the hepatitis C virus infection (HCV). The aim of the present study was to investigate the role of polymorphisms at this locus with progression and outcome of HCV infection in a Moroccan population. METHODS We analyzed a cohort of 438 individuals among them 232 patients with persistent HCV infection, of whom 115 patients had mild chronic hepatitis and 117 had advanced liver disease (cirrhosis and hepatocellular carcinoma), 68 individuals who had naturally cleared HCV and 138 healthy subjects. The IL28B SNPs rs12979860 and rs8099917 were genotyped using a TaqMan 5' allelic discrimination assay. RESULTS The protective rs12979860-C and rs8099917-T alleles were more common in subjects with spontaneous clearance (77.9% vs 55.2%; p = 0.00001 and 95.6% vs 83.2%; p = 0.0025, respectively). Individuals with clearance were 4.69 (95% CI, 1.99-11.07) times more likely to have the C/C genotype for rs12979860 polymorphism (p = 0.0017) and 3.55 (95% CI, 0.19-66.89) times more likely to have the T/T genotype at rs8099917. Patients with advanced liver disease carried the rs12979860-T/T genotype more frequently than patients with mild chronic hepatitis C (OR = 1.89; 95% CI, 0.99-3.61; p = 0.0532) and this risk was even more pronounced when we compared them with healthy controls (OR = 4.27; 95% CI, 2.08-8.76; p = 0.0005). The rs8099917-G allele was also associated with advanced liver disease (OR = 2.34; 95% CI, 1.40-3.93; p = 0.0100). CONCLUSIONS In the Moroccan population, polymorphisms near the IL28B gene play a role both in spontaneous clearance and progression of HCV infection.
Collapse
Affiliation(s)
- Sayeh Ezzikouri
- Virology Unit, Viral Hepatitis Laboratory, Pasteur Institute of Morocco, Casablanca, Morocco
| | - Rhimou Alaoui
- Service de Médecine B, CHU Ibn Rochd, Casablanca, Morocco
| | - Khadija Rebbani
- Virology Unit, Viral Hepatitis Laboratory, Pasteur Institute of Morocco, Casablanca, Morocco
| | - Ikram Brahim
- Virology Unit, Viral Hepatitis Laboratory, Pasteur Institute of Morocco, Casablanca, Morocco
| | - Fatima-Zohra Fakhir
- Virology Unit, Viral Hepatitis Laboratory, Pasteur Institute of Morocco, Casablanca, Morocco
| | - Salwa Nadir
- Service de Médecine B, CHU Ibn Rochd, Casablanca, Morocco
| | - Helmut Diepolder
- Ludwig-Maximilians-Universität München, Marchioninistrasse, München, Germany
| | - Salim I. Khakoo
- University of Southampton, Tremona Road, Southampton, United Kingdom
| | - Mark Thursz
- Department of Hepatology, Division of Medicine, Imperial College, London, United Kingdom
| | - Soumaya Benjelloun
- Virology Unit, Viral Hepatitis Laboratory, Pasteur Institute of Morocco, Casablanca, Morocco
| |
Collapse
|
|
21
|
Bellanti F, Vendemiale G, Altomare E, Serviddio G. The impact of interferon lambda 3 gene polymorphism on natural course and treatment of hepatitis C. Clin Dev Immunol 2012; 2012:849373. [PMID: 22966241 PMCID: PMC3433716 DOI: 10.1155/2012/849373] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2012] [Accepted: 07/02/2012] [Indexed: 02/08/2023]
Abstract
Host genetic factors may predict the outcome and treatment response in hepatitis C virus (HCV) infection. Very recently, three landmark genome-wide association studies identified single nucleotide polymorphisms near the interleukin 28B (IL28B) region which were more frequent in responders to treatment. IL28B encodes interferon (IFN)λ3, a type III IFN involved in host antiviral immunity. Favourable variants of the two most widely studied IL28B polymorphisms, rs12979860 and rs8099917, are strong pretreatment predictors of early viral clearance and sustained viral response in patients with genotype 1 HCV infection. Further investigations have implicated IL28B in the development of chronic HCV infection versus spontaneous resolution of acute infection and suggest that IL28B may be a key factor involved in host immunity against HCV. This paper presents an overview about the biological activity and clinical applications of IL28B, summarizing the available data on its impact on HCV infection. Moreover, the potential usefulness of IFNλ in the treatment and natural history of this disease is also discussed.
Collapse
Affiliation(s)
- F. Bellanti
- Department of Medical and Occupational Sciences, C.U.R.E. Centre for Liver Disease Research and Treatment, University of Foggia, Italy
| | - G. Vendemiale
- Department of Medical and Occupational Sciences, C.U.R.E. Centre for Liver Disease Research and Treatment, University of Foggia, Italy
- IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy
| | - E. Altomare
- Department of Medical and Occupational Sciences, C.U.R.E. Centre for Liver Disease Research and Treatment, University of Foggia, Italy
| | - G. Serviddio
- Department of Medical and Occupational Sciences, C.U.R.E. Centre for Liver Disease Research and Treatment, University of Foggia, Italy
| |
Collapse
|
|
22
|
Aghemo A. Understanding the role of PNPLA3 genetic variants in patients with chronic hepatitis C infection. Dig Dis Sci 2012; 57:1977-9. [PMID: 22736017 DOI: 10.1007/s10620-012-2277-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2012] [Accepted: 06/05/2012] [Indexed: 12/09/2022]
|