Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Hepatology International
Published in: Hepatology International 2/2011

01-06-2011 | Original Article

Combined effect of pro- and anti-inflammatory cytokine gene polymorphisms on susceptibility to liver cirrhosis in Tunisian HCV-infected patients

Authors: Nadia Bouzgarrou, Elham Hassen, Olfa Bahri, Sallouha Gabbouj, Nabil Ben Mami, Henda Triki, Lotfi Chouchane

Published in: Hepatology International | Issue 2/2011

Login to get access

Abstract

Purpose

Chronic hepatitis C progression is commonly attributed to the continuous activation of the immune response with an increased production of pro-inflammatory cytokines, leading to fibrosis and ultimately to cirrhosis. On the contrary, anti-inflammatory cytokines, mainly interleukin (IL)-10 have a modulatory effect on hepatic fibrogenesis. The association between individual polymorphisms within cytokine genes and hepatitis C outcome is often weak and non-informative. Interestingly, it has been demonstrated that a combination of specific genotypes may be a more significant and powerful approach for predicting disease risk.

Aim

This study is aimed at investigating the combined effect of single nucleotide polymorphism (SNP) in IL-18 (−607C/A, −137G/C), interferon (IFN)-γ (+874T/A) and IL-10 (−1082G/A) genes on cirrhosis risk in HCV-infected patients.

Methods

Seventy-seven chronic hepatitis C Tunisian subjects were included in this study. The patients were divided into two groups: the first included 31 non-cirrhotic patients, and the second included 46 liver cirrhosis patients. IL-18 genotyping was performed using the PCR amplification and the restriction fragment length polymorphism analysis (RFLP). IFN-γ and IL-10 polymorphisms were analyzed using the allele-specific PCR (AS-PCR).

Results

The combined high-risk genotype (IL-18 −607C/*, IL-18 −137G/*, IFN-γ +874T/*, IL-10 −1082A/A) frequency was compared between patients with and those without cirrhosis. Individuals were classified according the number of high-risk genotypes as follows: (0–2), patients with at most two high-risk genotypes; (3–4), patients with at least three of the high-risk genotypes. The logistic regression analysis showed that patients harboring 3–4 putative high-risk genotypes have a fivefold higher risk for developing cirrhosis in comparison to those harboring at most two high-risk genotypes (OR = 5.19; 95% CI = 1.49–18.05; p = 0.009).

Conclusion

Our study showed that the co-inheritance of IL-18, IFN-γ and IL-10 specific high-risk genotypes is associated with a greater risk for liver cirrhosis.
Literature
1.
Thio CL, Thomas DL, Carrington M. Chronic viral hepatitis and the human genome. Hepatology 2000;31:819–827PubMedCrossRef
2.
Bertoletti A, Ferrari C. Kinetics of the immune response during HBV and HCV infection. Hepatology 2003;38:4–13PubMedCrossRef
3.
Thio CL. Host genetic factors and antiviral immune responses to hepatitis C virus. Clin Liver Dis 2008;12:713–726PubMedCrossRef
4.
Cramp ME, Carucci P, Rossol S, Chokshi S, Maertens G, Williams R, et al. Hepatitis C virus (HCV) specific immune responses in anti-HCV positive patients without hepatitis C viraemia. Gut 1999;44:424–429PubMedCrossRef
5.
Pape GR, Gerlach TJ, Diepolder HM, Grüner N, Jung M, Santantonio T. Role of the specific T-cell response for clearance and control of hepatitis C virus. J Viral Hepat 1999;6:36–40PubMedCrossRef
6.
Marinho RT, Pinto R, Santos ML, Lobos IV, Moura MC. Effects of interferon and ribavirin combination therapy on CD4+ proliferation, lymphocyte activation, and Th1 and Th2 cytokine profiles in chronic hepatitis C. J Viral Hepat 2004;11:206–216PubMedCrossRef
7.
Kawakami Y, Nabeshima S, Furusyo N, Sawayama Y, Hayashi J, Kashiwagi S. Increased frequency of interferon-gamma-producing peripheral blood CD4+ T cells in chronic hepatitis C virus infection. Am J Gastroenterol 2000;95:3670–3673
8.
Napoli J, Bishop GA, McGuinness PH, Painter DM, McCaughan GW. Progressive liver injury in chronic hepatitis C infection correlates with increased intrahepatic expression of Th1-associated cytokines. Hepatology 1996;24:759–765PubMedCrossRef
9.
Sobue S, Nomura T, Ishikawa T, Ito S, Saso K, Ohara H, et al. Th1/Th2 cytokine profiles and their relationship to clinical features in patients with chronic hepatitis C virus infection. J Gastroenterol 2001;36:544–551PubMedCrossRef
10.
Falasca K, Ucciferri C, Dalessandro M, Zingariello P, Mancino P, Petrarca C, Pizzigallo E, Conti P, Vecchiet J. Cytokine patterns correlate with liver damage in patients with chronic hepatitis B and C. Ann Clin Lab Sci 2006;36:144–150PubMed
11.
Gigi E, Raptopoulou-Gigi M, Kalogeridis A, Masiou S, Orphanou E, Vrettou E, Lalla TH, Sinakos E, Tsapas V. Cytokine mRNA expression in hepatitis C virus infection: Th1 predominance in patients with chronic hepatitis C and Th1-Th2 cytokine profile in subjects with self-limited disease. J Viral Hepat 2008;15:145–154PubMed
12.
Bataller R, Brenner DA. Liver fibrosis. J Clin Invest 2005;115:209–218PubMed
13.
14.
Sobue S, Nomura T, Ishikawa T, Ito S, Saso K, Ohara H, Joh T, Itoh M, Kakumu S. Th1/Th2 cytokine profiles and their relationship to clinical features in patients with chronic hepatitis C virus infection. J Gastroenterol 2001;36:544–551PubMedCrossRef
15.
Mihm S, Hutschenreiter A, Fayyazi A, Pingel S, Ramadori G. High inflammatory activity is associated with an increased amount of IFNgamma transcripts in peripheral blood cells of patients with chronic hepatitis C virus infection. Med Microbiol Immunol 1996;185:95–102PubMedCrossRef
16.
Bertoletti A, D’Elios MM, Boni C, De Carli M, Zignego AL, Durazzo M, Missale G, Penna A, Fiaccadori F, Del Prete G, Ferrari C. Different cytokine profiles of intraphepatic T cells in chronic hepatitis B and hepatitis C virus infections. Gastroenterology 1997;112:193–199PubMedCrossRef
17.
Zhang LJ, Wang XZ. Interleukin-10 and chronic liver disease. World J Gastroenterol 2006;12:1681–1685PubMed
18.
Louis H, Van Laethem JL, Wu W, Quertinmont E, Degraef C, Van den Berg K, Demols A, Goldman M, Le Moine O, Geerts A, Devière J. Interleukin-10 controls neutrophilic infiltration, hepatocyte proliferation, and liver fibrosis induced by carbon tetrachloride in mice. Hepatology 1998;28:1607–1615PubMedCrossRef
19.
Nelson DR, Lauwers GY, Lau JY, Davis GL. Interleukin 10 treatment reduces fibrosis in patients with chronic hepatitis C: a pilot trial of interferon nonresponders. Gastroenterology 2000;118:655–660PubMedCrossRef
20.
Nelson DR, Tu Z, Soldevila-Pico C, Abdelmalek M, Zhu H, Xu YL, et al. Long-term interleukin 10 therapy in chronic hepatitis C patients has a proviral and anti-inflammatory effect. Hepatology 2003;38:859–868PubMed
21.
Fehniger TA, Shah MH, Turner MJ, VanDeusen JB, Whitman SP, Cooper MA, SuzukiK Wechser M, Goodsaid F, Caligiuri MA. Differential cytokine and chemiokine gene expression by human NK cells following activation with IL-18 or IL-15 in combination with IL-12: lmplication for the innate immune response. J Immunol 1999;162:4511–4520PubMed
22.
Puren AJ, Fantuzzi G, Gu Y, Su MS, Dinarello CA. Interleukin-18 (IFNgamma-inducing factor) induces IL-8 and IL-1beta via TNF-alpha production from non-CD14þ human blood mononuclear cells. J Clin Invest 1999;101:711CrossRef
23.
McGuinness PH, Painter D, Davies S, McCaughan GW. Increases in intrahepatic CD68 positive cells, MAC387 positive cells, and proinflammatory cytokines (particularly interleukin 18) in chronichepatitis C infection. Gut 2000;46:260–269PubMedCrossRef
24.
Neuman MG, Benhamou JP, Marcellin P, Valla D, Malkiewicz IM, Katz GG, Trepo C, Bourliere M, Cameron RG, Cohen L, Morgan M, Schmilovitz-Weiss H, Ben-Ari Z. Cytokine–chemokine and apoptotic signatures in patients with hepatitis C. Transl Res 2007;149:126–136PubMedCrossRef
25.
Bouzgarrou N, Hassen E, Schvoerer E, Stoll-Keller F, Bahri O, Gabbouj S, Cheikh I, Maamouri N, Mammi N, Saffar H, Trabelsi A, Triki H, Chouchane L. Association of interleukin-18 polymorphisms and plasma level with the outcome of chronic HCV infection. J Med Virol 2008;80:607–614PubMedCrossRef
26.
Sharma A, Chakraborti A, Das A, Dhiman RK, Chawla Y. Elevation of interleukin-18 in chronic hepatitis C: Implications for hepatitis C virus pathogenesis. Immunology 2009;128(1 Suppl):e514–e522PubMedCrossRef
27.
28.
Dai CY, Chuang WL, Lee LP, Chen SC, Hou NJ, Lin ZY, Hsieh MY, Hsieh MY, Wang LY, Chang WY, Yu ML. Associations of tumour necrosis factor alpha promoter polymorphisms at position -308 and -238 with clinical characteristics of chronic hepatitis C. J Viral Hepat 2006;13:770–774PubMedCrossRef
29.
Gao QJ, Liu DW, Zhang SY, Jia M, Wang LM, Wu LH, Wang SY, Tong LX. Polymorphisms of some cytokines and chronic hepatitis B and C virus infection. World J Gastroenterol 2009;15:5610–5619PubMedCrossRef
30.
Manohar K, Suneetha PV, Sukriti Pati NT, Gupta AC, Hissar S, Sakhuja P, Sarin SK. Association of IL-18 promoter polymorphism with liver disease severity in HCV-infected patients. Hepatol Int 2009;3:371–377PubMedCrossRef
31.
Paladino N, Fainboim H, Theiler G, Schroder T, Muñoz AE, Flores AC, Galdame O, Fainboim L. Gender susceptibility to chronic hepatitis C virus infection associated with interleukin 10 promoter polymorphism. J Virol 2006;80:9144–9150PubMedCrossRef
32.
Persico M, Capasso M, Persico E, Masarone M, Renzo A, Spano D, Bruno S, Iolascon A. Interleukin-10 -1082 GG polymorphism influences the occurrence and the clinical characteristics of hepatitis C virus infection. J Hepatol 2006;45:779–785PubMedCrossRef
33.
Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, O’Huigin C, Kidd J, Kidd K, Khakoo SI, Alexander G, Goedert JJ, Kirk GD, Donfield SM, Rosen HR, Tobler LH, Busch MP, McHutchison JG, Goldstein DB, Carrington M. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 2009;461:798–801PubMedCrossRef
34.
Bouzgarrou N, Hassen E, Farhat K, Bahri O, Gabbouj S, Maamouri N, Ben Mami N, Saffar H, Trabelsi A, Triki H, Chouchane L. Combined analysis of interferon-gamma and interleukin-10 gene polymorphisms and chronic hepatitis C severity. Hum Immunol 2009;70:230–236PubMedCrossRef
35.
Dai CY, Chuang WL, Hsieh MY, Lee LP, Hou NJ, Chen SC, et al. Polymorphism of interferon-gamma gene at position +874 and clinical characteristics of chronic hepatitis C. Transl Res 2006;148:128–133PubMedCrossRef
36.
Barrett S, Collins M, Kenny C, Ryan E, Keane CO, Crowe J. Polymorphisms in tumour necrosis factor-alpha, transforming growth factor-beta, interleukin-10, interleukin-6, interferon-gamma, and outcome of hepatitis C virus infection. J Med Virol 2003;71:212–218PubMedCrossRef
37.
Abbas Z, Moatter T, Hussainy A, Jafri W. Effect of cytokine gene polymorphism on histological activity index, viral load and response to treatment in patients with chronic hepatitis C genotype 3. World J Gastroenterol 2005;11:6656–6661PubMed
38.
Machado JC, Figueiredo C, Canedo P, Pharoah P, Carvalho R, Nabais S, Castro Alves C, Campos ML, Van Doorn LJ, Caldas C, Seruca R, Carneiro F, Sobrinho-Simões M. A proinflammatory genetic profile increases the risk for chronic atrophic gastritis and gastric carcinoma. Gastroenterology 2003;125:364–371PubMedCrossRef
39.
Richardson MM, Powell EE, Barrie HD, Clouston AD, Purdie DM, Jonsson JR. A combination of genetic polymorphisms increases the risk of progressive disease in chronic hepatitis C. J Med Genet 2005;42:e45PubMedCrossRef
40.
Beretta L, Cappiello F, Moore JH, Barili M, Greene CS, Scorza R. Ability of epistatic interactions of cytokine single-nucleotide polymorphisms to predict susceptibility to disease subsets in systemic sclerosis patients. Arthritis Rheum 2008;59:974–983PubMedCrossRef
41.
Chen DQ, Zeng Y, Zhou J, Yang L, Jiang S, Huang JD, Lu L, Zheng BJ. Association of candidate susceptible loci with chronic infection with hepatitis B virus in a Chinese population. J Med Virol 2010;82:371–378PubMedCrossRef
42.
Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988;16:1215PubMedCrossRef
43.
Mullighan CG, Marshall SE, Bunce M, Welsh KI. Variation in immunoregulatory genes determines the clinical phenotype of common variable immunodeficiency. Genes Immun 1999;1:137–148PubMedCrossRef
44.
Pravica V, Perrey C, Stevens A, Lee JH, Hutchinson IV. A single nucleotide polymorphism in the first intron of the human IFNgamma gene: Absolute correlation with a polymorphic CA microsatellite marker of high IFNgamma production. Hum Immunol 2000;61:863–866PubMedCrossRef
45.
Boyer N, Marcellin P. Pathogenesis, diagnosis and management of hepatitis C. J Hepatol 2000;32:98–112PubMedCrossRef
46.
Rehermann B, Nascimbeni M. Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol 2005;5:215–229PubMedCrossRef
47.
48.
Wang XH, Netski DM, Astemborski J, Mehta SH, Torbenson MS, Thomas DL, Ray SC. Progression of fibrosis during chronic hepatitis C is associated with rapid virus evolution. J Virol 2007;81:6513–6522PubMedCrossRef
49.
Hu SX, Kyulo NL, Xia VW, Hillebrand DJ, Hu KQ. Factors associated with hepatic fibrosis in patients with chronic hepatitis C: A retrospective study of a large cohort of U.S. patients. J Clin Gastroenterol 2009;43:758–64PubMedCrossRef
50.
Yamada M, Kakumu S, Yoshioka K, Higashi Y, Tanaka K, Ishikawa T, et al. Hepatitis C virus genotypes are not responsible for development of serious liver disease. Dig Dis Sci 1994;39:234–239PubMedCrossRef
51.
McGuinness PH, Bishop GA, Painter DM, Chan R, McCaughan GW. Intrahepatic hepatitis C RNA levels do not correlate with degree of liver injury in patients with chronic hepatitis C. Hepatology 1996;23:676–687PubMedCrossRef
52.
Yoshizawa K, Ota M, Saito S, Maruyama A, Yamaura T, Rokuhara A, Orii K, Ichijo T, Matsumoto A, Tanaka E, Kiyosawa K. Long-term follow-up of hepatitis C virus infection: HLA class II loci influences the natural history of the disease. Tissue Antigens 2003;61:159–165PubMedCrossRef
53.
Baroni GS, Pastorelli A, Manzin A, Benedetti A, Marucci L, Solforosi L, Di Sario A, Brunelli E, Orlandi F, Clementi M, Macarri G. Hepatic stellate cell activation and liver fibrosis are associated with necroinflammatory injury and Th1-like response in chronic hepatitis C. Liver 1999;19:212–219PubMedCrossRef
54.
Chen CC, Yang SY, Liu CJ, Lin CL, Liaw YF, Lin SM, Lee SD, Chen PJ, Chen CJ, Yu MW. Association of cytokine and DNA repair gene polymorphisms with hepatitis B-related hepatocellular carcinoma. Int J Epidemiol 2005;34:1310–1318PubMedCrossRef
55.
Sfar S, Saad H, Mosbah F, Chouchane L. Combined effects of the angiogenic genes polymorphisms on prostate cancer susceptibility and aggressiveness. Mol Biol Rep 2009;36:37–45PubMedCrossRef
56.
Ahluwalia TS, Khullar M, Ahuja M, Kohli HS, Bhansali A, Mohan V, Venkatesan R, Rai TS, Sud K, Singal PK. Common variants of inflammatory cytokine genes are associated with risk of nephropathy in type 2 diabetes among Asian Indians. PLoS One 2009;4:e5168PubMedCrossRef
57.
Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 2001;19:683–765PubMedCrossRef
58.
Couper KN, Blount DG, Riley EM. IL-10: the master regulator of immunity to infection. J Immunol 2008;180(9):5771–5777PubMed
59.
Crawley E, Kay R, Sillibourne J, Patel P, Hutchinson I, Woo P. Polymorphic haplotypes of the interleukin-10 5′ flanking region determine variable interleukin-10 transcription and are associated with particular phenotypes of juvenile rheumatoid arthritis. Arthritis Rheum 1999;42:1101–1108PubMedCrossRef
60.
Yilmaz V, Yentur SP, Saruhan-Direskeneli G. IL-12 and IL-10 polymorphisms and their effects on cytokine production. Cytokine 2005;30:188–194PubMedCrossRef
61.
Stanilova SA, Miteva LD, Karakolev ZT, Stefanov CS. Interleukin-10–1082 promoter polymorphism in association with cytokine production and sepsis susceptibility. Intensive Care Med 2006;32:260–266PubMedCrossRef
62.
Miteva L, Stanilova S. The combined effect of interleukin (IL)-10 and IL-12 polymorphisms on induced cytokine production. Hum Immunol 2008;69:562–566PubMedCrossRef
63.
Qiu FB, Wu LQ, Lu Y, Zhang S, Zhang BY. Predominant expression of Th1-type cytokines in primary hepatic cancer and adjacent liver tissues. Hepatobiliary Pancreat Dis Int 2007;6:63–66PubMed
Metadata
Title
Combined effect of pro- and anti-inflammatory cytokine gene polymorphisms on susceptibility to liver cirrhosis in Tunisian HCV-infected patients
Authors
Nadia Bouzgarrou
Elham Hassen
Olfa Bahri
Sallouha Gabbouj
Nabil Ben Mami
Henda Triki
Lotfi Chouchane
Publication date
01-06-2011
Publisher
Springer-Verlag
Published in
Hepatology International / Issue 2/2011
Print ISSN: 1936-0533
Electronic ISSN: 1936-0541
DOI
https://doi.org/10.1007/s12072-010-9232-0

Other articles of this Issue 2/2011

Hepatology International 2/2011 Go to the issue

Review Article

Current use of hepatitis B immune globulin for prevention of de novo hepatitis B in recipients receiving anti-HBc-positive livers

Original Article

De novo combination of lamivudine and adefovir versus entecavir monotherapy for the treatment of naïve HBeAg-negative chronic hepatitis B patients

Original Article

Caffeoyl pyrrolidine derivative LY52 inhibits hepatocellular carcinoma invasion via suppressing matrix metalloproteinase-2

Case Report

Nonleukemic myeloid sarcoma of the liver: a case report and review of literature

Review Article

Non-invasive assessment of liver fibrosis in chronic hepatitis C

Original Article

Differential response related to genotoxicity in multiple organs of cirrhotic rats
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits