Abstract
Autoimmune hepatitis (AIH) is a chronic hepatitis of unknown etiology and several proinflammatory cytokines are implicated in its pathogenesis. The association of TNF-α gene polymorphism with AIH onset is not fully elucidated especially in the Tunisian population. The aim of this study was to determine the association of TNF-α (-308 G > A) polymorphism with AIH susceptibility and with TNF-α expression or clinical manifestations of AIH. A total of 50 AIH patients and 150 controls were included. Evaluation of TNF-α polymorphism was performed by ARMS PCR method. A significantly higher frequence of the AA genotype was found in AIH patients compared to controls (34 vs. 8%, p = 0.00002, OR 5.88). The frequency of the A-allele was significantly higher in patients with AIH compared to controls (55 vs. 37.3%, p = 0.002, OR 2.05). The G-allele was significantly more frequent in healthy controls compared to AIH patients [43 vs. 61.3%, p = 0.001, OR 0.47 (0.3–0.75)]. There was a positive correlation between the A/A genotype and a higher serum expression of TNF-α. The TNF*A allele confer susceptibility to AIH in the Tunisian patients and is associated with increased production of TNF-α. Anti-TNF antibodies could be an alternative to the use of corticotherapy and may avoid the exacerbated immune response in AIH.
Similar content being viewed by others
Abbreviations
- AIH:
-
Autoimmune hepatitis
- TNF-α:
-
Tumor necrosis factor-α
- AMA-M2:
-
Anti-mitochondrial antibody-M2
- EBV:
-
Epstein–Barr virus
- ANA:
-
Anti-nuclear antibodies
- CMV:
-
Cytomegalovirus
- HLA:
-
Human leucocyte antigen
- LKM1:
-
Anti-liver/kidney microsomal antibodies type 1
- PBC:
-
Primary biliary cirrhosis
- PSC:
-
Primary sclerosing cholangitis
- SLA:
-
Antibodies against soluble liver antigen
- SMA:
-
Smooth-muscle antibodies
- ARMS PCR:
-
Amplification refractory mutation system polymerase chain reaction
References
Aizawa Y, Hokari A (2017) Autoimmune hepatitis: current challenges and future prospects. Clin Exp Gastroenterol 10:9–18. https://doi.org/10.2147/CEG.S101440
Bernal W, Moloney M, Underhill J, Donaldson PT (1999) Association of tumor necrosis factor polymorphism with primary sclerosing cholangitis. J Hepatol 30:237–241
Bittencourt PL, Palácios SA, Cancado EL et al (2001) Autoimmune hepatitis in Brazilian patients is not linked to tumor necrosis factor alpha polymorphisms at position -308. J Hepatol 35:24–28. https://doi.org/10.1016/S0168-8278(01)00072-1
Chaouali M, Kochkar R, Messadi A et al (2017) Distribution of HLA-DRB1/DQB1 alleles and DRB1-DQB1 haplotypes among Tunisian patients with autoimmune hepatitis. Egypt J Hum Med Genet 18:335–339. https://doi.org/10.1016/j.ejmhg.2017.02.003
Cookson S, Constantini PK, Clare M, Underhill JA, Bernal W, Czaja AJ, Donaldson PT (1999) Frequency and nature of cytokine gene polymorphisms in type 1 autoimmune hepatitis. Hepatology 30:851–856
Czaja AJ, Manns MP (1995) The validity and importance of subtypes of autoimmune hepatitis: a point of view. Am J Gastroenterol 90:1206–1211
Czaja AJ, Strettell MD, Thomson LJ, Santrach PJ, Moore SB, Donaldson PT, Williams R (1997) Associations between alleles of the major histocompatibility complex and type 1 autoimmune hepatitis. Hepatology 25:317–323. https://doi.org/10.1002/hep.510250211
Czaja AJ, Cookson S, Constantini PK, Clare M, Underhill JA, Donaldson PT (1999) Cytokine polymorphisms associated with clinical features and treatment outcome in type 1 autoimmune hepatitis. Gastroenterology 117:645–652
Fan LY, Zhong RQ, Tu XQ, Pfeiffer T, Feltens R, Zhu Y, Zhou L (2004) Genetic association of tumor necrosis factor (TNF)- alpha polymorphisms with primary biliary cirrhosis and autoimmune liver diseases in a Chinese population. Zhonghua Gan Zang Bing Za Zhi 12:160–162
Francque S, Vonghia L, Ramon A, Michielsen P (2012) Epidemiology and treatment of autoimmune hepatitis. Dove Med Press 4:1–10. https://doi.org/10.2147/HMER.S16321
Gatselis NK, Zachou K, Koukoulis GK, Dalekos GN (2015) Autoimmune hepatitis, one disease with many faces: etiopathogenetic, clinico-laboratory and histological characteristics. World J Gastroentrol 21(1):60–83. https://doi.org/10.3748/wjg.v21.i1.60
Hardtke-Wolenski M, Dywicki J, Fischer K et al (2017) The influence of genetic predisposition and autoimmune hepatitis inducing antigens in disease development. J Autoimmun 78:39–45. https://doi.org/10.1016/j.jaut.2016.12.001
Hennes EM, Zeniya M, Czaja AJ, Parés A, Dalekos GN, Krawitt EL, Bittencourt PL (2008) Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology 48:169–176
Invernizzi P (2010) Geoepidemiology of autoimmune liver diseases. J Autoimmun 34:300–306
Jacob CO, Fronek Z, Lewis GD, Koo M, Hansen JA, McDevitt HO (1990) Heritable major histocompatibility complex class II-associated differences in production of tumor necrosis factor a: relevance to genetic predisposition to systemic lupus erythematosus. Proc Natl Acad Sci USA 87:1233–1237
Jing H, Ngu MC, Wallace T, Merriman R, Gearry RB, Stedman CAM, Roberts RL (2013) Association of the HLA locus and TNF with type I autoimmune hepatitis susceptibility in New Zealand Caucasians. Springerplus. 2:355. https://doi.org/10.1186/2193-1801-2-355
Jones DEJ, Watt FE, Grove J et al (1999) Tumour necrosis factor-a promotor polymorphisms in primary biliary cirrhosis. J Hepatol 3:232–236
Kaur N, Minz RW, Anand S, Saikia B, Aggarwal R, Das A (2013) HLA DRB1 alleles discriminate the manifestation of autoimmune hepatitis as type 1 or type 2 in North Indian population. J Clin Exper Hepatol. 1:14–18. https://doi.org/10.1016/j.jceh.2013.12.002
Kawasaki H, Onuki R, Suyama E, Taira K (2002) Identification of genes that function in the TNF-alpha-mediated apoptotic pathway using randomized hybrid ribozyme libraries. Nat Biotechnol 4:376–380. https://doi.org/10.1038/nbt0402-376
Liberal R, Grant CR, Mieli-Vergani G, Vergani D (2013) Autoimmune hepatitis: a comprehensive review. J Autoimmun 41:126–139. https://doi.org/10.1016/j.jaut.2012.11.002
Liberal R, Vergani D, Mieli-Vergani G (2015) Update on autoimmune hepatitis. J Clin Transl Hepatol 3:42–52. https://doi.org/10.14218/JCTH.2014.00032
Lim YS, Oh HB, Choi SE, Kwon OJ, Heo YS, Lee HC (2008) Susceptibility to type 1 autoimmune hepatitis is associated with shared amino acid sequences at positions 70-74 of the HLA-DRB1 molecule. J Hepatol 48:133–139. https://doi.org/10.1016/j.jhep.2007.08.019
Lohse AW, Mieli-Vergani G (2011) Autoimmune hepatitis. J Hepatol 55:171–182
Ma X, Qiu DK (2004) Cytokine gene polymorphisms in Chinese patients with type I autoimmune hepatitis. Zhonghua Gan Zang Bing Za Zhi 12:296–298
Manns MP, Vogel A (2006) Autoimmune hepatitis, from mechanisms to therapy. Hepatology 43:132–144. https://doi.org/10.1002/hep.21059
Mohseni F, Rashvand Z, Najafipour R et al (2016) Evaluating -238 G > a polymorphism association in TNF-α Gene with metabolic parameters and nutritional intakes among the Iranian NAFLD patients. Biochem Genet 54:685–695
Pando M, Larriba J, Fernandez GC, Fainboim H, Ciocca M, Ramonet M (1999) Pediatric and adult forms of type I autoimmune hepatitis in Argentina: evidence for differential genetic predisposition. Hepatology 30:1374–1380. https://doi.org/10.1002/hep.510300611
Seki T, Ota M, Furuta S, Fukushima H, Kondo T, Hino K (1992) HLA class II molecules and autoimmune hepatitis susceptibility in Japanese patients. Gastroenterology 103:1041–1047
Strettell MD, Donaldson PT, Thomson LJ, Santrach PJ, Moore SB, Czaja AJ, Williams R (1997) Allelic basis for HLA-encoded susceptibility to type 1 autoimmune hepatitis. Gastroenterology 112:2028–2035
Tang J, Zhou C, Zhang Z, Zheng S (2012) Association of polymorphisms in non-classic MHC genes with susceptibility to autoimmune hepatitis. Hepatobiliary Pancreat Dis Int 11:125–131
Vazquez-Garcia MN, Alaez C, Olivo A, Debaz H, Pérez-Luque E, Burguete A (1998) MHC class II sequences of susceptibility and protection in Mexicans with autoimmune hepatitis. J Hepatol 28:985–990
Wang Q, Yang F, Miao Q, Krawitt EL, Gershwin ME, Ma X (2016) The clinical phenotypes of autoimmune hepatitis: a comprehensive review. J Autoimmun 66:98–107. https://doi.org/10.1016/j.jaut.2015.10.006
Watts AD, Hunt NH, Hambly BD, Chaudhri G (1997) Separation of Tumor necrosis factor alpha isoforms by two dimensional polyacrylamide gel electrophoresis. Electrophoresis 7:1086–1091. https://doi.org/10.1002/elps.1150180710
Weiler-Normann C, Schramm C, Quaas A, Wiegard C, Glaubke C, Pannicke N, Möller S, Lohse AW (2013) Infliximab as a rescue treatment in difficult-to-treat autoimmune hepatitis. J Hepatol 58:529–534. https://doi.org/10.1016/j.jhep.2012.11.010
Wilson AG, Gordon C, di Giovine FS, de Vries N, van de Putte L, Emery P, Duff GW (1994) A genetic association between systemic lupus erythematosus and tumor necrosis factor alpha. Eur J Immunol 24(1):191–195
Yoshizawa K, Ota M, Katsuyama Y, Ichijo T, Matsumoto A, Tanaka E et al (2005) Genetic analysis of the HLA region of Japanese patients with type 1 autoimmune hepatitis. J Hepatol 42:578–584
Acknowledgements
We thank all patients for their contribution to the study. We are indebted to Dr J Kharat, professor at the Gastroenterology Department of Habib Thameur Hospital and Dr K El Jeri, professor at the Gastroenterology Department of Charles Nicolle Hospital, for their help and their contribution. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Funding
This research did not receive any specific Grant from funding agencies in the public, commercial, or not-for-profit sectors.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
All authors have no conflict of interest.
Rights and permissions
About this article
Cite this article
Chaouali, M., Azaiez, M.B., Tezeghdenti, A. et al. Association of TNF-α-308 Polymorphism with Susceptibility to Autoimmune Hepatitis in Tunisians. Biochem Genet 56, 650–662 (2018). https://doi.org/10.1007/s10528-018-9867-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10528-018-9867-4