 |
 |
 |
 |
 |
 |
Sains Malaysiana 55(6)(2026): 1045-1055
http://doi.org/10.17576/jsm-2026-5506-09
Analysis of IFN-
in Chronic Hepatitis B and Liver Cirrhosis Patients
(Analisis Polimorfisme Gen IFN-
DEVI RAHMADHONA1,2,
BAMBANG PURWANTO3, HARIS WIDITA4, HARI BASUKI NOTOBROTO5 & ARYATI6,7,*
1Doctoral
Program of Medical Science, Faculty of Medicine, Universitas Airlangga,
Surabaya, Indonesia
2Faculty
of Medicine, Universitas Mataram, Mataram, Indonesia
3Department
of Physiology and Medical Biochemistry, Faculty of Medicine, Universitas
Airlangga, Surabaya, Indonesia
4Department of Internal Medicine, West Nusa
Tenggara General Hospital, Mataram, Indonesia
5Department of Epidemiology,
Biostatistics, Population Studies and Health Promotion, Faculty of Public
Health, Universitas Airlangga, Surabaya, Indonesia
6Department
of Clinical Pathology, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
7Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
Diserahkan: 5 Januari 2026/Diterima: 5 Jun 2026
Abstract
Interferon
gamma (IFN-γ) plays a central role in antiviral immunity and
immune-mediated liver injury in chronic hepatitis B virus (HBV) infection.
Genetic polymorphism affecting IFN-γ production may influence disease susceptibility
and progression. This study investigated
the association between the IFN-γ +874 T/A polymorphism, serum IFN-γ levels,
and clinical outcomes in patients with chronic hepatitis B (CHB) and liver
cirrhosis (LC). A total of 125 patients were enrolled, including 88 with CHB
and 37 with LC. IFN-γ +874 T/A polymorphism was analysed using PCR–RFLP,
and serum IFN-γ levels were measured. Genotype and allele distributions
were compared between groups, and genotype-specific differences in serum IFN-γ
were evaluated. The AA genotype and A allele were the most prevalent in both CHB
and LC groups, with no significant differences in genotype or allele
distributions. In contrast, serum
IFN-γ level were significantly higher in patients with LC compared with
those with CHB (p=0.018). Stratified analysis showed no significant differences
in IFN-γ levels among genotypes within each group; however, LC patients
carrying the AA genotypes had significantly higher IFN-γ levels than AA
carriers in the CHB group (p=0.047). In conclusion, elevated serum IFN-γ
levels are associated with advanced liver disease in chronic HBV infection,
whereas IFN-γ +874 T/A polymorphism alone does not independently predict
progression from CHB to LC. These finding underscore the importance of
disease-stage-dependent immune dysregulation HBV-related liver disease.
Keywords: Chronic hepatitis B; IFN-γ +874 T/A; liver cirrhosis; serum IFN-γ
Abstrak
Interferon gama (IFN-γ) memainkan peranan utama dalam imuniti antivirus dan kecederaan hepar yang dimediasi oleh sistem imun dalam jangkitan virus hepatitis B kronik (HBV). Polimorfisme genetik yang mempengaruhi penghasilan IFN-γ mungkin mempengaruhi kerentanan terhadap penyakit dan perkembangan penyakit. Kajian ini bertujuan untukmenilai hubunganantara polimorfisme IFN-γ +874 T/A, paras IFN-γ serum dan hasil klinikal dalam kalangan pesakit hepatitis B kronik (CHB) dan sirosis hati (LC). Seramai 125 pesakit telah direkrut, terdiri daripada 88 pesakit CHB dan 37 pesakit LC. Polimorfisme IFN-γ +874 T/A dianalisis menggunakan kaedah PCR-RFLP, manakala paras IFN-γ serum diukur. Taburan genotip dan alel dibandingkanantara kumpulandan perbezaan paras IFN-γ serum mengikut genotip turut dinilai. Genotip AA dan alel A merupakan yang paling kerap ditemui dalam kedua-dua kumpulan CHB dan LC tanpa perbezaan signifikan dalam taburan genotip atau alel. Sebaliknya, paras IFN-γ serum adalah lebih tinggi secara signifikan dalam kalangan pesakit LC berbanding CHB
(p=0.018). Analisis berstrata menunjukkan tiada perbezaan signifikan paras IFN-γ antara genotip dalam setiap kumpulan. Namun, pesakit LC yang membawa genotip AA mempunyai paras IFN-γ yang lebih tinggi signifikan berbanding pembawa genotip AA dalam kumpulan CHB (p=0.047). Kesimpulannya, peningkatan paras IFN-γ serum berkaitan dengan penyakit hepar yang lebih lanjut dalam jangkitan HBV kronik, manakala polimorfime IFN-γ
+874 T/A secara bersendirian tidak meramalkan perkembangan penyakit hati daripada CHB kepada sirosis hati. Penemuan ini menekankan kepentingan disregulasi imun yang bergantung pada peringkat penyakit dalam penyakit hepar berkaitan HBV.
Kata kunci: Hepatitis B kronik; IFN-γ +874 T/A; IFN-γ
serum; sirosis hati
RUJUKAN
Adu, F., Aniakwaa-Bonsu, E., Badu Nyarko,
S., Obeng, A.S., Ateko, R.O., Anyanful, A. & Thomford, N.E. 2024. Host
cytokine genetic polymorphisms in a selected population of persons living with
hepatitis B virus infection in the central region of Ghana. BMC
Gastroenterol. 24: 374. https://doi.org/10.1186/s12876-024-03456-9
Al Kadi, M. & Monem, F. 2017.
Polymorphism of IFN-γ (+874 T/A) in Syrian patients with chronic hepatitis
B. Gastroenterol. Hepatol. Bed Bench 10(1): 34-38.
Ben Selma, W., Laribi, A.B., Alibi, S.
& Boukadida, J. 2021. Association of an IFN-γ variant with susceptibility
to chronic hepatitis B by the enhancement of HBV DNA replication. Cytokine 143: 155525. https://doi.org/10.1016/j.cyto.2021.155525
Brown, R., Goulder, P. & Matthews,
P.C., 2022. Sexual dimorphism in chronic hepatitis B virus (HBV) infection:
Evidence to inform elimination efforts. Wellcome Open Res. 7: 32.
https://doi.org/10.12688/wellcomeopenres.17601.3
Chen, S-L., Xiao, H., Li, G-J. & Shen,
Y-J. 2023. Expression pattern of cytokines in patients with chronic hepatitis B
receiving PEGinterferon therapy. Int. J. Gen. Med. 16: 1771-1782.
Cooper, K.M., Delk, M., Devuni, D. &
Sarkar, M. 2023. Sex differences in chronic liver disease and benign liver
lesions. JHEP Rep. 5: 100870.
https://doi.org/10.1016/j.jhepr.2023.100870
Damanik, R., Effendy, E. & Husada,
M.S. 2020. The relation of gene polymorphism interferon gamma+874 A/T and schizophrenia
occurred in Batak ethnicity. Maced. J. Med. Sci. 8: 70-75.
https://doi.org/10.3889/oamjms.2020.3975
Daulay, R.S., Saragih, R.A.C., Daulay,
R.M., Ganie, R.A., Tann, G. & Supriyatno, B. 2021. Role of interferon-gamma
+874 a/t single-nucleotide polymorphism and tuberculosis susceptibility of
pediatric population in North Sumatera, Indonesia. Open Access Maced. J.
Med. Sci. 9(A): 1057-1060. https://doi.org/10.3889/oamjms.2021.7441
Dondeti, M.F., Abdelkhalek, M.S., El-Din
Elezawy, H.M., Alsanie, W.F., Raafat, B.M., Gamal-Eldeen, A.M. & Talaat,
R.M. 2022. Association between interferon-gamma (IFN-γ) gene polymorphisms
(+874A/T and +2109A/G), and susceptibility to hepatitis B viral infection
(HBV). J. Appl. Biomed. 20: 37-43. https://doi.org/10.32725/jab.2022.001
European Association for the Study of the
Liver (EASL). 2017. EASL 2017 clinical practice guidelines on the management of
hepatitis B virus infection. J. Hepatol. 67: 370-398.
Febriawan, R. 2022. The association
between interferon-gamma +874 T/A polymorphism and susceptibility of chronic
hepatitis B with liver cirrhosis: An update meta analysis. Presented at the
HBV International Liver Conference 2022, Singapore.
Ferreira, S.D.C., Chachá, S.G.F., Souza,
F.F., Teixeira, A.C., De Carvalho Santana, R., Deghaide, N.H.S., Rodrigues, S.,
Marano, L.A., Mendes-Junior, C.T., Zucoloto, S., Donadi, E.A. & De Lourdes
Candolo Martinelli, A. 2015. IL-18, TNF, and IFN-γ alleles and genotypes are associated with susceptibility to chronic hepatitis B
infection and severity of liver injury: IL-18, TNF, and IFN-γ alleles and genotypes. J. Med. Virol. 87: 1689-1696.
https://doi.org/10.1002/jmv.24225
Haghshenas, M.R., Arabi, M. & Mousavi,
T. 2014. Hepatitis B genotypes in Iran. Mater. Sociomed. 26: 129-133.
https://doi.org/10.5455/msm.2014.26.129-133
Hasa, E., Hartmann, P. & Schnabl, B.
2022. Liver cirrhosis and immune dysfunction. Int. Immunol. 34: 455-466.
https://doi.org/10.1093/intimm/dxac030
Heidari, Z., Moudi, B. &
Mahmoudzadeh-Sagheb, H. 2020. Interferon gamma gene polymorphisms and chronic
hepatitis B infections in an Iranian population. Turk. J. Gastroenterol. 31:
515-521. https://doi.org/10.5152/tjg.2020.181024
Hillaire, M.L.B., Lawrence, P. &
Lagrange, B. 2023. IFN-γ: A crucial player in the fight against HBV infection? Immune Netw. 23(4): e30. https://doi.org/10.4110/in.2023.23.e30
Irvine, K.M., Ratnasekera, I., Powell,
E.E. & Hume, D.A., 2019. Causes and consequences of innate immune
dysfunction in cirrhosis. Front. Immunol. 10: 293.
https://doi.org/10.3389/fimmu.2019.00293
Kiteswara, A.U.D., Sari, A.I.P. &
Pratamawati, T.M. 2024. Genetic polymorphism of interferon-gamma +874T/A as a risk
factor for pulmonary tuberculosis in Cirebon, Indonesia. GHMJ Glob. Health
Manag. J. 7: 174-179. https://doi.org/10.35898/ghmj-741107
Le, A.K., Yang, H-I., Yeh, M-L., Jin, M.,
Trinh, H.N., Henry, L., Liu, A., Zhang, J.Q., Li, J., Wong, C., Wong, C.,
Cheung, R., Yu, M-L. & Nguyen, M.H. 2021. Development and validation of a
risk score for liver cirrhosis prediction in untreated and treated chronic hepatitis
B. J. Infect. Dis. 223(1): 139-146.
https://doi.org/10.1093/infdis/jiaa330
Lei, Z., Wang, L., Gao, H., Guo, S., Kang,
X., Yuan, J., Lv, Z., Jiang, Y., Yi, J., Chen, Z. & Wang, G. 2024.
Mechanisms underlying the compromised clinical efficacy of interferon in
clearing HBV. Virol. J. 21: 314.
https://doi.org/10.1186/s12985-024-02589-3
Li, L. 2020. Association between the
interferon-γ +874T/A polymorphism and susceptibility to hepatitis B virus
infection: A meta-analysis. J. Int. Med. Res. 48: 0300060520945511.
https://doi.org/10.1177/0300060520945511
Li, Q., Sun, B., Zhuo, Y., Jiang, Z., Li,
R., Lin, C., Jin, Y., Gao, Y. & Wang, D. 2022. Interferon and
interferon-stimulated genes in HBV treatment. Front. Immunol. 13:
1034968. https://doi.org/10.3389/fimmu.2022.1034968
Liaskou, E. & Hirschfield, G.M. 2019.
Cirrhosis-associated immune dysfunction: Novel insights in impaired adaptive
immunity. EBioMedicine 50: 3-4.
https://doi.org/10.1016/j.ebiom.2019.10.056
Lu, F., Thévenot, T., Mancuso, A., Li, Y.,
Liu, L. & Qi, X. 2024. Editorial: Treatment and prognostic assessment of
liver cirrhosis and its complications. Front. Med. 10: 1359036.
https://doi.org/10.3389/fmed.2023.1359036
Lubis, A.F., Salim, E.M. & Hafy, Z.
2023. Correlation of the interferon gamma point +874 A/T gene polymorphism with
the occurrence of schizophrenia. J. Res. Sci. Educ. 9(11): 9750-9755.
https://doi.org/10.29303/jppipa.v9i11.5436
Maulani, C., Auerkari, E.I., Masulili,
S.L.C., Kusdhany, L.S., Soeroso, Y. & Soedarsono, N. 2022. Interferon-gamma
(IFNg) +874A/T polymorphism does not significantly affect the severity of
periodontitis. Eur. J. Dent. 16(2): 327-332.
https://doi.org/10.1055/s-0041-1735434
Naghizadeh, M.S., Naseri, M., Fereyduni,
M., Ziaee, M., Tane, A., Safari, H., Mahavar, N., Mahdavi, R. & Anani
Sarab, G. 2018. Single nucleotide polymorphism of the interferon-γ gene
(IFN-γ +874 T/A) and the prognosis of hepatitis B infection. J. Med.
Microbiol. Infect. Dis. 6: 43-47. https://doi.org/10.29252/JoMMID.6.2.3.43
Naghizadeh, M.S., Anani Sarab, G., Safari,
H. & Mahavar, N. 2017. Relation between IFN-γ polymorphism and the
outcome of hepatitis B infection in an Iranian population. Hepatitis
Monthly. Presented at the The 7th International
Tehran Hepatitis Conference, Tehran.
Nik Zuraina Nik Mohd Noor, Nur Annisa
Nasuha Mohd Sedi, Mohammed Dauda Goni, Suharni Mohamad, Mohd Nor Norazmi & Siti
Suraiya. 2025. Interferon-gamma and interleukin-10 genetic polymorphisms among
the pulmonary tuberculosis caused by Malaysia-specific Mycobacterium
tuberculosis strain: SIT745/EAI1-MYS. PeerJ 13: e19576.
https://doi.org/10.7717/peerj.19576
Panigoro, R., Maskoen, A., Susanto, H.
& Sahiratmadja, E. 2012. Association between +874 T>A polymorphism IFNG
gene and cervical cancer patients in Bandung. 2nd Bandung Molecular Medicine
Conference International Conference on Molecular Oncology: An Update in
Clinical Aplication Insight on Infection Related Oncology. Faculty of
Medicine Padjajaran University, Bandung.
Perhimpunan Peneliti Hati Indonesia. 2021. Konsensus Nasional Penatalaksanaan Hipertensi Portal di Indonesia. Perhimpunan Peneliti Hati Indonesia, Jakarta.
Pratim Das, P. & Medhi, S. 2023. Role
of inflammasomes and cytokines in immune dysfunction of liver cirrhosis. Cytokine 170: 156347. https://doi.org/10.1016/j.cyto.2023.156347
Ribeiro, C.R.D.A., Martinelli, K.G., De
Mello, V.D.M., Baptista, B.D.S., Dias, N.S.T., Paiva, I.A., Lewis-Ximenez,
L.L., Pinto, L.M.D.O. & De Paula, V.S. 2020. Cytokine, genotype, and viral
load profile in the acute and chronic hepatitis B. Viral Immunol. 33:
620-627. https://doi.org/10.1089/vim.2020.0176
Rodríguez-Negrete, E.V., Gálvez-Martínez,
M., Sánchez-Reyes, K., Fajardo-Felix, C.F., Pérez-Reséndiz, K.E.,
Madrigal-Santillán, E.O., Morales-González, Á. & Morales-González, J.A.
2024. Liver cirrhosis: The immunocompromised state. J. Clin. Med. 13(18):
5582. https://doi.org/10.3390/jcm13185582
Sun, Y., Lu, Y., Xie, L., Deng, Y., Li, S.
& Qin, X. 2015a. Interferon gamma polymorphisms and hepatitis B virus-related
liver cirrhosis risk in a Chinese population. Cancer Cell Int. 15: 35.
https://doi.org/10.1186/s12935-015-0184-2
Sun, Y., Lu, Y., Li, T., Xie, L., Deng,
Y., Li, S. & Qin, X. 2015b. Interferon Gamma +874T/A polymorphism increases
the risk of hepatitis virus-related diseases: Evidence from a meta-analysis. PLoS
ONE10(5): e0121168.
https://doi.org/10.1371/journal.pone.0121168
Tan, G., Song, H., Xu, F. & Cheng, G.
2018. When hepatitis B virus meets interferons. Front. Microbiol. 9:
1611. https://doi.org/10.3389/fmicb.2018.01611
Watson, A.G., Mulay, A.S. & Gill,
U.S., 2025. Chronic hepatitis B in 2025: Diagnosis, treatment and future
directions. Clin. Med. 25: 100527.
https://doi.org/10.1016/j.clinme.2025.100527
World Health Organization (WHO). 2024a. Global Hepatitis Report 2024: Action for Access in Low- and Middle-Income
Countries. 1st ed. Geneva: World Health Organization.
World Health Organization (WHO). 2024b. Guidelines
for the Prevention, Diagnosis, Care and Treatment for People with Chronic
Hepatitis B Infection. Geneva: World Health Organization.
Xiao, S., Pan, X., Huang, X., Liu, Y.,
Wen, S.W. & Liu, A. 2023. Gene polymorphisms of inflammatory factors in
liver cirrhosis. Front. Genet. 14: 1140427. https://doi.org/10.3389/fgene.2023.1140427
Zambon, C-F., Basso, D., Navaglia, F.,
Belluco, C., Falda, A., Fogar, P., Greco, E., Gallo, N., Rugge, M., Di Mario,
F. & Plebani, M. 2005. Pro- and anti-inflammatory cytokines gene
polymorphisms and Helicobacter pylori infection: Interactions influence
outcome. Cytokine 29(4): 141-152.
https://doi.org/10.1016/j.cyto.2004.10.013
Zhang, Z., Wang, C., Liu, Z., Zou, G., Li,
J. & Lu, M. 2019. Host genetic determinants of hepatitis B virus infection. Front. Genet. 10: 696. https://doi.org/10.3389/fgene.2019.00696
Zheng, M., Li, J., Fang, W., Luo, L.,
Ding, R., Zeng, H., Luo, H., Lin, X. & Duan, C. 2023. The TNF-α
rs361525 and IFN-γ rs2430561 polymorphisms are associated with liver
cirrhosis risk: A comprehensive meta-analysis. Front. Immunol. 14:
1129767. https://doi.org/10.3389/fimmu.2023.1129767
Zhong, S., Zhang, T., Tang, L. & Li,
Y. 2021. Cytokines and chemokines in HBV infection. Front. Mol. Biosci. 8:
805625. https://doi.org/10.3389/fmolb.2021.805625
*Pengarang untuk surat-menyurat; email: aryati@fk.unair.ac.id
|
|||
|
