Covid-19 Research

Original Article

Association between Signal Transducer and Activator of Transcription 4 Genetic Polymorphisms and the Spontaneous Clearance of Hepatitis B Surface Antigen: A Large Population Case Control Study in China

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Aim: Several host factors mediating immune response influence susceptibility to Hepatitis B Virus (HBV) infection, ability to clear the virus, and maintenance of a chronic state. Signal Transducer and Activator of Transcription 4 (STAT4) variations are correlated with the risk of developing autoimmune diseases. However, there have been few studies to assess the relationship between STAT4 variations and Hepatitis B surface Antigen (HBsAg) clearance in adults infected with HBV. Our aim was to evaluate the association between genetic variants in STAT4 and HBsAg clearance in a large sample size population.

Methods: This case control study included Chronic Hepatitis B (CHB) (n = 1.688), HBsAg Clearance after Treatment (TC) (n = 170), HBV Uninfected (HC) (n=1.012), and HBsAg Spontaneous Clearance (SC) (n = 1,052) patients. In the CHB group, patients were categorized into four subgroups: the Immune Tolerant (IT), Immune Active (IA), Inactive (IC), and Immune Reactivation (IR) phases, with 97, 855, 198, and 538 patients in each subgroup, respectively.

Results: We found that the G allele in STAT4 rs7574865 was more frequent in the CHB and TC groups, compared with the SC group, whereas the STAT4 rs7574865 GG genotype was more frequent in the CHB and TC group, compared with the SC group in the dominant model. However, there was no statistical significance in genotype between TC and CHB, nor between the IT, IA, IC, and IR groups.

Conclusions: The prevalence of the minor allele rs7574865 T was higher in subjects with spontaneously cleared HBV infections than in CHB patients.

Xun Qi, Qirong Jiang, Ying Lv, Sisi Yang, Jing Li, Yuxian Huang, Liang Chen* and Jiming Zhang*
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Volume1-Issue6 | Published: 2020-10-31

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References


  1. Schweitzer A, Horn J, Mikolajczyk RT, Krause G, Ott JJ. Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013. Lancet. 2015 Oct 17;386(10003):1546-55. doi: 10.1016/S0140-6736(15)61412-X. Epub 2015 Jul 28. PMID: 26231459.
  2. WHO. Global hepatitis report 2017. Geneva: World Health Organization, 2017.
  3. Liu J, Liang W, Jing W, Liu M. Countdown to 2030: eliminating hepatitis B disease, China. Bull World Health Organ. 2019 Mar 1;97(3):230-238. doi: 10.2471/BLT.18.219469. Epub 2019 Jan 28. PMID: 30992636; PMCID: PMC6453311.
  4. Te HS, Jensen DM. Epidemiology of hepatitis B and C viruses: a global overview. Clin Liver Dis. 2010 Feb;14(1):1-21, vii. doi: 10.1016/j.cld.2009.11.009. PMID: 20123436.
  5. Guidotti LG, Isogawa M, Chisari FV. Host-virus interactions in hepatitis B virus infection. Curr Opin Immunol. 2015 Oct;36:61-6. doi: 10.1016/j.coi.2015.06.016. Epub 2015 Jul 15. PMID: 26186123; PMCID: PMC4593767.
  6. Matsuura K, Isogawa M, Tanaka Y. Host genetic variants influencing the clinical course of hepatitis B virus infection. J Med Virol. 2016 Mar;88(3):371-9. doi: 10.1002/jmv.24350. Epub 2015 Aug 14. PMID: 26255971.
  7. Martin MP, Carrington M. Immunogenetics of viral infections. Curr Opin Immunol. 2005 Oct;17(5):510-6. doi: 10.1016/j.coi.2005.07.012. PMID: 16084708.
  8. Belli LS, Zavaglia C, Alberti AB, Poli F, Rondinara G, Silini E, Taioli E, de Carlis L, Scalamogna M, Forti D, Pinzello G, Idèo G. Influence of immunogenetic background on the outcome of recurrent hepatitis C after liver transplantation. Hepatology. 2000 Jun;31(6):1345-50. doi: 10.1053/jhep.2000.7879. PMID: 10827162.
  9. Jacobson NG, Szabo SJ, Weber-Nordt RM, Zhong Z, Schreiber RD, Darnell JE Jr, Murphy KM. Interleukin 12 signaling in T helper type 1 (Th1) cells involves tyrosine phosphorylation of signal transducer and activator of transcription (Stat)3 and Stat4. J Exp Med. 1995 May 1;181(5):1755-62. doi: 10.1084/jem.181.5.1755. PMID: 7722452; PMCID: PMC2191986.
  10. El-Lebedy D, Raslan H, Ibrahim A, Ashmawy I, El-Aziz SA, Mohammed AM. Association of STAT4 rs7574865 and PTPN22 rs2476601 polymorphisms with rheumatoid arthritis and non-systemically reacting antibodies in Egyptian patients. Clin Rheumatol. 2017 Sep;36(9):1981-1987. doi: 10.1007/s10067-017-3632-7. Epub 2017 Apr 19. PMID: 28424905.
  11. Conigliaro P, Ciccacci C, Politi C, Triggianese P, Rufini S, Kroegler B, Perricone C, Latini A, Novelli G, Borgiani P, Perricone R. Polymorphisms in STAT4, PTPN2, PSORS1C1 and TRAF3IP2 Genes Are Associated with the Response to TNF Inhibitors in Patients with Rheumatoid Arthritis. PLoS One. 2017 Jan 20;12(1):e0169956. doi: 10.1371/journal.pone.0169956. PMID: 28107378; PMCID: PMC5249113.
  12. Ciccacci C, Conigliaro P, Perricone C, Rufini S, Triggianese P, Politi C, Novelli G, Perricone R, Borgiani P. Polymorphisms in STAT-4, IL-10, PSORS1C1, PTPN2 and MIR146A genes are associated differently with prognostic factors in Italian patients affected by rheumatoid arthritis. Clin Exp Immunol. 2016 Nov;186(2):157-163. doi: 10.1111/cei.12831. Epub 2016 Aug 2. PMID: 27342690; PMCID: PMC5054570.
  13. Durán-Avelar MJ, Vibanco-Pérez N, Hernández-Pacheco RR, Castro-Zambrano AD, Ortiz-Martínez L, Zambrano-Zaragoza JF. STAT4 rs7574865 G/T polymorphism is associated with rheumatoid arthritis and disease activity, but not with anti-CCP antibody levels in a Mexican population. Clin Rheumatol. 2016 Dec;35(12):2909-2914. doi: 10.1007/s10067-016-3320-z. Epub 2016 May 28. PMID: 27234231.
  14. Hagberg N, Joelsson M, Leonard D, Reid S, Eloranta ML, Mo J, Nilsson MK, Syvänen AC, Bryceson YT, Rönnblom L. The STAT4 SLE risk allele rs7574865[T] is associated with increased IL-12-induced IFN-γ production in T cells from patients with SLE. Ann Rheum Dis. 2018 Jul;77(7):1070-1077. doi: 10.1136/annrheumdis-2017-212794. Epub 2018 Feb 23. PMID: 29475858; PMCID: PMC6029643.
  15. Bi C, Li B, Cheng Z, Hu Y, Fang Z, Zhai A. Association study of STAT4 polymorphisms and type 1 diabetes in Northeastern Chinese Han population. Tissue Antigens. 2013 Mar;81(3):137-40. doi: 10.1111/tan.12057. Epub 2013 Jan 30. PMID: 23360093.
  16. Rueda B, Broen J, Simeon C, Hesselstrand R, Diaz B, Suárez H, Ortego-Centeno N, Riemekasten G, Fonollosa V, Vonk MC, van den Hoogen FH, Sanchez-Román J, Aguirre-Zamorano MA, García-Portales R, Pros A, Camps MT, Gonzalez-Gay MA, Coenen MJ, Airo P, Beretta L, Scorza R, van Laar J, Gonzalez-Escribano MF, Nelson JL, Radstake TR, Martin J. The STAT4 gene influences the genetic predisposition to systemic sclerosis phenotype. Hum Mol Genet. 2009 Jun 1;18(11):2071-7. doi: 10.1093/hmg/ddp119. Epub 2009 Mar 13. PMID: 19286670.
  17. Jiang DK, Sun J, Cao G, Liu Y, Lin D, Gao YZ, Ren WH, Long XD, Zhang H, Ma XP, Wang Z, Jiang W, Chen TY, Gao Y, Sun LD, Long JR, Huang HX, Wang D, Yu H, Zhang P, Tang LS, Peng B, Cai H, Liu TT, Zhou P, Liu F, Lin X, Tao S, Wan B, Sai-Yin HX, Qin LX, Yin J, Liu L, Wu C, Pei Y, Zhou YF, Zhai Y, Lu PX, Tan A, Zuo XB, Fan J, Chang J, Gu X, Wang NJ, Li Y, Liu YK, Zhai K, Zhang H, Hu Z, Liu J, Yi Q, Xiang Y, Shi R, Ding Q, Zheng W, Shu XO, Mo Z, Shugart YY, Zhang XJ, Zhou G, Shen H, Zheng SL, Xu J, Yu L. Genetic variants in STAT4 and HLA-DQ genes confer risk of hepatitis B virus-related hepatocellular carcinoma. Nat Genet. 2013 Jan;45(1):72-5. doi: 10.1038/ng.2483. Epub 2012 Dec 16. PMID: 23242368; PMCID: PMC4105840.
  18. Jiang DK, Wu X, Qian J, Ma XP, Yang J, Li Z, Wang R, Sun L, Liu F, Zhang P, Zhu X, Wu J, Chen K, Conran C, Zheng SL, Lu D, Yu L, Liu Y, Xu J. Genetic variation in STAT4 predicts response to interferon-α therapy for hepatitis B e antigen-positive chronic hepatitis B. Hepatology. 2016 Apr;63(4):1102-11. doi: 10.1002/hep.28423. Epub 2016 Feb 19. PMID: 26704347.
  19. Chen H, Sun J, Zhou B, Xie Q, Liang X, Fan R, Conran C, Xu J, Ji Y, Zhang X, Sun L, Jia J, Wang G, Hou J, Jiang DK. Variants in STAT4 Associated With Cure of Chronic HBV Infection in HBeAg-positive Patients Treated With Pegylated Interferon-alpha. Clin Gastroenterol Hepatol. 2020 Jan;18(1):196-204.e8. doi: 10.1016/j.cgh.2019.04.044. Epub 2019 Apr 28. PMID: 31042581.
  20. Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH; American Association for the Study of Liver Diseases. AASLD guidelines for treatment of chronic hepatitis B. Hepatology. 2016 Jan;63(1):261-83. doi: 10.1002/hep.28156. Epub 2015 Nov 13. PMID: 26566064; PMCID: PMC5987259.
  21. Rehermann B, Fowler P, Sidney J, Person J, Redeker A, Brown M, Moss B, Sette A, Chisari FV. The cytotoxic T lymphocyte response to multiple hepatitis B virus polymerase epitopes during and after acute viral hepatitis. J Exp Med. 1995 Mar 1;181(3):1047-58. doi: 10.1084/jem.181.3.1047. PMID: 7532675; PMCID: PMC2191941.
  22. Thierfelder WE, van Deursen JM, Yamamoto K, Tripp RA, Sarawar SR, Carson RT, Sangster MY, Vignali DA, Doherty PC, Grosveld GC, Ihle JN. Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells. Nature. 1996 Jul 11;382(6587):171-4. doi: 10.1038/382171a0. PMID: 8700208.
  23. Nguyen KB, Watford WT, Salomon R, Hofmann SR, Pien GC, Morinobu A, Gadina M, O’Shea JJ, Biron CA. Critical role for STAT4 activation by type 1 interferons in the interferon-gamma response to viral infection. Science. 2002 Sep 20;297(5589):2063-6. doi: 10.1126/science.1074900. PMID: 12242445.
  24. Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer. 2009 Nov;9(11):798-809. doi: 10.1038/nrc2734. PMID: 19851315; PMCID: PMC4856025.
  25. Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G, Behrens TW, de Bakker PI, Le JM, Lee HS, Batliwalla F, Li W, Masters SL, Booty MG, Carulli JP, Padyukov L, Alfredsson L, Klareskog L, Chen WV, Amos CI, Criswell LA, Seldin MF, Kastner DL, Gregersen PK. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med. 2007 Sep 6;357(10):977-86. doi: 10.1056/NEJMoa073003. PMID: 17804842; PMCID: PMC2630215.
  26. Stahl EA, Raychaudhuri S, Remmers EF, Xie G, Eyre S, Thomson BP, Li Y, Kurreeman FA, Zhernakova A, Hinks A, Guiducci C, Chen R, Alfredsson L, Amos CI, Ardlie KG; BIRAC Consortium, Barton A, Bowes J, Brouwer E, Burtt NP, Catanese JJ, Coblyn J, Coenen MJ, Costenbader KH, Criswell LA, Crusius JB, Cui J, de Bakker PI, De Jager PL, Ding B, Emery P, Flynn E, Harrison P, Hocking LJ, Huizinga TW, Kastner DL, Ke X, Lee AT, Liu X, Martin P, Morgan AW, Padyukov L, Posthumus MD, Radstake TR, Reid DM, Seielstad M, Seldin MF, Shadick NA, Steer S, Tak PP, Thomson W, van der Helm-van Mil AH, van der Horst-Bruinsma IE, van der Schoot CE, van Riel PL, Weinblatt ME, Wilson AG, Wolbink GJ, Wordsworth BP; YEAR Consortium, Wijmenga C, Karlson EW, Toes RE, de Vries N, Begovich AB, Worthington J, Siminovitch KA, Gregersen PK, Klareskog L, Plenge RM. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet. 2010 Jun;42(6):508-14. doi: 10.1038/ng.582. Epub 2010 May 9. PMID: 20453842; PMCID: PMC4243840.
  27. Korman BD, Kastner DL, Gregersen PK, Remmers EF. STAT4: genetics, mechanisms, and implications for autoimmunity. Curr Allergy Asthma Rep. 2008 Sep;8(5):398-403. doi: 10.1007/s11882-008-0077-8. PMID: 18682104; PMCID: PMC2562257.
  28. Lu Y, Zhu Y, Peng J, Wang X, Wang F, Sun Z. STAT4 genetic polymorphisms association with spontaneous clearance of hepatitis B virus infection. Immunol Res. 2015 Jun;62(2):146-52. doi: 10.1007/s12026-015-8645-1. PMID: 25829184.
  29. Liao Y, Cai B, Li Y, Chen J, Ying B, Tao C, Zhao M, Ba Z, Zhang Z, Wang L. Association of HLA-DP/DQ, STAT4 and IL-28B variants with HBV viral clearance in Tibetans and Uygurs in China. Liver Int. 2015 Mar;35(3):886-96. doi: 10.1111/liv.12643. Epub 2014 Aug 5. PMID: 25041342.
  30. Liao Y, Cai B, Li Y, Chen J, Ying B, Tao C, Zhao M, Ba Z, Zhang Z, Wang L. Association of HLA-DP/DQ, STAT4 and IL-28B variants with HBV viral clearance in Tibetans and Uygurs in China. Liver Int. 2015 Mar;35(3):886-96. doi: 10.1111/liv.12643. Epub 2014 Aug 5. PMID: 25041342.
  31. Lamana A, López-Santalla M, Castillo-González R, Ortiz AM, Martín J, García-Vicuña R, González-Álvaro I. The Minor Allele of rs7574865 in the STAT4 Gene Is Associated with Increased mRNA and Protein Expression. PLoS One. 2015 Nov 16;10(11):e0142683. doi: 10.1371/journal.pone.0142683. PMID: 26569609; PMCID: PMC4646635.
  32. Abelson AK, Delgado-Vega AM, Kozyrev SV, Sánchez E, Velázquez-Cruz R, Eriksson N, Wojcik J, Linga Reddy MV, Lima G, D’Alfonso S, Migliaresi S, Baca V, Orozco L, Witte T, Ortego-Centeno N; AADEA group, Abderrahim H, Pons-Estel BA, Gutiérrez C, Suárez A, González-Escribano MF, Martin J, Alarcón-Riquelme ME. STAT4 associates with systemic lupus erythematosus through two independent effects that correlate with gene expression and act additively with IRF5 to increase risk. Ann Rheum Dis. 2009 Nov;68(11):1746-53. doi: 10.1136/ard.2008.097642. Epub 2008 Nov 19. PMID: 19019891; PMCID: PMC3878433.
  33. Morinobu A, Gadina M, Strober W, Visconti R, Fornace A, Montagna C, Feldman GM, Nishikomori R, O’Shea JJ. STAT4 serine phosphorylation is critical for IL-12-induced IFN-gamma production but not for cell proliferation. Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12281-6. doi: 10.1073/pnas.182618999. Epub 2002 Sep 4. PMID: 12213961; PMCID: PMC129436.

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