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Effect of FOXP3 gene variants on the immune-active HBV and inactive HBV phases

Year 2021, , 1485 - 1492, 30.12.2021
https://doi.org/10.17826/cumj.978353

Abstract

Purpose: FOXP3 gene rs2232365 A/G and the rs3761548 A/C polymorphisms were associated with immune system-related diseases such as Hepatitis B virus (HBV) infection. The function of Treg cells which act as immune-suppressors in the control of HBV-related liver inflammation may be affected by these polymorphisms. The aim of the present study was to evaluate the association between these polymorphisms with HBV infection phases.
Materials and Methods: The current study examined the FOXP3 gene polymorphisms in 116 patients with immune-active hepatitis B phase and in 116 individuals with inactive hepatitis B phase by a real-time polymerase chain reaction (RT-PCR).
Results: In females, the A allele and AA genotype of rs2232365 polymorphism was not statistically significant although it increased 1.28- and 1.67-fold immune-active HBV risk. Although the G allele of rs2232365 polymorphism increased 1.69-fold immune active HBV risk, it was not statistically significant in males, either. Likewise, the rs3761548 polymorphism could not reach a statistically significant value in males and females, either.
Conclusion: This research is to demonstrate the relation between phases of HBV infection and polymorphisms of the FOXP3 gene in the Turkish population. The results of this study showed that there is no effect of these polymorphisms on the immune-active phase of HBV, even though it increased immune-active HBV.

Supporting Institution

There were no funding sources supporting the work.

Project Number

None

Thanks

The author would like to thank all patients who participated in this study and Hikmet Akkız for general support.

References

  • 1. Png E, Thalamuthu A, Ong RT, Snippe H, Boland GJ, Seielstad M. A genome-wide association study of hepatitis B vaccine response in an Indonesian population reveals multiple independent risk variants in the HLA region. Hum Mol Genet 2011; 20: 3893-8.
  • 2. Croagh CM, Lubel JS. Natural history of chronic hepatitis B: phases in a complex relationship. World J Gastroenterol. 2014; 20: 10395–404.
  • 3. Sharifi Z. Natural history of chronic hepatitis B virus infection based on laboratory testing. Iran J Public Health. 2014; 43: 990–3.
  • 4. Aspinall EJ, Hawkins G, Fraser A, Hutchinson SJ, Goldberg D. Hepatitis B prevention, diagnosis, treatment and care: a review. Occup Med. 2011; 61: 531–40.
  • 5. Hu L, Zhai X, Liu J, Chu M, Pan S, Jiang J et al. Genetic variants in human leukocyte antigen/DP-DQ influence both hepatitis B virus clearance and hepatocellular carcinoma development. Hepatology 2012; 55: 1426-31. 6. Wong DK, Watanabe T, Tanaka Y, Seto WK, Lee CK, Fung J et al. Role of HLA-DP polymorphisms on chronicity and disease activity of hepatitis B infection in Southern Chinese. PLoS One 2013; 8: e66920.
  • 7. Stoop JN, van der Molen RG, Baan CC, van der Laan LJ, Kuipers EJ, Kusters JG et al. Regulatory T cells contribute to the impaired immune response in patients with chronic hepatitis B virus infection. Hepatology. 2005; 41: 771-778.
  • 8. Pereira LMS, Gomes STM, Ishak R, Vallinoto ACR. Regulatory T Cell and Forkhead Box Protein 3 as Modulators of Immune Homeostasis. Front Immunol. 2017; 8: 605. doi:10.3389/fimmu.2017.00605.
  • 9. Kryczek I, Liu R, Wang G, Wu K, Shu X, Szeliga W et al. FOXP3 defines regulatory T cells in human tumor and autoimmune disease. Cancer Res. 2009; 69(9): 3995-4000. doi: 10.1158/0008-5472.CAN-08-3804.
  • 10. Lord JD. Promises and Paradoxes of Regulatory T Cells in Inflammatory Bowel Disease. World J Gastroenterol. 2015; 21(40): 11236-45.
  • 11. Jafarzadeh A, Jamali M, Mahdavi R, Ebrahimi HA, Hajghani H, Khosravimashizi A et al. Circulating levels of interleukin-35 in patients with multiple sclerosis: evaluation of the influences of FOXP3 gene polymorphism and treatment program. Journal of Molecular Neuroscience. 2015; 55(4): 891-7. doi: 10.1007/s12031-014-0443-z.
  • 12. Nie H, Zheng Y, Li R, Guo TB, He D, Fang L et al. Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-alpha in rheumatoid arthritis. Nat Med. 2013; 19: 322-328. doi: 10.1038/nm.3085.
  • 13. Song P, Wang XW, Li HX, Li K, Liu L, Wei C et al. Association between FOXP3 polymorphisms and vitiligo in a Han Chinese population. Br J Dermatol. 2013; 169(3): 571-8. doi: 10.1111/bjd.12377.
  • 14. Xia SL, Ying SJ, Lin QR, Wang XQ, Hong WJ, Lin ZJ et al. Association of Ulcerative Colitis with FOXP3 Gene Polymorphisms and Its Colonic Expression in Chinese Patients. Gastroenterol Res Pract. 2019; 2019: 4052168. doi: 10.1155/2019/4052168.
  • 15. Akgöllü E. Evaluation of Forkhead Box P3 gene polymorphisms in chronic HBV infection. J Gene Med. 2020; 22(6): e3172. doi: 10.1002/jgm.3172.
  • 16. Hilbrands R, Howie D, Cobbold S, Waldmann H. Regulatory T cells and transplantation tolerance. Immunotherapy 2013; 5(7): 717-31. doi: 10.2217/imt.13.69.
  • 17. Safari MR, Ghafouri-Fard S, Noroozi R, Sayad A, Omrani MD, Komaki A et al. FOXP3 gene variations and susceptibility to autism: A case-control study. Gene. 2017; 596: 119-122. doi: 10.1016/j.gene.2016.10.019.
  • 18. Terrault NA, Lok ASF, Mcmahon BJ, Chang KM, Hwang JP, Jonas MM et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018; 67: 1560–99.
  • 19. Pereira LMS, Amoras EDSG, da Silva Conde SRS, Demachki S, Monteiro JC, Martins-Feitosa RN et al. The - 3279C> A and - 924A> G polymorphisms in the FOXP3 Gene Are Associated with Viral Load and Liver Enzyme Levels in Patients with Chronic Viral Liver Diseases. Front Immunol. 2018; 9: 2014. doi: 10.3389/fimmu.2018.02014. eCollection 2018.
  • 20. Shahera U, Munshi S, Jahan M, Nessa A, Alam S, Tabassum S. IP-10, p53, and Foxp3 expression in hepatocytes of chronic hepatitis B patients with cirrhosis and hepatocellular carcinoma. Eur J Hepato-Gastroenterol. 2016; 6: 149-153.
  • 21. Velikova T, Kyurkchiev D, Spassova Z, Karakolev I, Ivanova-Todorova E, Altankova I et al. Alterations in Cytokine Gene Expression Profile in Colon Mucosa of Inflammatory Bowel Disease Patients on Different Therapeutic Regimens. Cytokine. 2017; 92: 12-19. doi: 10.1016/j.cyto.2017.01.008.
  • 22. Ozawa PM, Ariza CB, Losi-Guembarovski R, Guembarovski AL, de Oliveira CE, Banin-Hirata BK et al. Wilms' tumor susceptibility: possible involvement of FOXP3 and CXCL12 genes. Molecular and cellular pediatrics. 2016; 3(1): 36. doi: 10.1186/s40348-016-0064-4.
  • 23. Maul J, Loddenkemper C, Mundt P, Berg E, Giese T, Stallmach A et al. Peripheral and Intestinal Regulatory CD4+ CD25 (high) T Cells in Inflammatory Bowel Disease. Gastroenterology. 2005; 128(7): 1868-78. doi: 10.1053/j.gastro.2005.03.043.
  • 24. Jahan P, Ramachander VR, Maruthi G, Nalini S, Latha KP, Murthy TS. Foxp3 promoter polymorphism (rs3761548) in breast cancer progression: a study from India. Tumour Biology. 2014; 35(4): 3785-91. doi: 10.1007/s13277-013-1501-9.
  • 25. Park O, Grishina I, Leung PS, Gershwin ME, Prindiville T. Analysis of the Foxp3/scurfin gene in Crohn's disease. Annals of the New York Academy of Sciences. 2005; 1051: 218-28. doi: 10.1196/annals.1361.125.
  • 26. Indhumathi S, Rajappa M, Chandrashekar L, Ananthanarayanan PH, Thappa DM, Negi VS. T helper-2 cytokine/regulatory T-cell gene polymorphisms and their relation with risk of psoriasis in a South Indian Tamil cohort. Human Immunology 2017; 78(2): 209-215.
  • 27. Misra MK, Mishra A, Pandey SK, Kapoor R, Sharma RK, Agrawal S. Association of functional genetic variants of transcription factor Forkhead Box P3 and Nuclear Factor-κB with end-stage renal disease and renal allograft outcome. Gene. 2016; 581(1): 57-65. doi: 10.1016/j.gene.2016.01.028.

FOXP3 gen varyantlarının immün-aktif HBV ve inaktif HBV fazları üzerindeki etkisi

Year 2021, , 1485 - 1492, 30.12.2021
https://doi.org/10.17826/cumj.978353

Abstract

Amaç: FOXP3 geni rs2232365 A/G ve rs3761548 A/C polimorfizmleri, Hepatit B virüsü (HBV) enfeksiyonu gibi bağışıklık sistemi ile ilgili hastalıklarla ilişkilendirilmiştir. HBV ile ilişkili karaciğer iltihabının kontrolünde immün baskılayıcı olarak görev yapan Treg hücrelerinin işlevi bu polimorfizmlerden etkilenebilir. Bu çalışmanın amacı, bu polimorfizmlerin HBV enfeksiyon evreleri ile ilişkisini değerlendirmektir.
Gereç ve Yöntem: Bu çalışmada, gerçek zamanlı polimeraz zincir reaksiyonu ile immün aktif hepatit B fazında olan 116 hasta ile inaktif hepatit B fazında olan 116 hastada FOXP3 gen polimorfizmleri incelenmiştir.
Bulgular: Kadınlarda, rs2232365 polimorfizminin A alleli ve AA genotipi, immün aktif HBV riskini 1.28 ve 1.67 kat artırmasına rağmen istatistiksel olarak anlamlı değildi. Erkeklerde ise rs2232365 polimorfizminin G alelinin immün aktif HBV riskini 1.69 kat arttırdığı ancak istatistiksel olarak anlamlı olmadığı bulunmuştur. Aynı şekilde rs3761548 polimorfizmi de erkek ve kadınlarda istatistiksel olarak anlamlı bir değere ulaşamamıştır.
Sonuç: Bu araştırma, Türk popülasyonunda HBV enfeksiyon evreleri ile FOXP3 gen polimorfizmleri arasındaki ilişkiyi gösteren bir çalışmadır. Mevcut çalışmanın sonuçları, bu polimorfizmlerin immün-aktif HBV riskini artırmasına rağmen immün-aktif HBV fazı üzerinde etkisinin olmadığını göstermiştir.

Project Number

None

References

  • 1. Png E, Thalamuthu A, Ong RT, Snippe H, Boland GJ, Seielstad M. A genome-wide association study of hepatitis B vaccine response in an Indonesian population reveals multiple independent risk variants in the HLA region. Hum Mol Genet 2011; 20: 3893-8.
  • 2. Croagh CM, Lubel JS. Natural history of chronic hepatitis B: phases in a complex relationship. World J Gastroenterol. 2014; 20: 10395–404.
  • 3. Sharifi Z. Natural history of chronic hepatitis B virus infection based on laboratory testing. Iran J Public Health. 2014; 43: 990–3.
  • 4. Aspinall EJ, Hawkins G, Fraser A, Hutchinson SJ, Goldberg D. Hepatitis B prevention, diagnosis, treatment and care: a review. Occup Med. 2011; 61: 531–40.
  • 5. Hu L, Zhai X, Liu J, Chu M, Pan S, Jiang J et al. Genetic variants in human leukocyte antigen/DP-DQ influence both hepatitis B virus clearance and hepatocellular carcinoma development. Hepatology 2012; 55: 1426-31. 6. Wong DK, Watanabe T, Tanaka Y, Seto WK, Lee CK, Fung J et al. Role of HLA-DP polymorphisms on chronicity and disease activity of hepatitis B infection in Southern Chinese. PLoS One 2013; 8: e66920.
  • 7. Stoop JN, van der Molen RG, Baan CC, van der Laan LJ, Kuipers EJ, Kusters JG et al. Regulatory T cells contribute to the impaired immune response in patients with chronic hepatitis B virus infection. Hepatology. 2005; 41: 771-778.
  • 8. Pereira LMS, Gomes STM, Ishak R, Vallinoto ACR. Regulatory T Cell and Forkhead Box Protein 3 as Modulators of Immune Homeostasis. Front Immunol. 2017; 8: 605. doi:10.3389/fimmu.2017.00605.
  • 9. Kryczek I, Liu R, Wang G, Wu K, Shu X, Szeliga W et al. FOXP3 defines regulatory T cells in human tumor and autoimmune disease. Cancer Res. 2009; 69(9): 3995-4000. doi: 10.1158/0008-5472.CAN-08-3804.
  • 10. Lord JD. Promises and Paradoxes of Regulatory T Cells in Inflammatory Bowel Disease. World J Gastroenterol. 2015; 21(40): 11236-45.
  • 11. Jafarzadeh A, Jamali M, Mahdavi R, Ebrahimi HA, Hajghani H, Khosravimashizi A et al. Circulating levels of interleukin-35 in patients with multiple sclerosis: evaluation of the influences of FOXP3 gene polymorphism and treatment program. Journal of Molecular Neuroscience. 2015; 55(4): 891-7. doi: 10.1007/s12031-014-0443-z.
  • 12. Nie H, Zheng Y, Li R, Guo TB, He D, Fang L et al. Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-alpha in rheumatoid arthritis. Nat Med. 2013; 19: 322-328. doi: 10.1038/nm.3085.
  • 13. Song P, Wang XW, Li HX, Li K, Liu L, Wei C et al. Association between FOXP3 polymorphisms and vitiligo in a Han Chinese population. Br J Dermatol. 2013; 169(3): 571-8. doi: 10.1111/bjd.12377.
  • 14. Xia SL, Ying SJ, Lin QR, Wang XQ, Hong WJ, Lin ZJ et al. Association of Ulcerative Colitis with FOXP3 Gene Polymorphisms and Its Colonic Expression in Chinese Patients. Gastroenterol Res Pract. 2019; 2019: 4052168. doi: 10.1155/2019/4052168.
  • 15. Akgöllü E. Evaluation of Forkhead Box P3 gene polymorphisms in chronic HBV infection. J Gene Med. 2020; 22(6): e3172. doi: 10.1002/jgm.3172.
  • 16. Hilbrands R, Howie D, Cobbold S, Waldmann H. Regulatory T cells and transplantation tolerance. Immunotherapy 2013; 5(7): 717-31. doi: 10.2217/imt.13.69.
  • 17. Safari MR, Ghafouri-Fard S, Noroozi R, Sayad A, Omrani MD, Komaki A et al. FOXP3 gene variations and susceptibility to autism: A case-control study. Gene. 2017; 596: 119-122. doi: 10.1016/j.gene.2016.10.019.
  • 18. Terrault NA, Lok ASF, Mcmahon BJ, Chang KM, Hwang JP, Jonas MM et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018; 67: 1560–99.
  • 19. Pereira LMS, Amoras EDSG, da Silva Conde SRS, Demachki S, Monteiro JC, Martins-Feitosa RN et al. The - 3279C> A and - 924A> G polymorphisms in the FOXP3 Gene Are Associated with Viral Load and Liver Enzyme Levels in Patients with Chronic Viral Liver Diseases. Front Immunol. 2018; 9: 2014. doi: 10.3389/fimmu.2018.02014. eCollection 2018.
  • 20. Shahera U, Munshi S, Jahan M, Nessa A, Alam S, Tabassum S. IP-10, p53, and Foxp3 expression in hepatocytes of chronic hepatitis B patients with cirrhosis and hepatocellular carcinoma. Eur J Hepato-Gastroenterol. 2016; 6: 149-153.
  • 21. Velikova T, Kyurkchiev D, Spassova Z, Karakolev I, Ivanova-Todorova E, Altankova I et al. Alterations in Cytokine Gene Expression Profile in Colon Mucosa of Inflammatory Bowel Disease Patients on Different Therapeutic Regimens. Cytokine. 2017; 92: 12-19. doi: 10.1016/j.cyto.2017.01.008.
  • 22. Ozawa PM, Ariza CB, Losi-Guembarovski R, Guembarovski AL, de Oliveira CE, Banin-Hirata BK et al. Wilms' tumor susceptibility: possible involvement of FOXP3 and CXCL12 genes. Molecular and cellular pediatrics. 2016; 3(1): 36. doi: 10.1186/s40348-016-0064-4.
  • 23. Maul J, Loddenkemper C, Mundt P, Berg E, Giese T, Stallmach A et al. Peripheral and Intestinal Regulatory CD4+ CD25 (high) T Cells in Inflammatory Bowel Disease. Gastroenterology. 2005; 128(7): 1868-78. doi: 10.1053/j.gastro.2005.03.043.
  • 24. Jahan P, Ramachander VR, Maruthi G, Nalini S, Latha KP, Murthy TS. Foxp3 promoter polymorphism (rs3761548) in breast cancer progression: a study from India. Tumour Biology. 2014; 35(4): 3785-91. doi: 10.1007/s13277-013-1501-9.
  • 25. Park O, Grishina I, Leung PS, Gershwin ME, Prindiville T. Analysis of the Foxp3/scurfin gene in Crohn's disease. Annals of the New York Academy of Sciences. 2005; 1051: 218-28. doi: 10.1196/annals.1361.125.
  • 26. Indhumathi S, Rajappa M, Chandrashekar L, Ananthanarayanan PH, Thappa DM, Negi VS. T helper-2 cytokine/regulatory T-cell gene polymorphisms and their relation with risk of psoriasis in a South Indian Tamil cohort. Human Immunology 2017; 78(2): 209-215.
  • 27. Misra MK, Mishra A, Pandey SK, Kapoor R, Sharma RK, Agrawal S. Association of functional genetic variants of transcription factor Forkhead Box P3 and Nuclear Factor-κB with end-stage renal disease and renal allograft outcome. Gene. 2016; 581(1): 57-65. doi: 10.1016/j.gene.2016.01.028.
There are 26 citations in total.

Details

Primary Language English
Subjects Clinical Sciences
Journal Section Research
Authors

Ersin Akgöllü 0000-0003-3636-401X

Project Number None
Publication Date December 30, 2021
Acceptance Date September 25, 2021
Published in Issue Year 2021

Cite

MLA Akgöllü, Ersin. “Effect of FOXP3 Gene Variants on the Immune-Active HBV and Inactive HBV Phases”. Cukurova Medical Journal, vol. 46, no. 4, 2021, pp. 1485-92, doi:10.17826/cumj.978353.