Top

Published in:

01-04-2018 | Original Article

Influence of genetic polymorphisms of IL23R, STAT3, IL12B, and STAT4 on the risk of aplastic anemia and the effect of immunosuppressive therapy

Authors: Li Zhao, Huanling Zhu, Bing Han, Lixin Wang, Yuming Sun, Xiaojun Lu, Chunyan Huang, Bin Tan, Chunxia Chen, Li Qin

Published in: Annals of Hematology | Issue 4/2018

Abstract

Studies have suggested that IL-23/STAT3 and IL-12/STAT4 signaling pathways associate with aplastic anemia (AA) occurrence. Polymorphisms in pathway-related genes may contribute to AA risk. In the current study, we investigated the association between polymorphisms in genes of IL23R, STAT3, IL12B, and STAT4 and occurrence, severity, and immunosuppressive outcome of AA in the Han population in southwest China. In the current 164 AA cases and 211 controls study, we found T allele and TT genotype of rs7574865 were more frequent in the cases than that in the controls. In the additive model, individual carrying rs7574865 T allele demonstrated a 37% (OR (95% CI) = 1.37 (1.02–1.85), Pper = 0.036) increased AA risk. In the recessive model, carrier with rs7574865 TT genotype showed a 2.08-fold increased AA risk (OR (95% CI) = 2.08 (1.14–3.70), Pper = 0.017). Additionally, we showed that G allele and GG genotype of rs11209032 were more frequent in the 88 non-severe AA cases than that in the 76 severe AA ones. Our study also found G allele and GG genotype of rs11209032, and GG-genotype of rs744166 associated with the immunosuppressive therapy outcome in AA patients. Current study results support that functional STAT4 (rs7574865), IL23R (rs11209032), and STAT3 (rs744166) variants may associate with occurrence, severity, and immunosuppressive outcome of AA in the Han population in southwest China.

Issaragrisil S, Kaufman DW, Anderson T, Chansung K, Leaverton PE, Shapiro S, Young NS (2006) The epidemiology of aplastic anemia in Thailand. Blood 107(4):1299–1307. https://doi.org/10.1182/blood-2005-01-0161 CrossRefPubMedPubMedCentral

Jeong DC, Chung NG, Kang HJ, Koo HH, Kook H, Kim SK, Kim SY, Kim HS, Kim HM, Park KD (2011) Epidemiology and clinical long-term outcome of childhood aplastic anemia in Korea for 15 years: retrospective study of the Korean Society of Pediatric Hematology Oncology (KSPHO). J Pediatr Hematol Oncol 33(3):172–178. https://doi.org/10.1097/MPH.0b013e31820826a8 CrossRefPubMed

Tweddle D, Reid M (1996) Aplastic anaemia in the northern region of England. Acta Paediatr 85(11):1388–1389. https://doi.org/10.1111/j.1651-2227.1996.tb13938.x CrossRefPubMed

Mary J, Baumelou E, Guiguet M (1990) Epidemiology of aplastic anemia in France: a prospective multicentric study. The French Cooperative Group for Epidemiological Study of Aplastic anemia. Blood 75(8):1646–1653PubMed

Morinobu A, Gadina M, Strober W, Visconti R, Fornace A, Montagna C, Feldman GM, Nishikomori R, O'Shea JJ (2002) STAT4 serine phosphorylation is critical for IL-12-induced IFN-γ production but not for cell proliferation. Proc Natl Acad Sci 99(19):12281–12286. https://doi.org/10.1073/pnas.182618999 CrossRefPubMedPubMedCentral

de Bruin AM, Demirel O, Hooibrink B, Brandts CH, Nolte MA (2013) Interferon-gamma impairs proliferation of hematopoietic stem cells in mice. Blood 121(18):3578–3585. https://doi.org/10.1182/blood-2012-05-432906 CrossRefPubMed

de Latour RP, Visconte V, Takaku T, Wu C, Erie AJ, Sarcon AK, Desierto MJ, Scheinberg P, Keyvanfar K, Nunez O (2010) Th17 immune responses contribute to the pathophysiology of aplastic anemia. Blood 116(20):4175–4184. https://doi.org/10.1182/blood-2010-01-266098 CrossRefPubMedPubMedCentral

Gu Y, Hu X, Liu C, Qv X, Xu C (2008) Interleukin (IL)-17 promotes macrophages to produce IL-8, IL-6 and tumour necrosis factor-α in aplastic anaemia. Br J Haematol 142(1):109–114. https://doi.org/10.1111/j.1365-2141.2008.07161.x CrossRefPubMed

Chen Y, CG X, Guo NJ, Huang P, Xiao DJ, Ding BT, Ge LF, Yu Z, Chang YL, Zhou YW (2007) Preliminary study of multivariable model in predicting response to immunosuppressive therapy in patients with aplastic anemia. Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi 28(9):583–586PubMed

10.

Dong H, Li Q, Zhang Y, Tan W, Jiang Z (2013) IL23R gene confers susceptibility to ankylosing spondylitis concomitant with uveitis in a Han Chinese population. PLoS One 8(6):e67505. https://doi.org/10.1371/journal.pone.0067505 CrossRefPubMedPubMedCentral

11.

Eiris N, Gonzalez-Lara L, Santos-Juanes J, Queiro R, Coto E, Coto-Segura P (2014) Genetic variation at IL12B, IL23R and IL23A is associated with psoriasis severity, psoriatic arthritis and type 2 diabetes mellitus. J Dermatol Sci 75(3):167–172. https://doi.org/10.1016/j.jdermsci.2014.05.010 CrossRefPubMed

12.

Wang Z, Xu B, Zhang H, Fan R, Zhou J, Zhong J (2014) Association between STAT3 gene polymorphisms and Crohn’s disease susceptibility: a case-control study in a Chinese Han population. Diagn Pathol 9(1):104. https://doi.org/10.1186/1746-1596-9-104 CrossRefPubMedPubMedCentral

13.

Camitta BM, Thomas ED, Nathan DG, Santos G, Gordon-Smith EC, Gale RP, Rappeport JM, Storb R (1976) Severe aplastic anemia: a prospective study of the effect of early marrow transplantation on acute mortality. Blood 48(1):63–70PubMed

14.

Zhang Z (2007) Di Shen. Science Press, Standard of diagnosis and curative effect of blood diseases

15.

Wang L, Liu W, Jiang W, Lin J, Jiang Y, Li B, Pang D (2012) A miRNA binding site single-nucleotide polymorphism in the 3′-UTR region of the IL23R gene is associated with breast cancer. PLoS One 7(12):e49823. https://doi.org/10.1371/journal.pone.0049823 CrossRefPubMedPubMedCentral

16.

Ge M, Zheng Y, Li X, Shi J, Ge J, Li H, Feng S (2012) The polymorphisms of T cell–specific TBX21 and STAT4 genes may contribute to the susceptibility of Chinese individuals to aplastic anemia. Hum Immunol 73(1):118–121. https://doi.org/10.1016/j.humimm.2011.11.007 CrossRefPubMed

17.

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 (2007) STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med 357(10):977–986. https://doi.org/10.1056/NEJMoa073003 CrossRefPubMedPubMedCentral

18.

Gregersen PK, Behrens TW (2006) Genetics of autoimmune diseases—disorders of immune homeostasis. Nat Rev Genet 7(12):917–928. https://doi.org/10.1038/nrg1944 CrossRefPubMed

19.

Jiang X, Zhou Z, Zhang Y, Yang H, Ren K (2014) An updated meta-analysis of the signal transducer and activator of transcription 4 (STAT4) rs7574865 G/T polymorphism and rheumatoid arthritis risk in an Asian population. Scand J Rheumatol 43(6):477–480. https://doi.org/10.3109/03009742.2014.918174 CrossRefPubMed

20.

Xu L, Dai WQ, Wang F, He L, Zhou YQ, Lu J, Xu XF, Guo CY (2014) Association of STAT4 gene rs7574865 G > T polymorphism with ulcerative colitis risk: evidence from 1532 cases and 3786 controls. Archives of medical science: AMS 10(3):419–424. https://doi.org/10.5114/aoms.2014.43735 CrossRefPubMedPubMedCentral

21.

Yan N, Meng S, Zhou J, Xu J, Muhali FS, Jiang W, Shi L, Shi X, Zhang J (2014) Association between STAT4 gene polymorphisms and autoimmune thyroid diseases in a Chinese population. Int J Mol Sci 15(7):12280–12293. https://doi.org/10.3390/ijms150712280 CrossRefPubMedPubMedCentral

22.

Coffre M, Roumier M, Rybczynska M, Sechet E, Law HK, Gossec L, Dougados M, Bianchi E, Rogge L (2013) Combinatorial control of Th17 and Th1 cell functions by genetic variations in genes associated with the interleukin-23 signaling pathway in spondyloarthritis. Arthritis Rheum 65(6):1510–1521. https://doi.org/10.1002/art.37936 CrossRefPubMed

23.

Qin Yanping, Qinxue(2012) Research progress of IL-23R gene polymorphism and susceptibility to the diseases. Medical Recapitulate 18(16)

24.

Scheinberg P, Nunez O, Weinstein B, Scheinberg P, Biancotto A, CO W, Young NS (2011) Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. N Engl J Med 365(5):430–438. https://doi.org/10.1056/NEJMoa1103975 CrossRefPubMedPubMedCentral

25.

Atta EH, Dias DS, Marra VL, de Azevedo AM (2010) Comparison between horse and rabbit antithymocyte globulin as first-line treatment for patients with severe aplastic anemia: a single-center retrospective study. Ann Hematol 89(9):851–859. https://doi.org/10.1007/s00277-010-0944-y CrossRefPubMed

26.

Scheinberg P, CO W, Nunez O, Young NS (2009) Predicting response to immunosuppressive therapy and survival in severe aplastic anaemia. Br J Haematol 144(2):206–216. https://doi.org/10.1111/j.1365-2141.2008.07450.x CrossRefPubMed

Title: Influence of genetic polymorphisms of IL23R, STAT3, IL12B, and STAT4 on the risk of aplastic anemia and the effect of immunosuppressive therapy
Authors: Li Zhao
Huanling Zhu
Bing Han
Lixin Wang
Yuming Sun
Xiaojun Lu
Chunyan Huang
Bin Tan
Chunxia Chen
Li Qin
Publication date: 01-04-2018
Publisher: Springer Berlin Heidelberg
Published in: Annals of Hematology / Issue 4/2018
Print ISSN: 0939-5555
Electronic ISSN: 1432-0584
DOI: https://doi.org/10.1007/s00277-018-3227-7

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

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

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 4/2018

Progression to polythythemia vera from familial thrombocytosis with germline JAK2 R867Q mutation

Is there a role for the international prognostic index in follicular lymphoma?

Non-severe form of severe fever with thrombocytopenia syndrome (SFTS)

The Deauville criteria cannot differentiate between responding and non-responding non-Hodgkin lymphoma patients

Primary effusion lymphoma-like lymphoma with a T cell phenotype

Low-virulent Babesia venatorum infection masquerading as hemophagocytic syndrome

Keynote webinar | Spotlight on medication adherence

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

At a glance: The STEP trials