Gene Polymorphisms of 22 Cytokines in Macedonian Children with Hyperimmunoglobulinemia E

Slavica Hristomanova Mitkovska, Dejan Trajkov, Jelena Mihajlovikj, Mirko Spiroski


Introduction: For some time it is known that cytokines and their receptors are encoded by highly polymorphic genes. These polymorphisms can be responsible for differences in the production of cytokines between individuals. Large number of the polymorphisms within the regulatory regions of the cytokine genes is in correlation with the production and there are variations among populations.

Aim: The aim of this study was to analyze association between polymorphisms in the IFN-gamma, IL-1alpha, IL-1beta, IL-1R, IL-1RA, IL-2, IL-4, IL-4Ralpha, IL-6, IL-10, IL-12B, TGF-beta1 and TNF-alpha and hyperimmunoglobulinemia E.

Material and Methods: The study included 28 unrelated patients with high IgE levels in serum and the control group consisted of 301 unrelated healthy individuals. Cytokine genotyping was performed with PCR-SSP method. We analyzed the allele frequencies, genotypes, haplotypes and diplotypes of the cytokine genes. The differences were analyzed using χ2 test, odds ratio and Confidence Interval.

Results: Susceptible association with hyperimmunoglobulinemia E was found for four different cytokine alleles (IL-4 -33/T, TGF-beta1 cdn25/C, IL-1 alpha -889/T andTNF-alpha -238/A), ten different genotypes (IL4 -1098/G:G, IL4 -33/T:T, IL-1 alpha -889/C :T, IFN gamma utr5644/A:T, TGF-beta1 cdn25/C:G, IL-6  -174/G:G, IL-1 beta -511/C:T, IL-10 -1082/A:G, TNF alpha -238/A:G andIL-1 beta +3962/C:T) and five different combinations of haplotypes (IL-4/GTT, IL-4/TCT, IL-6/TCC, TNF-alpha/GA and TGF-beta1/CC). Protective association with hyperimmunoglobulinemia E was found in four cytokine alleles (IL-4 -33/C, TGF-beta1 cdn25/G, IL-1 alpha -889/C andTNF-alpha -238/G), three genotypes (IL-10 -1082/A:A, IL-1 alpha -889/C:C i IL4 -33/C:C) and for only one haplotype (IL-4/GCC).

Conclusion: Several susceptible and protective associations between cytokine gene polymorphisms and hyperimmunoglobulinemia E were found. However, it is still speculative weather these polymorphisms contribute to susceptibility/protection from hyperimmunoglobulinemia E or they might be in significant linkage disequilibrium with some unknown gene responsible for the disease. It is also possible that different ethnical groups show different association with cytokine polymorphisms.


cytokines; Hyperimmunoglobulinemia E; cytokine gene polymorphisms

Full Text:



Davis SD, Schaller J, Wedgwood RJ. Job’s syndrome: recurrent, “cold,” staphylococcal abscesses. Lancet 1966;1:1013-5.

Buckley RH, Wray BB, Belmaker EZ. Extreme hyperimmunoglobulinemia E and undue susceptibility to infection. Pediatrics 1972;49:59-70.

Hill, H. R., Quie, P. G. Raised serum-IgE levels and defective neutrophil chemotaxis in three children with eczema and recurrent bacterial infections. Lancet 1974; 303: 183-187.

Van Scoy RE, Hill HR, Ritts RE, Quie PG. Familial neutrophil chemotaxis defect, recurrent bacterial infections, mucocutaneous candidiasis, and hyperimmunoglobulinemia E. Ann Intern Med. 1975 Jun;82(6):766-71.

Brestel EP, Klingberg WG, Veltri RW, Dorn JS. Osteogenesis imperfecta tarda in a child with hyper-IgE syndrome. Am J Dis Child. 1982 Sep;136(9):774-6.

Robinson MF, McGregor R, Collins R, Cheung K. Combined neutrophil and T-cell deficiency: initial report of a kindred with features of the hyper-IgE syndrome and chronic granulomatous disease.Am J Med. 1982 Jul;73(1):63-70.

Donabedian H, Gallin JI. Mononuclear cells from patients with the hyperimmunoglobulin E-recurrent infection syndrome produce an inhibitor of leukocyte chemotaxis.J Clin Invest. 1982 May;69(5):1155-63.

Hoger PH, Boltshauser E, Hitzig WH. Craniosynostosis in hyper-IgE syndrome. European Journal of Pediatrics. 1985;144:414 – 417

Donabedian H, Gallin JI. The hyperimmunoglobulin E recurrent-infection (Job's) syndrome. A review of the NIH experience and the literature.Medicine (Baltimore). 1983 Jul;62(4):195-208.

Dreskin SC, Goldsmith PK, Gallin JI. Immunoglobulins in the hyperimmunoglobulin E and recurrent infection (Job's) syndrome. Deficiency of anti-Staphylococcus aureus immunoglobulin A.J Clin Invest. 1985 Jan;75(1):26-34.

Lui RC, Inculet RI. Job's syndrome: a rare cause of recurrent lung abscess in childhood. Ann Thorac Surg. 1990 Dec;50(6):992-4.

Borges WG, Hensley T, Carey JC, Petrak BA, Hill HR. The face of Job. J Pediatr. 1998 Aug;133(2):303-5.

Grimbacher B, Holland SM, Gallin JI, Greenberg F, Hill SC, Malech HL, Miller JA, O'Connell AC, Puck JM. Hyper-IgE syndrome with recurrent infections--an autosomal dominant multisystem disorder. N Engl J Med. 1999 Mar 4;340(9):692-702.

Minegishi Y, Saito M, Tsuchiya S, Tsuge I, Takada H, Hara T, Kawamura N, Ariga T, Pasic S, Stojkovic O, Metin A, Karasuyama H. Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature. 2007 Aug 30;448(7157):1058-62.

Holland SM, DeLeo FR, Elloumi HZ, Hsu AP, Uzel G, Brodsky N, Freeman AF, Demidowich A, Davis J, Turner ML, Anderson VL, Darnell DN, Welch PA, Kuhns DB, Frucht DM, Malech HL, Gallin JI, Kobayashi SD, Whitney AR, Voyich JM, Musser JM, Woellner C, Schäffer AA, Puck JM, Grimbacher B. STAT3 mutations in the hyper-IgE syndrome. N Engl J Med. 2007 Oct 18;357(16):1608-19.

Zhang, Q., Davis, J. C., Lamborn, I. T., Freeman, A. F., Jing, H., Favreau, A. J., Matthews, H. F., Davis, J., Turner, M. L., Uzel, G., Holland, S. M., Su, H. C. Combined immunodeficiency associated with DOCK8 mutations. New Eng. J. Med. 361: 2046-2055, 2009.

Alsum Z, Hawwari A, Alsmadi O, Al-Hissi S, Borrero E, Abu-Staiteh A, Khalak HG, Wakil S, Eldali AM, Arnaout R, Al-Ghonaium A, Al-Muhsen S, Al-Dhekri H, Al-Saud B, Al-Mousa H.Clinical, immunological and molecular characterization of DOCK8 and DOCK8-like deficient patients: single center experience of twenty five patients. J Clin Immunol. 2013 Jan;33(1):55-67.

Lan Q, Zheng T, Rothman N, Zhang Y, Wang SS, Shen M, Berndt SI, Zahm SH, Holford TR, Leaderer B, Yeager M, Welch R, Boyle P, Zhang B, Zou K, Zhu Y, Chanock S. Cytokine polymorphisms in the Th1/Th2 pathway and susceptibility to non-Hodgkin lymphoma. Blood 2006 May 15;107(10):4101-8.

Nieters A, Linсеiсеn J, Becker N. Association of polymorphisms in Th1, Th2 cytokine genes with hay fever and atopy in a subsample of EPIC-Heidelberg. Clin Exp Allergy 2004 Mar;34(3):346-53.

Muller B, Gimsa U, Mitchison NA, Radbruch A, Sieper J, Yin Z. Modulating the Th1/Th2 balance in inflammatory arthritis. Springer Сеmin Immunopathol 1998;20(1-2):181-96.

Towner P. Purification of DNA. Essential molecular biology. In: Brown TA, editor. Oxford University Press, Oxford 1995; 47-54.

Spiroski M, Arsov T, Petlichkovski A, Strezova A, Trajkov D, Efinska-Mladenovska O, et al. Case Study: Macedonian human DNA bank (hDNAMKD) as a source for public health Genetics. In: Georgieva L, Burazeri G, Editors. Health determinants in the scope of new public health. Sofia: Hans Jacobs Company, 2005: 33-44.

Tseng LH, Chen PJ, Lin MT, Singleton K, Martin EG, Yen AH, Martin PJ, Hansen JA. Simultaneous genotyping of single nucleotide polymorphisms in the IL-1 gene complex by multiplex polymerase chain reaction-restriction fragment length polymorphism. J Immunol Methods. 2002;267(2):151-6.

Lancaster A, Nelson MP, Meyer D, Thomson G, Single RM. PyPop: a software framework for population genomics: analyzing large-scale multi-locus genotype data. Pac Symp Biocomput. 2003:514-25.

Lancaster AK, Single RM, Solberg OD, Nelson MP, Thomson G. PyPop update--a software pipeline for largescale multilocus population genomics. Tissue Antigens. 2007; 69 (Suppl 1):192-7.

Single RM, Meyer D, Mack SJ, Lancaster A, Erlich HA, Thomson G. 14th International HLA and Immunogenetics Workshop: report of progress in methodology, data collection, and analyses. Tissue Antigens. 2007;69(Suppl 1):185-7.

Schneider S, Roessli D, Excoffier L. Arlequin version 2.000: software for population genetics data analysis. Geneva (Switzerland): Genetics and Biometry Laboratory, University of Geneva, 2000.

Trajkov D, Trajchevska M, Arsov T, Petlichkovski A, Strezova A, Efinska-Mladenovska O, Sandevski A, Spiroski M. Association of 22 cytokine gene polyphorphisms with tuberculosis in Macedonians. Indian J Tuberc 2009; 56:117-131.

Spiroska V, Kedev S, Antov S, Trajkov D, Petlichkovski A, Strezova A, Efinska-Mladenovska O, Sibinovska O, Hristomanova S, Djulejic E, Petrov J, Spiroski M. Association of 22 cytokine gene polymorphisms with dilated cardiomyopathy in Macedonian patients. Kardiol Pol 2009; 67:1237-1247.

Trajkov D, Mishevska-Perchinkova S, Karadzova-Stojanoska A, Petlichkovski A, Strezova A, Spiroski M. Association of 22 cytokine gene polymorphisms with rheumatoid arthritis in population of ethnic Macedonians. Clin Rheumatol (2009) 28:1291–1300. DOI 10.1007/s10067-009-1238-4

Trajkov D, Mirkovska-Stojkovikj J, Arsov T, Petlichkovski A, Strezova A, Efinska-Mladenovska O, Sandevska E, Gogusev J, Spiroski M. Association of Cytokine Gene Polymorphisms with Bronchial Asthma in Macedonians. Iran J Allergy Asthma Immunol 2008; 7(3): 143-156.

Trajkov D, Mirkovska-Stojkovikj J, Petlichkovski A, Strezova A, Efinska-Mladenovska O, Sandevska E, Sibinovska O, Hristomanova S, Djulejic E, Petrov J, Gogusev J, Spiroski M. Association of Cytokine Gene Polymorphisms with Chronic Obstructive Pulmonary Disease in Macedonians. Iran J Allergy Asthma Immunol 2009; 8 (1): 31-42.

Casanova JL, Abel L. Genetic dissection of immunity to mycobacteria: the human model. Annu Rev Immunol 2002; 20: 581-620.

Schluger NW, Rom WN. The host immune response to tuberculosis. Am J Respir Crit Care Med 1998;157: 679-91.

Seegers D, Zwiers A, Strober W, Pena AS, Bouma G. A Taq1 polymorphiasm in the 3’UTR of the IL-12 p40 gene correlates with increased IL-12 secretion. Genes Immun 2002;3: 419-23.

Stanilova S, Miteva L. Taq-I polymorphism in 3UTR of the IL12B and association with IL-12p40 production from human PBMC. Genes Immun 2005;6: 364-6.

Tso HW, Lau YL, Tam CM, Wong HS, Chiang AKS. Associations between IL12B polymorphisms and tuberculosis in the Hong Kong Chinese population. J Infect Dis 2004;190: 913–9.

Sahiratmadja E, Baak-Pablo R, de Visser AW, Alisjahbana B, Adnan I, van Crevel R, Marzuki S, van Dissel JT, Ottenhoff THM, van de Vosse E. Association of polymorphisms in IL-12/IFN-gamma pathway genes with susceptibility to pulmonary tuberculosis in Indonesia. Tuberculosis 2007;87: 303-311.

Dorman SE, Holland SM. Interferon-g and interleukin-12 pathway defects and human disease. Cytokine Growth Factor Rev 2000;11:321–33.

Cooke GS, Campbell SJ, Sillah J, Gustafson P, Bah B, Sirugo G, Bennett S, McAdam KPWJ, Sow O, Lienhardt C, Hill AVS. Polymorphism within the Interferon-/Receptor complex is associated with pulmonary tuberculosis. Am J Respir Crit Care Med 2006;174: 339–343.

Blobe GC, Schiemann WP, Lodish HF. Role of transforming growth factor beta in human disease. N Engl J Med 2000;342: 1350–1358.

Munger JS, Huang X, Kawakatsu H, Griffiths MJ, Dalton SL, Wu J, Pittet JF, Kaminski N, Garat C, Matthay MA, Rifkin DB, Sheppard D. The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 1999;96: 319–328.

Eickelberg O, Kohler E, Reichenberger F,Bertschin S, Woodtli T, Erne P, Perruchoud AP, Roth M. Extracellular matrix deposition by primary human lung fibroblasts in response to TGF-beta 1 and TGF-beta 3. Am J Physiol 1999:276: L814-24.

Fang KC, Wolters PJ, Steinhoff M, Bidgol A, Blount JL, Caughey GH. Mast cell expresion of gelatinases A and B is regulated by kit ligand and TGF-beta. J Immunol 1999;162: 5528-35.

Garcia I, Miyazaki Y, Marchal G, Lesslauer W, Vassalli P. High sensitivity of transgenic mice expressing soluble TNFR1 fusion protein to mycobacterial infections: synergistic action of TNF and IFN-gamma in the differentiation of protective granulomas. Eur J Immunol 1997;27: 3182 –90.

Emala CW, Kuhl J, Hungerford CL, Hirshman CA. TNF-alpha inhibits isoproterenol stimulated adenylyl cyclase activity in cultured airway smooth muscle cells. Am J Physiol 1997;272: L644-L650.

Rook GA, Taverne J, Leveton C, Steele J. The role of gamma-interferon, vitamin D3 metabolites and tumour necrosis factor in the pathogenesis of tuberculosis. Immunology 1987;62(2):229–34.

Bekker L-G, Moreira AL, Bergtold A, Freeman S, Ryffel B, Kaplan G. Immunopathologic effects of tumor necrosis factor alpha in murine mycobacterial infection are dose dependent. Infect Immun 2000;68(1): 6954–61.

Selvaraj P, Sriram U, Mathan Kurian S, Reetha AM, Narayanan PR. Tumor necrosis factor alpha (-238 and –308) and beta gene polymorphisms in pulmonary tuberculosis: haplotype analysis with HLA-A, B and DR genes. Tuberculosis 2001; 81 (5-6): 335-41.

Seder RA, Paul WE. Acquisition of lymphokine-producting phenotype by CD4+ T cell. Annu Rev Immunol 1994;12:635-73.

Dabbagh K, Takeyama K, Lee HM, Ufki IF, Lausier JA, Nadel JA. IL-4 induces mucin gene expression and goblet cell metaplasia in vitro and in vivo. J Immunol 1999;162: 6233-37.

Saunders BM, Frank AA, Orme IM, Cooper AM. Interleukin-6 induces early gamma interferon production in the infected lung but is not required for generation of specific immunity to Mycobacterium tuberculosis infection. Infect Immun 2000;68 (6): 3322–6.

Ladel CH, Blum C, Dreher A, Reifenberg K, Kopf M, Kaufmann SH. Lethal tuberculosis in interleukin-6-deficient mutant mice. Infect Immun 1997;65(11): 4843–9.

Howard M, O'Garra A, Ishida H, de Waal Malefyt R, de Vries J. Biological properties of interleukin-10. J Clin Immunol 1992;12: 239-47.

de Waal Malefyt R, Abram J, Benett B, Figdor CG, de Vries J. Interleukin 10 (IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med 1991;174: 1209-20.

Choi Y, Kim JJ. B cells activated in the presence of Th1-cytokines inhibit osteoclastogenesis. Exp Mol Med 2003;35: 385-92

Redpath S, Ghazal P,Gascoigne NR. Hijacking, exploitation of IL-10 by intracellular pathogens. Trends Microbiol 2001;9: 86-92

Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 2001;19: 683–765.

Zhang Y, Zhang J, Tian C, Xiao Y, He C, Li X, Bogati A, Huang J, Fan H. The -308 G/A polymorphism in TNF-α gene is associated with asthma risk: an update by meta-analysis. J Clin Immunol. 2011;31(2):174-85.

Lee YH, Bae SC, Choi SJ, Ji JD, Song GG. Associations between interleukin-10 polymorphisms and susceptibility to rheumatoid arthritis: a meta-analysis. Mol Biol Rep. 2012;39(1):81-7.

Wang Q, Zhan P, Qiu LX, Qian Q, Yu LK. TNF-308 gene polymorphism and tuberculosis susceptibility: a meta-analysis involving 18 studies. Mol Biol Rep. 2012;39(4):3393-400.


Article Metrics

Metrics Loading ...

Metrics powered by PLOS ALM


  • There are currently no refbacks.

Copyright (c) 2015 Slavica Hristomanova Mitkovska, Dejan Trajkov, Jelena Mihajlovikj, Mirko Spiroski


Published by: Id Design 2012/DOOEL Skopje, Republic of Macedonia