Gene Polymorphisms of 22 Cytokines in Macedonian Children with Hyperimmunoglobulinemia E

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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.


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Hristomanova Mitkovska, S., Trajkov, D., Mihajlovikj, J., & Spiroski, M. (2015). Gene Polymorphisms of 22 Cytokines in Macedonian Children with Hyperimmunoglobulinemia E. South East European Journal of Immunology (SEEJIM), 1(1), 1–8.
Author Biography

Slavica Hristomanova Mitkovska, Institute of Immunobiology and Human Genetics, Medical Faculty, St. Cyril and Methodius University of Skopje, Skopje


Slavica Hristomanova Mitkovska, MD, was born in Skopje in 1978. Since February 2005 she is employed at the Institute of Immunobiology and Human Genetics, Institutes, Faculty of Medicine, Skopje. She has graduated in 2004 at the SsCyrilandMethodius, Faculty of Medicine, Skopje, Macedonia. Her current activities at the Institute of Immunobiology and Human Genetics include educational activities involving practical work and educational seminars with medical students, in vitro allergy testing (determination of concentration of specific IgE antibodies), autoantibodies and tumor markers investigation, functional tests of phagocytosis, DNA isolation and subsequent genotyping of different genetic polymorphisms (cytokines, HLA, KIR) using methods as PCR, Reverse Line Strip Typing (RLS), Sequence Specific Priming (SSP). During education she has attended international seminars, workshops and congresses. She speaks English and German fluently and Russian passive.





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