_______________________________________________________________________________________________________________________________ SEE J Immunol. 1 ID Design 2012/DOOEL Skopje South East European Journal of Immunology Volume 2015; Article ID 20001, 8 pages http://dx.doi.org/10.3889/seejim.2015.20001 Immunogenetics Gene Polymorphisms of 22 Cytokines in Macedonian Children with Hyperimmunoglobulinemia E Slavica Hristomanova Mitkovska, Dejan Trajkov, Jelena Mihajlovikj, Mirko Spiroski Institute of Immunobiology and Human Genetics, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia Citation: Hristomanova Mitkovska S, Trajkov D, Mihajlovikj J, Spiroski M. Gene Polymorphisms of 22 Cytokines in Macedonian Children with Hyperimmunoglobulinemia E. SEE J Immunol. http://dx.doi.org/10.3889/seejim.2015.20001 Key words: cytokines; Hyperimmunoglobulinemia E; cytokine gene polymorphisms. * Correspondence: Assist. Dr. Slavica Hristomanova Mitkovska. Institute of Immunobiology and Human Genetics, Medical Faculty, St. Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia. E-mail: cacka_h@yahoo.com Received: 14-Nov-2014; Revised: 21-Dec-2014; Accepted: 12-Jan-2015; Published: 23-Jan-2015 Copyright: © 2015 Slavica Hristomanova Mitkovska, Dejan Trajkov, Jelena Mihajlovikj, Mirko Spiroski. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Competing Interests: The author have declared that no competing interests exist. Abstract 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 2 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. Introduction Hyperimmunoglobulinemia E Syndrome (HIES) was described by Davis and Wedgwood in 1966 [1, 2]. Through the years different groups further characterized the syndrome by reporting immunological and clinical features of Hyperimmunoglobulinemia E and established two forms of the Syndrome: a dominant and a recessive form [3–13]. Minegishi et al. in 2007 found that eight out of fifteen unrelated non-familial HIES patients had heterozygous STAT3 mutations, but their parents and siblings did not have the mutant STAT3 alleles, suggesting that these were de novo mutations. Five different mutations were established, all of which were located in the STAT3 DNA-binding domain. In the patients’ peripheral blood cells they found i mpaired responses to cytokines, including IL-6 and IL-10. They also discovered that the DNA-binding ability of STAT3 in these cells was very moderate. All of them demonstrated dominant-negative effects when they were co-expressed with wild-type STAT3. These