Articles
 

Gene Polymorphisms of 22 Cytokines in Macedonian Children with Atopic Dermatitis

Abstract

Atopic dermatitis (AD) is a common chronically relapsing skin disease associated with abnormal cytokine production, and activation of T-helper 2 cells. The aim if this study was to determine whether cytokine gene polymorphisms might influence the development of AD. Single nucleotide polymorphisms in the genes for I-L1alpha, IL-1beta, IL-1R, IL-2, IL-4, IL-6, IL-10, IL-12, TGF beta, TNF and IFNgamma were investigated by PCR and sequence specific primers in Macedonian patients with AD (67 children, age of 6 months to 5 years) and  301 normal  unrelated  individuals. Susceptible cytokine polymorphisms  for  AD  for eleven genotypes (IL-4 -33/T:T  IL-4 -1098/G:G, TGFbeta cdn25C:G,    IL-4 -1098/T:T,  IL-1alpha -889/C:T, IL-2 +166/T:T, IL-1beta -511/C:T, IL-12 -1188/C:T, IL-10 -1082/A:G, IL-1beta +3962/C:T, IFNgamma +874/A:T), five diplotypes, six haplotypes, and for alleles were found. Protective cytokine polymorphisms for AD for seven cytokine genotypes (IL-4 -1098/G:T,  TGFbeta  cdn25/G:G,  IL-4  -33/C:C,  IL-1alpha -889/C:C,  IFNgamma  +874/A:A, IL-10 -1082/A:A,   IL-1beta -511/C:C), one cytokine diplotypes, two cytokine haplotypes, and four cytokine alleles were also found. We concluded that several cytokine polymorphisms are protective, or susceptible associated with AD in population of Macedonians.

1. Novak N, Bieber T, Leung DY. Immune mechanisms leading to atopic dermatitis. J Allergy Clin Immunol 2003; 112(6 Suppl):128-39.
2. Maintz L, Novak N. Getting more and more complex: the pathophysiology of atopic eczema. Eur J Dermatol 2007;17(4):267-83.
3. Warlé MC, Farhan A, Metselaar HJ, Hop WC, Perrey C, Zondervan PE, et al. Are cytokine gene polymorphisms related to in vitro cytokine production profiles? Liver Transpl 2003; 9(2):170-81.
4. Hoffmann SC, Stanley EM, Cox ED, DiMercurio BS, Koziol DE, Harlan DM, et al. Ethnicity greatly influences cytokine gene polymorphism distribution. Am J Transplant 2002; 2(6):560-7.
5. Barnes KC. An update on the genetics of atopic dermatitis: scratching the surface in 2009. J Allergy ClinImmunol 2010; 125(1):16-29.
6. Trajkov D, Arsov T, Petlichkovski A, Strezova A, Efinska-Mladenovska O, Spiroski M. Cytokine gene polymorphisms in population of ethnic Macedonians. Croat Med J 2005; 46(4):685-92.
7. Towner P. Purification of DNA. In: Brown TA. Essential molecular biology. UK, Oxford: Oxford University Press 1995; 47-54.
8. 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.
9. Tseng LH, Chen PJ, Lin MT, Singleton K, Martin EG, Yen AH, et al. 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.
10. 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.
11. 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.
12. 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(Suppl1):185-7.
13. 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.
14. Nicklin MJ, Weith A, Duff GW. A physical map of theregion encompassing the human interleukin-1 alpha, interleukin-1 beta, and interleukin-1 receptor antagonist genes. Genomics 1994; 19(2):382-4.
15. Hoffjan S, Ostrovnaja I, Nicolae D, Newman DL, Nicolae R, Gangnon R, et al. Genetic variation in immunoregulatory pathways and atopic phenotypes in infancy. J Allergy Clin Immunol 2004; 113(3):511-8.
16. Reich K, Westphal G, König IR, Mössner R, Schupp P,Gutgesell C, et al. Cytokine gene polymorphisms in atopic dermatitis. Br J Dermatol 2003; 148(6):1237-41.
17. Rafatpanah H, Bennett E, Pravica V, McCoy MJ, David TJ, Hutchinson IV, et al. Association between novel GM- CSF gene polymorphisms and the frequency and severity of atopic dermatitis. J Allergy Clin Immunol 2003;112(3):593-8.
18. de Jongh CM, John SM, Bruynzeel DP, Calkoen F, van Dijk FJ, Khrenova L, et al. Cytokine gene polymorphisms and susceptibility to chronic irritant contact dermatitis. Contact Dermatitis 2008; 58(5):269-77.
19. Nomura I, Goleva E, Howell MD, Hamid QA, Ong PY,Hall CF, et al. Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes. J Immunol 2003; 171(6):3262-9.
20. Chang YT, Lee WR, Yu CW, Liu HN, Lin MW, Huang CH, et al. No association of cytokine gene polymorphisms in Chinese patients with atopic dermatitis. Clin Exp Dermatol 2006; 31(3):419-23.
21. Takahashi N, Akahoshi M, Matsuda A, Ebe K, Inomata N, Obara K, et al. Association of the IL12RB1 promoter polymorphisms with increased risk of atopic dermatitis and other allergic phenotypes. Hum Mol Genet 2005; 14(21):3149-59.
22. Namkung JH, Lee JE, Kim E, Kim S, Kim S, Shin ES, et al. Association of single nucleotide polymorphisms in the IL-12 (IL-12A and B) and IL-12 receptor (IL-12Rbeta1 and beta2) genes and gene-gene interactions with atopic dermatitis in Koreans. J Dermatol Sci 2010; 57(3):199-206.
23. Tsunemi Y, Saeki H, Nakamura K, Sekiya T, Hirai K, Fujita H, et al. Interleukin-12 p40 gene (IL12B) 3'- untranslated region polymorphism is associated with susceptibility to atopic dermatitis and psoriasis vulgaris. Dermatol Sci 2002; 30(2):161-6.
24. Trajkov D, Mirkovska-Stojkovikj J, Arsov T,Petlichkovski A, Strezova A, Efinska-Mladenovska O, et al. Association of cytokine gene polymorphisms with bronchial asthma in Macedonians. Iran J Allergy Asthma Immunol 2008; 7(3):143-56.
25. Hussein YM, Ahmad AS, Ibrahem MM, El Tarhouny SA, Shalaby SM, Elshal AS, et al. Interferon gamma gene polymorphism as a biochemical marker in Egyptian atopic patients. J Investig Allergol Clin Immunol 2009;19(4):292-8.
26. Pravica V, Perrey C, Stevens A, Lee JH, Hutchinson IV.A single nucleotide polymorphism in the first intron of the human IFN-gamma gene: absolute correlation with a polymorphic CA microsatellite marker of high IFN-gamma production. Hum Immunol 2000; 61(9):863- 6.
27. Ohly A. The common variant / common disease hypothesis on the example of the allergy [doctoral thesis]. Giessen: Justus- Liebig University; 2006.
28. Verhagen J, Akdis M, Traidl-Hoffmann C, Schmid- Grendelmeier P, Hijnen D, Knol EF, et al. Absence of T- regulatory cell expression and function in atopic dermatitis skin. J Allergy Clin Immunol 2006;117(1):176-83.
29. Trautmann A, Akdis M, Kleemann D, Altznauer F, Simon HU, Graeve T, et al. T cell-mediated Fas-induced keratinocyte apoptosis plays a key pathogenetic role in eczematous dermatitis. J Clin Invest 2000; 106(1):25-35.
30. Arkwright PD, Chase JM, Babbage S, Pravica V, David TJ, Hutchinson IV. Atopic dermatitis is associated with a low-producer transforming growth factor beta(1) cytokine genotype. J Allergy Clin Immunol 2001;108(2):281-4.
31. Lebman DA, Coffman RL. Interleukin 4 causes isotype switching to IgE in T cell-stimulated clonal B cell cultures. J Exp Med 1988; 168(3):853-62.
32. Elbe-Burger A, Egyed A, Olt S, Klubal R, Mann U,Rappersberger K, et al. Overexpression of IL-4 alters the homeostasis in the skin. J Invest Dermatol 2002;118(5):767-78.
33. Sediva A, Sismova K, Vernerova E, Capkova S, Cinek O, Malinova V. Polymorphisms of cytokine genes in atopic dermatitis. J Allergy Clin Immunol 2004; 113(2Suppl):54-55.
34. Dizier MH, Sandford A, Walley A, Philippi A, Cookson W, Demenais F. Indication of linkage of serum IgE levels to the interleukin-4 gene and exclusion of the contribution of the (–590C to T) interleukin-4 promoter polymorphism to IgE variation. Genet Epidemiol 1999;16:84-94.
35. Liu X, Beaty TH, Deindl P, Huang SK, Lau S, Sommerfeld C, et al. Associations between total serum IgE levels and the 6 potentially functional variants within the genes IL4, IL13, and IL4RA in German children: the German Multicenter Atopy Study. J Allergy Clin Immunol 2003; 112(2):382-8.
36. He JQ, Chan-Yeung M, Becker AB, Dimich-Ward H, Ferguson AC, Manfreda J, et al. Genetic variants of the IL13 and IL4 genes and atopic diseases in at-risk children. Genes Immun 2003; 4(5):385-9.
37. Kawashima T, Noguchi E, Arinami T, Yamakawa ,Kobayashi K, Nakagawa H, Otsuka F, et al. Linkage and association of an interleukin 4 gene polymorphism with atopic dermatitis in Japanese families. J Med Genet 1998;35(6):502-504.
38. Hershey GK, Friedrich MF, Esswein LA, Thomas ML, Chatila TA. The association of atopy with a gain-of- function mutation in the alpha subunit of the interleukin-4 receptor. N Engl J Med 1997; 337(24):1720-5.
39. Tanaka K, Sugiura H, Uehara M, Hashimoto Y, Donnelly C, Montgomery DS. Lack of association between atopic eczema and the genetic variants of interleukin-4 and the interleukin-4 receptor alpha chain gene: heterogeneity of genetic backgrounds on immunoglobulin E production in atopic eczema patients. Clin Exp Allergy 2001;31(10):1522-7.
40. Hosomi N, Fukai K, Oiso N, Kato A, Ishii M, Kunimoto H, et al. Polymorphisms in the promoter of the interleukin-4 receptor alpha chain gene are associated with atopic dermatitis in Japan. J Invest Dermatol 2004;122(3):843-5.
41. Callard RE, Hamvas R, Chatterton C, Blanco C, Pembrey M, Jones R, et al. ALSPAC Study Team. Avon Longitudinal Study of Parents and Children. An interaction between the IL-4Ralpha gene and infection is associated with atopic eczema in young children. Clin Exp Allergy 2002; 32(7):990-3.
42. Oiso N, Fukai K, Ishii M. Interleukin 4 receptor alpha chain polymorphism Gln551Arg is associated with adult atopic dermatitis in Japan. Br J Dermatol 2000;142(5):1003–1006.
43. Sohn MH, Song JS, Kim KW, Kim ES, Kim KE, Lee JM.Association of interleukin- 10 gene promoter polymorphism in children with atopic dermatitis. J Pediatr 2007; 150(1):106-8.

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IssueVol 11, No 1 (2012) QRcode
SectionArticles
Keywords
Atopic dermatitis Cytokine gene polymorphisms Macedonian population SSP genotyping

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How to Cite
1.
Stavric K, Peova S, Trajkov D, Spiroski M. Gene Polymorphisms of 22 Cytokines in Macedonian Children with Atopic Dermatitis. Iran J Allergy Asthma Immunol. 1;11(1):37-50.