Endotelyal nitrik oksit sentaz (eNOS) ve miyeloperoksidaz (MPO) genlerin mikrotiyadaki rolü

Abstract

Objective: The aim of this study was to determine the relationship between polymorphisms of endothelial nitric oxide synthase (eNOS) and myeloperoxidase (MPO) genes and development of microtia.
Methods: Nineteen (11 males, 8 females) unrelated cases with microtia and 40 healthy controls were enrolled in the present study. The study focused on three functional variants; a variant in exon 7 (G894T) and a variable number of 27 bp tandem repeats in intron 4 (VNTR) of eNOS gene and a variant in the promoter region (G463A) of MPO gene. We genotyped these variants using the polymerase chain reaction (PCR) and/or PCR-restriction fragment length polymorphism (RFLP) method. The distribution of allele and genotype in eNOS and MPO genes were compared between cases with microtia and healthy controls using chi-square test.
Results: With regard to the eNOS (G894T) variant, there was a significant difference in genotype distribution between cases with microtia and healthy controls (OR: 1.267, 95% CI: 1.004–1.598; p=0.009). Our study demonstrated that cases with eNOS (G894T) TT genotype had increased risk of microtia. The allele frequencies of eNOS (VNTR) variant showed
statistically significant difference between cases with microtia and healthy controls (OR: 2.947, 95% CI: 1.188–7.311; p=0.028). eNOS (VNTR) B allele was higher in the cases. However, there was no significant difference for MPO (G463A) variant according to genotype distribution and allele frequency between cases with microtia and healthy controls.
Conclusion: To the best of our knowledge, this is the first analysis of the eNOS (G894T and VNTR) and MPO (G463A) variants in cases with microtia. Our data demonstrate that eNOS gene variants might play crucial role on the etiopathogenesis of microtia in Turkish population. The findings of the current study highlight the necessity for prospective longitudinal studies in elucidating the relative contributions of various factors in diseases with a multifactorial etiology where there is interplay among genetic susceptibility and exogenous factors.

Keywords

• Mikrotiya,endotelyal nitrik oksit sentaz,miyeloperoksidaz,PCR,RFLP,Microtia,endothelial nitric oxide synthase,myeloperoxidase

Kaynakça

1. 1. Kountakis SE Helidonis E, Jahrsdoerfer RA. Microtia grade as an indicator of middle ear development in aural atresia. Arch Otolaryngol Head Neck Surg 1995;121:885–6.
2. 2. Harris J Källén B, Robert E. The epidemiology of anotia and microtia. J Med Genet 1996;33:809–13.
3. 3. Shaw GM, Carmichael SL, Kaidarova Z, Harris JA. Epidemiologic characteristics of anotia and microtia in California, 1989–1997. Birth Defects Res A Clin Mol Teratol 2004;70:472–5.
4. 4. Castilla EE, Orioli IM. Prevalence rates of microtia in South America. Int J Epidemiol 1986;15:364–8.
5. 5. Mastroiacovo P, Corchia C, Botto LD, Lanni R, Zampino G, Fusco D. Epidemiology and genetics of microtia-anotia: a registry based study on over one million births. J Med Genet 1995;32: 453–7.
6. 6. Tiboni GM, Ponzano A. Nitric oxide and teratogenesis: an update. Curr Pharm Des 2014;20:5443–7.
7. 7. Dosenko VE, Zagoriy VY, Haytovich NV, Gordok OA, Moibenko AA. Allelic polymorphism of endothelial NO synthase gene and its functional manifestations. Acta Biochim Pol 2006;53: 299–302.
8. 8. Ohnishi S, Murata M, Kawanishi S. DNA damage induced by hypochlorite and hypobromite with reference to inflammationassociated carcinogenesis. Cancer Lett 2002;178:37–42.

9. 9. Wheatley-Price P, Asomaning K, Reid A, et al. Myeloperoxidase and superoxide dismutase polymorphisms are associated with an increased risk of developing pancreatic adenocarcinoma. Cancer 2008;112:1037–42.
10. 10. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988;16:1215.
11. 11. Hingorani AD, Liang CF, Fatibene J, et al. A common variant of the endothelial nitric oxide synthase (Glu298->Asp) is a major risk factor for coronary artery disease in the UK. Circulation 1999;100: 1515–20.
12. 12. Walch K, Kolbus A, Hefler-Frischmuth K. Polymorphisms of the endothelial nitric oxide synthase gene in premenopausal women with polycystic ovary syndrome. Maturitas 2008;61:256–9.
13. 13. Cascorbi I, Henning S, Brockmöller J, et al. Substantially reduced risk of cancer of the aerodigestive tract in subjects with variant-- 463A of the myeloperoxidase gene. Cancer Res 2000;60:644–9.
14. 14. Ellul J, Markoula S, Marousi S, et al. Association of endothelial nitric oxide synthase polymorphism G894T with functional outcome in acute stroke patients. Neurol Res 2011;33:835–40.
15. 15. De Caterina R, Libby P, Peng HB, et al. Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest 1995;96:60–8.
16. 16. Plachta N, Traister A, Weil M. Nitric oxide is involved in establishing the balance between cell cycle progression and cell death in the developing neural tube. Exp Cell Res 2003;288:354–62.
17. 17. Kuzin B, Roberts I, Peunova N, Enikolopov G. Nitric oxide regulates cell proliferation during Drosophila development. Cell 1996; 87:639–49.
18. 18. Su Y, Kondrikov D, Block ER. Cytoskeletal regulation of nitric oxide synthase. Cell Biochem Biophys 2005;43:439–49.
19. 19. Persu A, Stoenoiu MS, Messiaen T, et al. Modifier effect of ENOS in autosomal dominant polycystic kidney disease. Hum Mol Genet 2002;11:229–41.
20. 20. Wang XL, Mahaney MC, Sim AS, et al. Genetic contribution of the endothelial constitutive nitric oxide synthase gene to plasma nitric oxide levels. Arterioscler Thromb Vasc Biol 1997;17:3147–53.
21. 21. Ahn J, Gammon MD, Santella RM, et al. Myeloperoxidase genotype, fruit and vegetable consumption, and breast cancer risk. Cancer Res 2004;64:7634–9.
22. 22. Dennery PA. Effects of oxidative stress on embryonic development. Birth Defects Res C Embryo Today 2007;81:155–62.
23. 23. Pabalan N, Jarjanazi H, Sung L, Li H, Ozcelik H. Menopausal status modifies breast cancer risk associated with the myeloperoxidase (MPO) G463A polymorphism in Caucasian women: a meta-analysis. PLoS One 2012;7:e32389.