Endothelial Nitric Oxide Synthase Enzyme Gene Polymorphism (Exon 7, 894 G→T, Glu298Asp) in Behçet's Patients: a Case-Control Study
Keywords:
Behçet's Disease, eNOS, Glu298Asp, Polymerase Chain ReactionAbstract
Background The etiology of Behçet's disease (BD) remains partially unknown and the eNOS gene polymorphism indicated a particular characteristic of vasculitis in the disease progress. Methods The study was planned as a case-control study. The BD group included 36 patients, 22 (61.1%) female patients and 14 male (38.9%), aged 20-70 years while the control group consisted of 36 volunteers, 20 (55.6%) female volunteers and 16 (44.4%) male with similar age distributions. Polymerase Chain Reaction (PCR) - restricted fragment length (RFL) polymorphism analysis was used to determine Glu298Asp variants in all samples. Results In the RLP analysis conducted in the BD group, the TT (5.6%) genotype was detected in 2 patients, the GG (55.6%) in 20, and the GT genotype in 14 (38.9%). While the TT genotype was not found in the control group, the GG genotype was detected in 30 individuals (83.3%) and the GT genotype in 6 individuals (16.7%). The GG genotype was significantly higher in the control group and the GT genotype significantly higher in the GH group (p= 0.027). While 18 (25.0%) T alleles and 54 (75.0%) G alleles were detected in the BD group, 6 (8.3%) T alleles and 66 (91.7%) G alleles were detected in the control group (p=0.007). The risk of having the T allele in patients with Behçet's disease was 3.7 times higher when compared to that of the control group (OR=3.7, 95% Cl for OR: 1.36-9.88, p<0.05). Conclusions A significant association of the Glu298Asp polymorphism of the eNOS gene with BH in the Turkish population is found.References
Yurdakul S, Yazici H. Behçet’s syndrome. Best Pract Res Clin Rheumatol. 2008;22(5):793–809.
Capittini C, Rebuffi C, Lenti MV, Di Sabatino A, Tinelli C, Martinetti M, et al. Global Meta-Analysis on the Association between Behcet Syndrome and Polymorphisms from the HLA Class I (A, B, and C) and Class II (DRB1, DQB1, and DPB1) Genes. Dis Markers. 2021;2021.
Hatemi G, Seyahi E, Fresko I, Talarico R, Hamuryudan V. One year in review 2020: Behçet’s syndrome. Clin Exp Rheumatol. 2020;38(5):3–10.
Bulur I, Onder M. Behçet disease: New aspects. Clin Dermatol. 2017;35(5):421–34.
İlgen U. Clusters in Behçet’s syndrome. Arthritis Res Ther. 2022;24(1):22–5.
Soejima Y, Kirino Y, Takeno M, Kurosawa M, Takeuchi M, Yoshimi R, et al. Changes in the proportion of clinical clusters contribute to the phenotypic evolution of Behçet’s disease in Japan. Arthritis Res Ther. 2021;23(1):1–11.
Yazici Y, Hatemi G, Bodaghi B, Cheon JH, Suzuki N, Ambrose N, et al. Behçet syndrome. Nat Rev Dis Prim [Internet]. 2021;7(1). Available from: http://dx.doi.org/10.1038/s41572-021-00301-1
Palmer RMJ, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Vol. 333, Nature. 1988. p. 664–6.
Boughaleb H, Lobysheva I, Dei Zotti F, Balligand JL, Montiel V. Biological Assessment of the NO-Dependent Endothelial Function. Molecules. 2022;27(22).
Stuehr DJ, Haque MM. Nitric oxide synthase enzymology in the 20 years after the Nobel Prize. Br J Pharmacol. 2019;176(2):177–88.
Luizon MR, Pereira DA, Tanus-Santos JE. Pharmacogenetic relevance of endothelial nitric oxide synthase polymorphisms and gene interactions. Pharmacogenomics. 2018;19(18):1423–35.
Babaoğlu MÖ. İnsanda Endotelyal Nitrik Oksit Sentaz E298D Genetik Polimorfizminin Damar Yanıtları ve Nitrik Salıverilmesi ÜzerineEtkileri. Türkiye Tıp Dergisi. :2004; 11(3): 109-115.
Król M, Kepinska M. Human nitric oxide synthase—its functions, polymorphisms, and inhibitors in the context of inflammation, diabetes and cardiovascular diseases. Int J Mol Sci. 2021;22(1):1–18.
Cozma A, Fodor A, Orasan OH, Vulturar R, Samplelean D, Negrean V, et al. Pharmacogenetic implications of eNOS polymorphisms (Glu298Asp, T786C, 4b/4a) in cardiovascular drug therapy. In Vivo (Brooklyn). 2019;33(4):1051–8.
Oliveira-Paula GH, Lacchini R, Tanus-Santos JE. Clinical and pharmacogenetic impact of endothelial nitric oxide synthase polymorphisms on cardiovascular diseases. Nitric Oxide - Biol Chem [Internet]. 2017;63:39–51. Available from: http://dx.doi.org/10.1016/j.niox.2016.08.004
Criteria for diagnosis of Behçet’s disease. International Study Group for Behçet’s Disease. Lancet (London, England) [Internet]. 1990;335(8697):1078–80. Available from: http://www.ncbi.nlm.nih.gov/pubmed/1970380
Walsh PS, Metzger DA, Higushi R. Chelex 100 as a medium for simple extraction of DNA for PCR-based typing from forensic material. BioTechniques 10(4): 506-13 (April 1991). Biotechniques. 2013;54(3):134–9.
SALVARANI C. Endothelial Nitric Oxide Synthase Gene Polymorphisms in Behçet’s Disease. Clin Genet. 2002;61(6):423–9.
Kim JU, Chang HK, Lee SS, Kim JW, Kim KT, Lee SW, et al. Endothelial nitric oxide synthase gene polymorphisms in Behçet’s disease and rheumatic diseases with vasculitis. Ann Rheum Dis. 2003;62(11):1083–7.
Oflaz H, Mercanoglu F, Karaman O, Kamali S, Erer B, Genchellac H, et al. Impaired endothelium-dependent flow-mediated dilation in Behçet’s disease: More prominent endothelial dysfunction in patients with vascular involvement. Int J Clin Pract. 2005;59(7):777–81.
Haznedaroǧlu IC, Özcebe OI, Özdemir O, Çelik I, Dündar S V., Kirazli Ş. Impaired haemostatic kinetics and endothelial function in Behcet’s disease. J Intern Med. 1996;240(4):181–7.
Chambers JC, Haskard DO, Kooner JS. Vascular endothelial function and oxidative stress mechanisms in patients with Behçet’s syndrome. J Am Coll Cardiol [Internet]. 2001;37(2):517–20. Available from: http://dx.doi.org/10.1016/S0735-1097(00)01137-2
Örem A, Vanizor B, Çimşit G, Kiran E, Deǧer O, Malkoç M. Decreased nitric oxide production in patients with Behcet’s disease. Dermatology. 1999;198(1):33–6.
Çekmen M, Evereklioglu C, Er H, Inalöz HS, Doganay S, Yürköz Y, et al. Vascular endothelial growth factor levels are increased and associated with disease activity in patients with Behçet’s syndrome. Int J Dermatol. 2003;42(11):870–5.
Casas JP, Cavalleri GL, Bautista LE, Smeeth L, Humphries SE, Hingorani AD. Endothelial nitric oxide synthase gene polymorphisms and cardiovascular disease: A HuGE review. Am J Epidemiol. 2006;164(10):921–35.
Wang XL, Wang J. Endothelial nitric oxide synthase gene sequence variations and vascular disease. Mol Genet Metab. 2000;70(4):241–51.
Cheng Y, Xiong M, Liu Y, Tang B. Lack of association between endothelial nitric oxide synthase gene polymorphisms with vasculitis: a meta-analysis. Clin Exp Rheumatol. 2015;33(2):2–7.
Karasneh JA, Hajeer AH, Silman A, Worthington J, Ollier WER, Gul A. Polymorphisms in the endothelial nitric oxide synthase gene are associated with Behçet’s disease. Rheumatology. 2005;44(5):614–7.
