EVALUATION OF THE ROLE OF POLYMORPHIC VARIANTS OF NO-SYNTHASES GENES OF IN PATHOGENESIS OF PSORIASIS

DOI: https://doi.org/10.29296/24999490-2018-04-11

E.А. Klimov(1, 2, 3), A.V. Tretiakov(1), E.S. Gapanovich(1), Z.G. Kokaeva(1), A.G. Soboleva(4), L.R. Sakaniya(4), I.M. Korsunskaya(4), V.V. Sobolev(2, 4, 5) 1-Lomonosov Moscow State University, Leninskye Gory, 1–12, Moscow, 119234, Russian Federation; 2-University Diagnostic Laboratory, LLC, Vernadskogo av., 29, room I, Moscow, 119331, Russian Federation; 3-Center of Experimental Embryology and Reproductive Biotechnologies, Kostyakova str., 12–4, Moscow, 127422, Russian Federation; 4-Centre of Theoretical Problems of Physico-Chemical Pharmacology, Kosygina str., 4, Moscow, 119334, Russian Federation -5I.I. Mechnikov Research Institute for Vaccines and Sera Malyy Kazennyyby street, 5, Moscow, 105064, Russian Federation E-mail: [email protected]

The aim of the study was to analyze two single nucleotide substitutions in the NOS2 (rs2779249, c-1290G>T, 5'-region) and NOS3 (rs2070744, c-813C>T, in tron 1) genes in psoriasis patients. Materials and methods. DNA samples from 88 psoriasis patients and 365 control samples (population control) were studied. The analysis was carried out by Real-Time PCR with allele-specific probes. Results. There were obtained frequencies of studied genotypes of the substitutions. No associations between single nucleotide variants (SNVs) and the disease: NOS3 (rs2070744) – χ2=0,487; p=0,485 иNOS2 (rs2779249) – χ2=0,859; p=0,354 were found. In this case a significant deviation from the Hardy-Weinberg equilibrium in the frequencies of the replacement genotypes in the NOS3 gene was revealed in patients [χ2=46,32 (p=0)], in control group – χ2=225,86 (p=0). Conclusion. The obtained results failed to show significant associations of investigated substitutions with psoriasis. Their influence was assumed to be more noticeable in the conjunction with other replacements of these genes or on a larger sample. Perhaps, just like the hyperactivation, the regulation of the expression of NO synthases in psoriasis, does not depend on the presence of the investigated polymorphic variants of genes.
Keywords: 
psoriasis, nitric oxide synthase, NOS2, NOS3, DNA polymorphism, genetic associations
Список литературы: 
  1. Coto-Segura P., Coto E., Mas-Vidal A., Morales B., Alvarez V., Diaz M., Santos-Juanes J. Influence of endothelial nitric oxide synthase polymorphisms in psoriasis risk. Archives of Dermatological Research. 2011; 303 (6): 445–9. DOI: 10.1007/s00403-011-1129-9.
  2. Rieder E., Tausk, F. Psoriasis, a model of dermatologic psychosomatic disease: Psychiatric implications and treatments. International J. of Dermatology. 2012; 51: 12–26. DOI: 10.1111/j.1365-4632.2011.05071.x.
  3. Di Meglio P., Villanova F., Nestle F. O. Psoriasis. Cold Spring Harbor Perspectives in Medicine. 2014; 4 (8): 1–30. DOI: 10.1101/cshperspect.a015354.
  4. Bolevich S. B., Urazalina A. A. Psoriaz: sovremennyy vzglyad na e`tiopatogenez. Vestnik Rossiyskoy Voenno-Medicinskoy Akademii. 2013; 2 (42): 202–6. [Bolevich S.B., Urazalina A.A. Psoriasis: modern view at aetiopathogenesis. Vestnik rossijskoj voenno-medicinskoj akademii. 2013; 2 (42): 202–6 (In Russian)]
  5. Ryan C., Korman N.J., Gelfand J.M., Lim H.W., Elmets C.A., Feldman S.R., Menter A. Research gaps in psoriasis: Opportunities for future studies. J. of the American Academy of Dermatology. 2014; 70 (1): 146–67. DOI: 10.1016/j.jaad.2013.08.042.
  6. Mineeva A. A., Kozhushnaya O. S., Volnuhin V. A., Frigo N. V., Znamenskaya L. F., Kubanov A. A., Melehina L. E. Izuchenie geneticheskih faktorov predraspolozhennosti k razvitiyu psoriaza. Vestnik dermatologii i venerologii. 2012; 3: 30–8. [Mineeva A.A., Kozhushnaya O.S., Volnukhin V.A., Frigo N.V., Znamenskaya L.F., Kubanov A.A., Melekhina L.E. Study of the genetic factors predisposing to the development of psoriasis. Vestnik dermatologii i venerologii. 2012; 3: 30–8 (In Russian)]
  7. Chandra A., Ray A., Senapati S., Chatterjee R. Genetic and epigenetic basis of psoriasis pathogenesis. Molecular Immunology. 2015; 64 (2): 313–23. DOI: 10.1016/j.molimm.2014.12.014.
  8. Li Y., Zhang G., Xiao R., Chen H., Wen H. Expression of NOS2 and HIF-1alpha with angiogenesis in affected skin biopsies from patients with psoriasis. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2010; 35 (9): 952–7. DOI: 10.3969/j.issn.1672-7347.2010.09.009.
  9. Sherratt J.A., Weller R., Savill N.J. Modelling blood flow regulation by nitric oxide in psoriatic plaques. Bull Math Biol. 2002; 64 (4): 623–41. DOI: 10.1006/bulm.2001.0271.
  10. Bruch-Gerharz D., Schnorr O., Suschek C., Beck K.F., Pfeilschifter J., Ruzicka T., Kolb-Bachofen V. Arginase 1 overexpression in psoriasis: limitation of inducible nitric oxide synthase activity as a molecular mechanism for keratinocyte hyperproliferation. Am. J. Pathol. 2003; 162 (1): 203–11. DOI: 10.1016/S0002-9440(10)63811-4.
  11. Gokhale N.R., Belgaumkar V.A., Pandit D.P., Deshpande S., Damle D.K. A study of serum nitric oxide levels in psoriasis. Indian J. Dermatol. Venereol. Leprol. 2005; 71 (3): 175–8. DOI: 10.4103/0378-6323.16232.
  12. Trepicchio W.L., Ozawa M., Walters I.B., Kikuchi T., Gilleaudeau P., Bliss J.L., Schwertschlag U., Dorner A.J., Krueger J.G. Interleukin-11 therapy selectively downregulates type I cytokine proinflammatory pathways in psoriasis lesions. J. Clin. Invest. 1999; 104 (11): 1527–37. DOI: 10.1172/JCI6910.
  13. Schwentker A., Billiar T.R. Nitric oxide and wound repair. Surg Clin. North Am. 2003; 83 (3): 521–30. DOI: 10.1016/S0039-6109(02)00207-4.
  14. Simonetti O., Lucarini G., Campanati A., Goteri G., Zizzi A., Marconi B., Ganzetti G., Minardi D., Di Primio R., Offidani A. VEGF, survivin and NOS overexpression in psoriatic skin: critical role of nitric oxide synthases. J. Dermatol Sci. 2009; 54 (3): 205–8. DOI: 10.1016/j.jdermsci.2008.12.012.
  15. Senturk N., Kara N., Aydin F., Gunes S., Yuksel E.P., Canturk T., Bagci H., Turanli A.Y. Association of eNOS gene polymorphism (Glu298Asp) with psoriasis. J. Dermatol. Sci. 2006; 44 (1): 52–5. DOI: 10.1016/j.jdermsci.2006.05.011.
  16. Stuart P.E., Nair R.P., Ellinghaus E., Ding J., Tejasvi T., Gudjonsson J.E., Li Y., Weidinger S., Eberlein B., Gieger C., Wichmann H.E., Kunz M., Ike R., Krueger G.G., Bowcock A.M., Mrowietz U., Lim H.W., Voorhees J.J., Abecasis G.R., Weichenthal M., Franke A., Rahman P., Gladman D.D., Elder J.T. Genome-wide association analysis identifies three psoriasis susceptibility loci. Nat Genet. 2010; 42 (11): 1000–4. DOI: 10.1038/ng.693.
  17. Fu L., Zhao Y., Lu J., Shi J., Li C., Liu H., Li Y. Functional single nucleotide polymorphism-1026C/A of inducible nitric oxide synthase gene with increased YY1-binding affinity is associated with hypertension in a Chinese Han population. J. Hypertens. 2009; 27 (5): 991–1000. DOI: 10.1097/HJH.0b013e3283294bec.
  18. Nakayama M., Yasue H., Yoshimura M., Shimasaki Y., Kugiyama K., Ogawa H., Motoyama T., Saito Y., Ogawa Y., Miyamoto Y., Nakao K. T-786-->C mutation in the 5’-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm. Circulation. 1999; 99 (22): 2864–70. DOI: 10.1161/01.CIR.99.22.2864.