Received: 17.01.2022; Accepted: 31.03.2022; Published on-line: 15.06.2022
Association of primary open-angle glaucoma with endothelial NO-synthase (NOS3) rs2070744 (T-786C) in a Ukrainian population
O. A. Isaiev, V. M. Serdiuk
Dnipro State Medical University; Dnipropetrovsk Regional Clinical Ophthalmology Hospital; Dnipro (Ukraine)
Isaiev OA, Serdiuk VM. Association of primary open-angle glaucoma with endothelial NO-synthase (NOS3) rs2070744 (T-786C) in a Ukrainian population. http://doi.org/10.31288/oftalmolzh2022339
Background: Endothelial dysfunction and endothelial nitric oxide-synthase (NOS3) polymorphism play an important role in the pathogenesis of glaucomatous optic neuropathy (GON) in primary open-angle glaucoma (POAG). The rs2070744 (T-786C) variant is located in the promoter of the NOS3 gene and has been shown to be promising for association with POAG.
Purpose: To identify an association between POAG and the rs2070744 (T-786C) variant in the NOS3 gene in a Ukrainian population.
Material and Methods: We examined 200 patients, including 153 patients (153 eyes) diagnosed with POAG (the study group) and 47 patients (47 eyes) without POAG (the control group). The study group included patients with a mean age of 65.0 ± 13.1 years and disease duration of 4.9 ± 5.3 years. Genotypes were determined by real-time polymerase chain reaction (PCR). Mutation detection and quantification were performed using TaqMan Mutation Detection Assays (Life Technologies, Carlsbad, CA). Statistical analyses were performed using Statistica 10 software (StatSoft, Tulsa, OK, USA).
Results: The minor T allele of rs2070744 was associated with a 1.7-fold decreased risk of POAG (OR = 0.589; 95% CI, 0.370-0.938; p = 0.025). The ancestral C allele of rs2070744 determined the genetic susceptibility of an individual to POAG. Patient carriers of the CC genotype of rs2070744 were 13.9 years and 13.2 years, respectively, younger (p < 0.001) than patient carriers of the СТ and ТТ genotypes. In addition, patient carriers of the C allele were younger than patient carriers of the T allele (61.9 ± 14.4 years versus 69.3 ± 9.6 years; p < 0.001). Eyes of patient carriers of the TT genotype showed better perimetric visual field mean deviation (MD) and pattern standard deviation (PSD), and thicker retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC), compared to eyes of carriers of other genotypes.
Conclusion: Allelic polymorphism rs2070744 in NOS3 had a protective effect against POAG, facilitating less severe manifestations and less severe progression of GON in a Ukrainian population.
Keywords: primary open-angle glaucoma, rs2070744 (T-786C) NOS3.
1.Ling JD, Bell NP. Role of cataract surgery in the management of glaucoma. Int Ophthalmol Clin. 2018;58(3):87-100.
2.Cieza A, Keel S, Kocur I, Mccoy M, Mariotti SP. World report on vision. Geneva: World Health Organization; 2019. [Internet]. Available from: https://www.who.int/health-topics/blindness-and-vision-loss#tab=tab_1.
3.Wang W, He M, Li Z, Huang W. Epidemiological variations and trends in health burden of glaucoma worldwide. Acta Ophthalmol. 2019;97(3):e349-e355.
4.Flaxman SR, Bourne RR, Resnikoff S, Ackland P, Braithwaite T, Cicinelli MV et alt. Vision loss expert group of the global burden of disease study. Global causes of blindness and distance vision impairment 1990-2020: a systematic review and meta-analysis. Lancet Glob Health. 2017;5(12):e1221-e34.
5.Tham, Li X, Wong TY, Quigley HA, Aung T, Cheng CY. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmology. 2014;121(11):2081-90.
6.Glaucoma. American Optometric Association [Internet]. Available from: https://www.aoa.org/healthy-eyes/eye-and-vision-conditions/glaucoma?sso=y.
7.Agrawal P, Bradshaw SE. Systematic literature review of clinical and economic outcomes of micro-invasive glaucoma surgery (MIGS) in primary open-angle glaucoma. Ophthalmol Ther. 2018;7(1):49-73.
8.Kapetanakis VV, Chan MP, Foster PJ, Cook DG, Owen CG, Rudnicka AR. Global variations and time trends in the prevalence of primary open angle glaucoma (POAG): a systematic review and meta-analysis. Br J Ophthalmol. 2016;100(1):86-93.
9.Flammer J. The vascular concept of glaucoma. Surv Ophthalmol. 1994;38 Suppl:S3-6.
10.Mudassar IB, Yew KK, Thambiraja R, Sulong S, Ghulam RA, Ahmad TL. Microvascular endothelial function and primary open angle glaucoma. Ther Adv Ophthalmol. 2019;11:2515841419868100.
11.Hoguet A, Chen PP, Junk AK, Mruthyunjaya P, Nouri-Mahdavi K, Radhakrishnan S, Takusagawa HL, Chen TC. The Effect of Anti-Vascular Endothelial Growth Factor Agents on Intraocular Pressure and Glaucoma: A Report by the American Academy of Ophthalmology. Ophthalmology. 2019 Apr;126(4):611-622.
12.Vargas-Valderrama A, Messina A, Mitjavila-Garcia MT, Guenou H. The endothelium, a key actor in organ development and hPSC-derived organoid vascularization. J Biomed Sci. 2020;27(1):67.
13.Krüger-Genge A, Blocki A, Franke RP, Jung F. Vascular endothelial cell biology: an update. Int J Mol Sci. 2019;20(18):4411.
14.Cyr AR, Huckaby LV, Shiva SS, Zuckerbraun BS. Nitric oxide and endothelial dysfunction. Crit Care Clin. 2020;36(2):307-321.
15.Godo S, Shimokawa H. Endothelial functions. Arterioscler Thromb Vasc Biol. 2017;37(9):e108-e14.
16.Wettschureck N, Strilic B, Offermanns S. Passing the vascular barrier: endothelial signaling processes controlling extravasation. Physiol Rev. 2019;99(3):1467-1525.
17.Efendieva MH, Budzinskaya MV, Kadyshev VV, Zinchenko RA, Savochkina OA, Pupysheva AD. [Molecular and genetic aspects of age-related macular degeneration and glaucoma]. Vestn Oftalmol. 2019;135(3):121-127. Russian.
18.Liu Y, Allingham RR. Major review: Molecular genetics of primary open-angle glaucoma. Exp Eye Res. 2017;160:62-84.
19.Salari N, Bokaee S, Farshchian N, Mohammadi M, Kazeminia M. The role of polymorphisms rs2070744 and rs1799983 eNOS gene in patients with POAG: a systematic review and meta-analysis. Int Ophthalmol. 2021 Apr 10. https://doi.org/10.1007/s10792-021-01832-y. Epub ahead of print. PMID: 33837898.
20.Emam WA, Zidan HE, Abdulhalim BE, Dabour SA, Ghali MA, Kamal AT. Endothelial nitric oxide synthase polymorphisms and susceptibility to high-tension primary open-angle glaucoma in an Egyptian cohort. Mol Vis. 2014;20:804-11. PMID: 24940036; PMCID: PMC4057245.
21.Kang JH, Wiggs JL, Rosner BA, Haines J, Abdrabou W, Pasquale LR. Endothelial nitric oxide synthase gene variants and primary open-angle glaucoma: interactions with hypertension, alcohol intake, and cigarette smoking. Arch Ophthalmol. 2011 Jun;129(6):773-80.
22.Magalhães da Silva T, Rocha AV, Lacchini R, Marques CR, Silva ES, Tanus-Santos JE, Rios-Santos F. Association of polymorphisms of endothelial nitric oxide synthase (eNOS) gene with the risk of primary open angle glaucoma in a Brazilian population. Gene. 2012 Jul 10;502(2):142-6.
23.Kondkar AA, Azad TA, Sultan T, Osman EA, Almobarak FA, Al-Obeidan SA. Association of endothelial nitric oxide synthase (NOS3) gene polymorphisms with primary open-angle glaucoma in a Saudi cohort. PLoS ONE. 2020;15(1): e0227417.
25.Kang JH, Wiggs JL, Haines J, Abdrabou W, Pasquale LR. Reproductive factors and NOS3 variant interactions in primary open-angle glaucoma. Mol Vis. 2011;17:2544-51. Epub 2011 Sep 30. PMID: 22025889; PMCID: PMC3198482.
26.Kang JH, Wiggs JL, Rosner BA, Hankinson SE, Abdrabou W, Fan BJ, Haines J, Pasquale LR. Endothelial nitric oxide synthase gene variants and primary open-angle glaucoma: interactions with sex and postmenopausal hormone use. Invest Ophthalmol Vis Sci. 2010 Feb;51(2):971-9.
27.McMonnies CW. Glaucoma history and risk factors. J Optom. 2017;10(2):71-8.
Corresponding author: O.A. Isaiev, email: firstname.lastname@example.org
Disclosures: The authors state that there is no conflict of interest in the preparation of this article.
Source(s) of support: There are no external sources of funding.
Abbreviations: NOS3, nitric oxide-synthase; GON, glaucomatous optic neuropathy; GON, glaucomatous optic neuropathy; POAG, primary open-angle glaucoma; PCR, polymerase chain reaction; MD, mean deviation; PSD, pattern standard deviation; RNFL, retinal nerve fiber layer; GCC, ganglion cell complex; CI, confidence interval; CrI, credible interval; eNOS, NOS3, the enzyme entodthelial NO synthase; NO, nitric oxide; cGMP, cyclic guanosine monophosphate; IOP, intraocular pressure; OCT, ocular coherence tomography; M, mean; SD, standard deviation; OR, Odd ratios.