The connection of polymorphism and diurnal changes of the biological clock gene expression with the risk of progression of primary open-angle glaucoma

The purpose of this work is to study the connection betweengenetic factors (polymorphism and expression of key genes of the biological clock (KGBC), key genes controlled by KGBC, melatonin receptors) and the diurnal oscillation of melatonin in patients with stable and progressing primary open-angle glaucoma. 
Materials and methods. The study involved 115 patients aged 53–86 (averagely, 68.8 ± 7.9 years) with stable and progressive glaucoma. All patients underwent primary ophthalmological examination, tested for diurnal body temperature profile, intraocular pressure (IOP), melatonin (by the DLMO protocol) and were typed for key genes of the biological clock using the real-time polymerase chain reaction. We studied the sleep phase shift to later hours in carriers of the G-allele of the melatonin receptor gene during the progression of glaucoma. 
Results. The study of the clinical and genotypic features of the POAG course revealed phasal shifts of the circadian rhythms of body temperature, IOP, salivary melatonin levels and sleep phases which contributed to the progression of glaucomatous optic neuropathy. Certain polymorphic variants of genes contribute to individual frequent manifestations of desynchronosis. The clock rs1801260 and MTNR1B rs10830963 gene polymorphism was found to be related to disturbances in melatonin production and sleep phase. 
Conclusion. Complex manifestations of circadian desynchronization accompanying the progressive course of glaucoma are the late phase of rhythms and a decrease in sleep duration, body temperature, salivary melatonin and IOP, internal desynchronization between IOP and body temperature, IOP and sleep, evening dyslipidemia. The revealed patterns open up prospects for future studies of the relationship between polymorphism and daily changes of the expression of key genes in the biological clock with the risk of progression of primary open angle glaucoma.

1. Neroev V.V., Kiseleva O.A., Bessmertny A.M. The main results of a multicenter study of epidemiological features of primary open-angle glaucoma in the Russian Federation. Russian ophthalmological journal. 2013; 3: 43–6 (In Russian).

2. Cook C., Foster P. Epidemiology of glaucoma: What’s new? Canad. J. Ophthalmol. 2012; 47 (3): 223–6. doi: 10.1016/j.jcjo.2012.02.003

3. Rossetti L., Digiuni M., Giovanni M., et al. Blindness and glaucoma: a multicenter data review from 7 academic eye clinics. PLoS ONE. 2015; 10 (8): e0136632. https://doi.org/10.1371/journal.pone.0136632

4. Klein B.E., Klein R. Projected prevalences of age-related eye diseases. Invest. Ophthalmol. Vis. Sci. 2013; 54 (14): 14–7. doi: 10.1167/iovs.13-12782

5. Liu B., McNally S., Kilpatrick J.I., Jarvis S.P., O'Brien C.J. Aging and ocular issue stiffness in glaucoma. Surv. Ophthalmol. 2018; 63 (1): 56–74. doi: 10.1016/j.survophthal.2017.06.007

6. Quigley H.A., Broman A.T. The number of people with glaucoma worldwide in 2010 and 2020. Br. J. Ophthalmol. 2006; 90 (3): 262–7.

7. Tham Y.C., Li X., Wong T.Y., et al. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmology. 2014; 121 (11): 2081–90. doi: 10.1016/j.ophtha.2014.05.013

8. Neroev V.V., Mikhajlova L.A. Ophthalmological morbidity in Russia. In: Avetisov S.E., Egorov E.A., Moshetova L.K., Takhchidi H.P., eds. Ophthalmology. National leadership. Moscow: GEOTAR-Media; 2018 (In Russian).

9. Leske M.C., Connell A.M., Schachat A.P., Hyman L. The Barbados Eye Study: prevalence of open-angle glaucoma. Arch. Ophthalmol. 1994; 112 (6): 821–9.

10. Nesterov A.P. Glaucoma. Moscow: Medicinskoe informacionnoe agentstvo; 2008 (In Russian).

11. Volkov V.V. Open-angle glaucoma. Moscow: Meditcinskoe informacionnoe agentstvo; 2008 (In Russian).

12. Flammer D. Glaucoma. Moscow: MEDpress-inform; 2008 (In Russian).

13. Lo М., Bandín C., Yang H., et al. CLOCK 3111T/C genetic variant influences the daily rhythm of autonomic nervous function: relevance to body weight control. International Journal of Obesity. 2018 (42); 190–7. doi: 10.1038/ijo.2017.168

14. Gubin D.G., Vajnert D. Biorhythms and age. Uspekhi fiziologicheskikh nauk. 1991; 1 (22): 77–96 (In Russian).

15. Gubin G.D., Gubin D.G., Kulikova S.V. Spectral structure of body temperature biorhythms in human ontogenesis. Uspekhi sovremennogo estestvoznanija. 2006; 12: 48–51 (In Russian).

16. Gardiner S.K., Demirel S., Gordon M.O., et al. Ocular Hypertension Treatment Study Group. Seasonal changes in visual field sensitivity and intraocular pressure in the ocular hypertension treatment study. Ophthalmology. 2013; 120 (4): 724–30. doi: 10.1016/j.ophtha.2012.09.056

17. Gordon M.O., Beiser J.A., Brandt J.D., et al. The Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma. Arch. Ophthalmol. 2002; Jun; 120 (6): 714–20; discussion 829–30. doi: 10.1001/archopht.120.6.714

18. Bengtsson B., Leske M.C., Hyman L., Heijl A. Fluctuation of intraocular pressure and glaucoma progression in the early manifest glaucoma trial. Ophthalmology. 2007; 114 (2): 205–9. doi:10.1016/j.ophtha.2006.07.060

19. The AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS), 7: the relationship between control of intraocular pressure and visual field deterioration. Am. J. Ophthalmol. 2000; 130 (4): 429–40. https://doi.org/10.1016/S0002-9394(00)00538-9

20. Bengtsson B., Heijl A. Diurnal IOP fluctuation: not an in dependent risk factor for glaucoma to us visual field loss in high — risk ocular hypertension. Graefes Arch. Clin. Exp. Ophthalmol. 2005; 243 (6): 513–8.

21. Mosaed S., Liu J. H., Weinreb R.N. Correlation between office and peak nocturnal intraocular pressures in healthy subjects and glaucoma patients. Am. J. Ophthalmol. 2005; 139: 320–4. doi:10.1016/j.ajo.2004.09.062

22. Agez L., Laurent V., Guerrero H.Y., et al. Endogenous melatonin provides an effective circadian message to both the suprachiasmatic nuclei and the pars tuberalis of the rat. J. Pineal Res. 2009; 46: 95–105. doi: 10.1111/j.1600-079X.2008.00636.x

23. Blasiak J., Reiter R.J., Kaarniranta K. Melatonin in retinal physiology and pathology: the case of age-related macular degeneration. Oxid. Med. Cell. Longev. 2016: 6819736. https://doi.org/10.1155/2016/6819736

24. Bonmati-Carrion M.A., Arguelles-Prieto R., Martinez Madrid M.J., et al. Protecting the Melatonin Rhythm through Circadian Healthy Light Exposure. Int. J. Mol. Sci. 2014; 15 (12): 23448–500. doi: 10.3390/ijms151223448

25. Collin F., Bonnefont-Rousselot D. Melatonin: Action as antioxidant and potential applications in human disease and aging. Toxicology. 2010; 278 (1): 55–67. doi: 10.1016/j.tox.2010.04.008

26. Brodsky V.Y., Zvezdina N.D. Melatonin as the most effective organizer of the rhythm of protein synthesis in hepatocytes in vitro and in vivо. Cell Biol. Int. 2010; 34 (12): 1199–204. doi: 10.1042/CBI20100036

27. Abu-Amero K., Kondkar A.A., Chalam K.V. An Updated review on the genetics of primary open angle glaucoma. Int. J. Mol. Sci. 2015; 16 (12): 28886–911. doi: 10.3390/ijms161226135

28. Fuse N. Genetic bases of glaucoma. Tohoku Journal of Experimental Medicine, 2010; 221: 1–10. doi:10.1620/tjem.221.1

29. Choquet H., Paylakhi S., Kneeland S.C., et al. A multiethnic genome-wide association study of primary open-angle glaucoma identifies novel risk loci. Nat. Commun. 2018; 9 (1): 2278. doi: 10.1038/s41467-018-04555-4.

30. Zawilska J.B., Skene D.J., Arendt J. Physiology and pharmacology of melatonin in relation to biological rhythms. Pharmacology Reproduction, 2009; 61 (3): 383–410. doi: 10.1016/s1734-1140(09)70081-7

31. Schwertner A., Conceição dos Santos C., Costa D.G., et al. Efficacy of melatonin in the treatment of endometriosis: A phase II, randomized, doubleblind, placebo-controlled trial. Pain. 2013; 154 (6): 874–81. doi: 10.1016/j.pain.2013.02.025

32. Wiechmann A.F., Summers J.A. Circadian rhythms in the eye: the physiological significance of melatonin receptors in ocular tissues. Prog Retin Eye Res. 2008; 27: 137–60. doi: 10.1016/j.preteyeres.2007.10.001

33. Boland M., Qiu M., Ramulu P. Association between sleep parameters and glaucoma in the United States population: National Health and Nutrition Examination Survey. Journal of Glaucoma. 2019; 2 (28): 97–104. doi: 10.1097/IJG.0000000000001169

34. Gubin D.G., Malishevskaya T.N., Astakhov Yu.S., et al. Progressive retinal cell loss in primary open angle glaucoma is associated with temperature circadian rhythm phase delay and compromised sleep. Chronobiology International. 2019; 36 (4): 564–77. doi:10.1080/07420528.2019.1566741

35. Gubin D., Neroev V., Malishevskaya T., et al. Melatonin mitigates disrupted circadian rhythms, lowers intraocular pressure, and improves retinal ganglion cells function in glaucoma. J. Pineal. Res. 2021; 17:e12730. doi: 10.1111/jpi.12730

36. Pandi-Perumal Seithikurippu R., Smits M., Spence D., et al. Dim light melatonin onset (DLMO): A tool for the analysis of circadian phase in human sleep and chronobiological disorders. Progress in neuropsychopharmacology biological psychiatry. 2007; (31): 1–11. doi: 10.1016/j.pnpbp.2006.06.020