Problems of Radiation Medicine and Radiobiology

D. О. Bilyi, O. M. Nastina, G. V. Sydorenko, N. I. Bilous, N. V. Kursina, G. V. Pleskach,
O. D. Bazyka, O. M. Makarevysh, O. S. Kovaliov, A. A. Chumak, I. V. Abramenko

State Institution «National Research Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine», 53 Melnykova str., Kyiv, 04050, Ukraine

GENDER DISPARITIES OF CIRCULATORY DISEASE PROGRESS IN THE CHORNOBYL ACCIDENT CLEAN-UP WORKERS AND PHOS-PHODIESTERASE 4D GENE rs966221 POLYMORPHISM

Objective. Evaluation of the hypertensive disease (HD) and coronary heart disease (CHD) progress in the Chornobyl NPP (ChNPP) accident clean-up workers (ACUW) and persons not exposed to ionizing radiation depending on gender and genotype of the phosphodiesterase 4D (PDE4D) gene rs966221 polymorphism.
Materials and methods. There were male ACUW (ACUWm; n=515) and female ACUW (ACUWf; n=145) involved in the study since 2013 till 2018. Participation in the clean-up works took place in 1986–1987. The control group included male (CGm; n=162) and female (CGf; n=120) persons not exposed to ionizing radiation. All study subjects have had neither signs nor symptoms of HD or CHD before the ChNPP accident.
Results. Review of the Kaplan-Meier survival tables indicated that according to median survival the HD emerged in ACUWm and ACUWf in a younger age (47.5 ± 0.6 and 50.7 ± 0.7 years old, respectively) vs. CGm or CGf (54.9 ± 1.1 and 54.4 ± 1.1 years, respectively). The same was true for CHD where the median values were (56.8 ± 0.5), (61.2 ± 0.8), (61.6 ± 1.0) and (64.2 ± 1.4) years respectively. Review of cumulative incidence of HD and CHD revealed no association of the PDE4D gene rs966221 polymorphism with the diseases of concern. The TT gene carrier state compared to the CC or CT genes features an increased risk of myocardial infarction (MI) 2.9 times in ACUWm, 4-fold in CGm, and 5.5 times in CGf (p < 0.05). No any gene carrier state was associated with MI in the ACUWf. Onset of menopause was followed by an increase in HD incidence vs. males.
Conclusions. The male and female ChNPP ACUW were developing HD and CAD at a younger age compared with corresponding non-irradiated control. In male ACUW in comparison with female ACUW the cumulative morbidity rate for MI was higher in any age range, whereas for CAD it was higher from 23 to 74 years, and for HD from 25 to 53 years of age. In male and female ACUW as well as in non-irradiated control the HD developed much earlier than CHD. The carrier state of TT genotype of PDE4D gene rs966221 polymorphism increases the risk of MI in males of all ages, in the non-irradiated controls it is increased in 65 years for men and in 60 years for women. No data on association of the genotype of the described gene polymorphism with MI were found in female ACUW.
Key words: Chornobyl accident clean-up workers, ionizing radiation, arterial hypertension, coronary heart disease, myocardial infarction, gender disparities, PDE4D gene rs966221 polymorphism.

Problems of radiation medicine and radiobiology.
2018;23:263_282. doi: 10.33145/2304-8336-2018-23-263-282.

full text

1. Wilkins E, Wilson L, Wickramasinghe K, Bhatnagar P, Leal J, Luengo-Fernandez R, et al. European cardiovascular disease statistics 2017. Brussels: European Heart Network; 2017. 192 p.

2. Shames AB. [Coronary heart disease at women]. Moscow: Publishing house «BINOM»; 2013. 176 p. Russian.

3. Bobrov VA, Davydova IV, Medvedenko OI. [Cardiovascular diseases in women]. Therapia. Ukrainian Medical Bulletin. 2006;12:40-5. Russian.

4. Dvoretsky LI, Gibradze NT, Cherkasova N.A. [Coronary heart disease at women]. Russian medical Journal. 2011;2:79-83. Russian.

5. Yakovleva NF. Genetic determinants of chronic heart failure and the severity of endothelial dysfunction in patients with coronary heart disease and arterial hypertension [PhD dissertation thesis]. Novosibirsk; 2008. 23 p. Russian.

6. Smalinskiene A, Petkeviciene J, Luksiene D, Jureniene K, Klumbiene J, Lesauskaite V. Association between APOE, SCARB1, PPAR? polymorphisms and serum lipids in a population of Lithuanian adults. Lipids Health Dis. 2013;12:120. doi: 10.1186/1476511X-12-120.

7. Pleskach HV, Chumak AA, Zelin’ska AV, Shedenko LІ. [Association of rs966221 phosphodiesterase 4D gene’s polymorphism with risk of myocardial infarction]. Likarska Sprava. 2012;8:42-6. Ukrainian.

8. Pleskach HV, Nastina OM, Belyi DO, Chumak AA. [Association of phosphodiesterase 4D polymorphism with risk of myocardial infarction development in clean-up workers of Chornobyl NPP accident]. Ukrainian Medical Journal. 2014;3:126-30. Ukrainian.

9. Kovalenko VM, Lutay MІ, Sirenko YM, Sychov OS, editors. [Cardiovascular disease. Classification, standards of diagnosis and treatment]. Kyiv: MORION; 2016. 192 p. Ukrainian.

10. Belyi D, Pleskach G, Nastina O, Sidorenko G, Kursina N, Bazyka O, et al. Features of coronary heart disease development in emergency workers of the Chornobyl accident depending on the action of radiation and non-radiation risk factors and genotypes of single nucleotide polymorphism rs966221 of phosphodiesterase 4D gene. Probl Radiac Med Radiobiol. 2016;21:204-17.

11. Nastina OM, Sidorenko GV, Kursina NV, Bazyka OD, Makarevich OM, Kruglova VO, et al. [Features of cardiovascular diseases onset in liquidators of the Chernobyl accident]. Journal of National Academy of Medical Sciences. 2016;22(2):179-86. Ukrainian.

12. Liventseva MM. [Gender features of cardiovascular diseases]. Medical News. 2012;9:11-14. Russian.

13. Bland M. An introduction to medical statistics. New York: Oxford University Press Inc.; 1995. 396 p.

14. Korolenko SS, Kuriata OV. [The clinico-hemodynamic and psychological characteristics of the course of hypertension in those who cleaned up the aftermath of the accident at the Chornobyl Nuclear Power Plant]. Likarska Sprava. 1997;1:10-4. Ukrainian.

15. Kovalenko OM. [Irradiation conditions and radiation factors]. In: Kovalenko OM, editor. Acute radiation sickness (medical consequences of the Chernobyl catastrophe). Kyiv: Publishing House «Ivan Fedorov»; 1998. p. 12-13. Ukrainian.

16. Gorishna OV, Pechiborshch VP, Іvаnko OM, Babienko VV., Kosarchuk VV. [Features of diagnosis of health of servicemen who participated in the accident at the Chernobyl Nuclear Power Plant]. Bulletin of Biology and Medicine. 2014;3(4):114-7. Ukrainian.

17. Ilyin LA, Kryuchkov VP, Osanov DP, Pavlov DA. [Exposure levels of clean-up workers of the Chernobyl accident in 1986-1987 and verification of dosimetry data]. Radiobiology. 1995;35(6):803-28. Russian.

18. Pilinskaya MA, Shemetun AM, Redko DV, Cherkasskaya A M. [Cytogenetic effect in human peripheral blood lymphocytes under the influence of the Chernobyl accident factors]. In: The accident at Chernobyl Nuclear Power Plant: radiation monitoring, clinical problems, socio-psychological aspects, the demographic situation, small doses of ionizing radiation. Informational bulletin. Kyiv. 1992;2(2):86-94. Russian.

19. Nikiforov AM, Shcherbak SG, Pershin AV, Zagumenny VV, Melnichuk VI, Podmankov II, et al. [Genotoxic effects of the consequences of Chernobyl accident]. In: «Liquidators of the consequences of Chernobyl NPP accident. State of health». Materials of the World Health Organization. International program on study of medical consequences of the Chernobyl accident. Moscow: IzdAT; 1995. p. 71-7. Russian.

20. Petin VG, Dergacheva IP, Zhurakovskaya GP. [Combined biological effect of ionizing radiation and other hazardous environmental factors (scientific review)]. Radiation and Risk. 2001;12:117-34. Russian.

21. Kovaleva OM, Ambrosova TM. [Gender characteristics of the course of cardiovascular diseases: the focus on hormones]. Circulation & Haemostasis. 2012;3:45-50. Ukrainian.

22. Vozianov OF, Bebeshko VG, Bazyka DA, editors. Medical consequences of the accident at Chernobyl Nuclear Power Plant. Kyiv: DIA; 2007. 800 p. Ukrainian.

23. Serdiuk A, Bebeshko V, Bazyka D, Yamashita S, editors.Health effects of the Chernobyl accident - a quarter of century aftermath. Kyiv: DIA;2011. 648 p.

24. Bazyka D, Sushko V, Chumak A, Chumak V, Yanovych L, editors. Health effects of the Chornobyl accident - thirty years aftermath. Kyiv: DIA; 2016. 524 p.

25. Moskalenko VF, Bobilyova OV, editors. A state of health of the affected population of Ukraine and health resources after 15 years after the Chernobyl catastrophe (statistical and analytical directory in two parts). Part 1. Kirovograd: Publishing house NDVP «Technedekol»; 2001. Ukrainian.

26. Skibitsky VV, Medvedeva YN, Shukhardina EL, Skibitskaya SV. [Risk factors and the structure of cardiovascular pathology in women in the climax of various origins]. Problems of Women’s Health. 2007;2(3):21-8. Russian.

27. Pitetskaya NI, Kovaleva OM. [Cardiovascular risk factors: gender features]. Transport Medicine of Ukraine. 2011;4:83-9. Ukrainian.

28. Kuznetsova KV, Azizova TV, Bannikova MV, Bagaeva YP, Fotyeva NP, Azizova EV. [Arterial hypertension incidence rates in a cohort of nuclear workers]. Arterial Hypertension. 2016;22(3):299- 308. Russian.

29. Gretarsdottir S, Thorleifsson G, Reynisdottir ST, Manolescu A, Jonsdottir S, Jonsdottir T, et al. The gene encoding phosphodiesterase 4D confers risk of ischemic. Nat Genet. 2003;35(2):131-8.

30. Saleheen D, Bukhari S, Haider SR, Nazir A, Khanum S, Shafqat S, et al. Association of phosphodiesterase 4D gene with ischemic stroke in a Pakistani population. Stroke. 2005;36(10):2275-7.

31. Song Q, Cole JW, O’Connell JR, Stine OC, Gallagher M, Giles WH, et al. Phosphodiesterase 4D polymorphisms and the risk of cerebral infarction in a biracial population: the Stroke Prevention in Young Women Study. Hum Mol Genet. 2006;15(16):2468-78.

32. Kalita J, Somarajan BI, Kumar B, Kumar S, Mittal B, Misra UK. Phosphodiesterase 4D gene polymorphism in relation to intracranial and extracranial atherosclerosis in ischemic stroke. Dis Markers. 2011;31(4):191-7. doi: 10.3233/DMA-2011-0810.

33. Banerjee I, Pandey U, Hasan OM, Parihar R, Tripathi V, Ganesh S. Association between inflammatory gene polymorphisms and coronary artery disease in an Indian population. J Thromb Thrombolysis. 2009;27(1):88-94.

34. Sinha E, Meitei SY, Garg PR, Saraswathy KN. PDE4D gene polymorphisms and coronary heart disease: a case-control study in a north Indian population. J Clin Lab Anal. 2013;27(4):297-300. doi: 10.1002/jcla.21601.

35. Ivanov VK, Menyaylo AN, Kashcheev VV, Chekin SYu, Maksioutov MA, Pryakhin EA, et al. [Health effects of the accident at the Chernobyl NPP female cohort of the emergency accident workers. Part 1. Prognosis estimates]. Radiation and Risk. 2011;20(3):16-39. Russian.

36. Houslay MD., Adams DR. PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization. Biochem J. 2003;370:1-18.

37. Rao YJ, Xi L. Pivotal effects of phosphodiesterase inhibitors on myocyte contractility and viability in normal and ischemic hearts. Acta Pharmacol Sin. 2009;30(1):1-24. doi: 10.1038/aps.2008.1.

38. Fukumoto S, Koyama H, Hosoi M, Yamakawa K, Tanaka S, Morii H, et al. Distinct role of cAMP and cGMP in the cell cycle control of vascular smooth muscle cells: cGMP delays cell cycle transition through suppression of cyclin D1 and cyclin-dependent kinase 4 activation. Circ Res. 1999;85(11):985-91.

39. Liu L, Xu X, Li J, Li X, Sheng W. Lentiviral-mediated shRNA silencing of PDE4D gene inhibits platelet-derived growth factor-induced proliferation and migration of rat aortic smooth muscle cells. Stroke Res Treat. 2011;2011:534257. doi: 10.4061/ 2011/534257.

40. Parnell E, Smith BO, Palmer TM, Terrin A, Zaccolo M, Yarwood SJ. Regulation of the inflammatory response of vascular endothelial cells by EPAC1. Br J Pharmacol. 2012;166(2):434-46. doi: 10.1111/j.1476-5381.2011.01808.x.

41. Kryuchkov V, Chumak V, Maceika E, Anspaugh LR, Cardis E, Bakhanova E, et al. RADRUE method for reconstruction of external photon doses to Chernobyl liquidators in epidemiological studies. Health Phys. 2009;97(4):275-98. doi: 10.1097/HP. 0b013e3181ac9306.