vestimИзвестия Национальной академии наук Беларуси. Серия медицинских наукProceedings of the National Academy of Sciences of Belarus, Medical series1814-60232524-2350The Republican Unitary Enterprise Publishing House "Belaruskaya Navuka"10.29235/1814-6023-2024-21-4-294-304vestim-998Research ArticleКЛИНИЧЕСКАЯ И ЭКСПЕРИМЕНТАЛЬНАЯ МЕДИЦИНАCLINICAL AND EXPERIMENTAL MEDICINEАссоциация полиморфизма генов, кодирующих ренин-ангиотензиновую систему, и гена LZTFL1 с тяжестью течения SARS-CoV-2Association of the polymorphism of the genes coding the renin-angiotensin system and the LZTFL1 gene with the severity and outcomes of SARS-CoV-2 infectionhttps://orcid.org/0000-0001-8492-6377МатиевскаяН. В.MatsiyeuskayaN. V.

Матиевская Наталья Васильевна – д-р мед. наук,  профессор, заведующий кафедрой

ул. Горького, 80, 230009, г. Гродно

Natalia V. Matsiyeuskaya ‒ D. Sc. (Med.), Professor, Head of the Department

80, Gorky Str., 230009, Grodno

natamati@mail.ruКузнецоваЕ. В.KuzniatsovaK. U.

Кузнецова Екатерина Владимировна – ст. преподаватель

ул. Горького, 80, 230009, г. Гродно

Katsiaryna U. Kuzniatsova ‒ Senior Lecturer

80, Gorky Str., 230009, Grodno

kat.kuzniatsova@gmail.comhttps://orcid.org/0000-0002-5973-7870МорозикП. М.MarozikP. M.

Морозик Павел Михайлович – канд. биол. наук, доцент, заместитель директора по научной работе

ул. Академическая, 27, 220072, г. Минск

Pavel M. Marozik – Ph. D. (Biol.), Associate Professor, Deputy Director

27, Akademicheskaya Str., 220072, Minsk

P.Marozik@igc.byhttps://orcid.org/0000-0002-8153-7963КозловскийВ. И.KozlovskiV. I.

Козловский Валерий Иванович – доцент, заведующий кафедрой

ул. Горького, 80, 230009, г. Гродно

Valery I. Kozlovski – Associate Professor, Head of the Department

80, Gorky Str., 230009, Grodno

vkz45@yahoo.comГорчаковаО. В.HarchakovaV. U.

Горчакова Ольга Владимировна – магистр мед. наук, ст. науч. сотрудник

ул. Горького, 80, 230009, г. Гродно

Volha U. Harchakova – Master of Med. Sci., Senior Researcher

80, Gorky Str., 230009, Grodno

daniil_go@inbox.ruГродненский государственный медицинский университетGrodno State Medical UniversityИнститут генетики и цитологии НАН БеларусиInstitute of Genetics and Cytology of the National Academy of Sciences of Belarus202430112024214294304Copyright © Матиевская Н.В., Кузнецова Е.В., Морозик П.М., Козловский В.И., Горчакова О.В., 20242024Матиевская Н.В., Кузнецова Е.В., Морозик П.М., Козловский В.И., Горчакова О.В.Matsiyeuskaya N.V., Kuzniatsova K.U., Marozik P.M., Kozlovski V.I., Harchakova V.U.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://vestimed.belnauka.by/jour/article/view/998

Цель исследования ‒ установить ассоциацию ряда вариантов генов, вовлеченных в ренин-ангиотензиновую систему, с тяжестью течения SARS-CoV-2-инфекции.

В исследование было включено 206 госпитализированных пациентов с COVID-19, разделенных на две группы: 1-я группа – 99 пациентов с тяжелой формой COVID-19; 2-я группа ‒ 107 пациентов со средней и легкой формами заболевания. Анализ полиморфных вариантов генов ACE rs4646994, ACE2 rs2074192, rs2285666 и rs413031713 и LZTFL1 rs10490770 осуществляли с помощью количественной ПЦР с зондами TaqMan («Праймтех», Беларусь) на приборе CFX96 (Bio-Rad, США). Варианты генов AGT rs699 и AGTR1 rs5186 определяли на приборе Rotor-Gene Q (QIAGEN,

Германия) в соответствии с протоколами производителя наборов реагентов («Литех», Россия).

Установлено, что генетическими маркерами тяжелого течения COVID-19 среди белорусских пациентов являются гетерозиготный генотип LZTFL1 rs10490770 T/С, а также гаплотип А-А по локусам ACE2 rs2074192 и rs2285666 и аллельная комбинация A-A-C по локусам ACE2 rs2074192, ACE2 rs2285666 и AGT rs699. Выявлены генетические маркеры, ассоциированные с легкой/средней тяжестью течения COVID-19: гетерозиготный вариант AGTR1 rs5186 A/C, аллельная комбинация G-G-T по локусам ACE2 rs2074192 и rs2285666, AGT rs699 (у носителей этих вариантов генов снижен риск тяжелого течения заболевания).

Таким образом, локусы генов, вовлеченных в регуляцию ренин-ангиотензиновой системы (ACE2 rs2074192 и rs2285666, AGTR1 rs5186) и гена LZTFL1 rs10490770, а также их гаплотипы являются информативными маркерами для прогнозирования тяжести течения COVID-19.

The aim of the study is to establish the association of variants of a number of genes involved in the reninangiotensin system with the severity of SARS-CoV-2 infection.

The study included 206 hospitalized patients with COVID-19: Group 1 – 99 patients with severe COVID-19; Group 2 ‒ 107 with moderate and mild forms of the disease.

Polymorphic variants of the ACE rs4646994, ACE2 rs2074192 rs2285666 and rs413031713 and LZTFL1 rs10490770 genes were analyzed using quantitative PCR with TaqMan probes (Primetech, Belarus) on a CFX96 thermocycler (Bio-Rad, USA). AGT rs699 and AGTR1 rs5186 gene variants were determined using a Rotor-Gene Q thermocycler (QIAGEN, Germany),  in accordance to the protocols of the manufacturer (Litekh, Russia).

We revealed that the genetic markers of the severe COVID-19 infection in the Belarusian patients are the heterozygous T/C genotype of the LZTFL1 rs10490770 variant, as well as the A-A haplotype of the ACE2 rs2074192 and rs2285666 loci, and the A-A-C allelic combination of the ACE2 rs2074192, rs2285666 and AGT rs699 genes. Genetic markers associated with mild/moderate severity of COVID-19 were also identified: heterozygous A/C genotype of the AGTR1 rs5186 variant,  G-G-T allelic combination at the ACE2 rs2074192 and rs2285666, AGT rs699 loci (among carriers of these gene variants,  the risk of severe disease is reduced).

The loci of the genes encoding the renin-angiotensin system – ACE2 rs2074192 and rs2285666, AGTR1 rs5186,  and the LZTFL1 rs10490770 genes, as well as allelic combinations between the ACE2 rs2074192, rs2285666 and AGT rs699 loci are informative markers for predicting the severity of COVID-19.

СOVID-19ACE2 rs2074192ACE2 rs2285666AGT rs699LZTFL1 rs10490770AGTR1 rs5186ренин-ангиотензиновая системаСOVID-19ACE2 rs2074192ACE2 rs2285666AGT rs699LZTFL1 rs10490770AGTR1 rs5186reninangiotensin systemРабота выполнена при поддержке Acknowledgеments. The work was carried out with the БРФФИ (проект № М21КОВИД-036 от 01.02.2021 г.).The work was carried out with the support of the BRFFR (project no. M21COVID-036 dated 01.02.2021).ReferencesКоростовцева, Л. С. COVID-19: каковы риски пациентов с артериальной гипертензией? / Л. С. Коростовцева, О. П. Ротарь, А. О. Конради // Артериал. гипертензия. – 2020. – Т. 26, № 2. – С. 124–132.Korostovtseva L. S., Rotar’ O. P., Konradi A. O. COVID 19: What are the risks of patients with hypertension? Arterial’naya gipertenziya [Arterial hypertension], 2020, vol. 26, no. 2, pp. 124–132 (in Russian).Devaux, C. A. An update on angiotensin-converting enzyme 2 structure/functions, polymorphism, and duplicitous nature in the pathophysiology of coronavirus disease 2019: Implications for vascular and coagulation disease associated with severe acute respiratory syndrome coronavirus infection / C. A. Devaux, L. Camoin-Jau // Front. Microbiol. – 2022. – Vol. 13. – Art. 1042200. https://doi.org/10.3389/fmicb.2022.1042200Devaux C. A., Camoin-Jau L. An update on angiotensin-converting enzyme 2 structure/functions, polymorphism, and duplicitous nature in the pathophysiology of coronavirus disease 2019: Implications. for vascular and coagulation disease associated with severe acute respiratory syndrome coronavirus infection. Frontiers in Microbiology, 2022, vol. 13, art. 1042200. https://doi.org/10.3389/fmicb.2022.1042200Елькина, А. Ю. Полиморфные варианты генов ангиотензинпревращающего фермента, ангиотензиногена, гена рецептора 1 типа к ангиотензину-ІІ как генетические предикторы развития артериальной гипертонии / А. Ю. Елькина, Н. С. Акимова, Ю. Г. Шварц // Рос. кардиол. журн. – 2021. ‒ Т. 26, № S1. ‒ С. 35‒40.El’kina A. Yu., Akimova N. S., Shvarts Yu. G. Polymorphism of ACE, AGT, AGTR1 genes as genetic predictors of hypertension. Rossiiskii kardiologicheskii zhurnal [Russian cardiological journal], 2021, vol. 26, no. S1, pp. 35‒40 (in Russian).Angiotensin-converting enzymes (ACE, ACE2) gene variants and COVID-19 outcome / J. Gómez [et al.] // Gene. – 2020. – Vol. 762. ‒ Art. 145102. https://doi.org/10.1016/j.gene.2020.145102Gómez J., Albaiceta G. M., García-Clemente M., López-Larrea C., Amado-Rodríguez L., Lopez-Alonso I. [et al.]. Angiotensin-converting enzymes (ACE, ACE2) gene variants and COVID-19 outcome. Gene, 2020, vol. 762, art. 145102. https://doi.org/10.1016/j.gene.2020.145102ACE I/D polymorphism in Czech first-wave SARS-CoV-2-positive survivors / J. A. Hubacek [et al.] // Clin. Chim. Acta. – 2021. – Vol. 519. – P. 206–209. https://doi.org/10.1016/j.cca.2021.04.024Hubacek J. A., Dusek L., Majek O., Adamek V., Cervinkova T., Dlouha D., Adamkova V. ACE I/D polymorphism in Czech first-wave SARS-CoV-2-positive survivors. Clinica Chimica Acta, 2021, vol. 519, pp. 206–209. https://doi.org/10.1016/j.cca.2021.04.024Шишиморов, И. Н. Генетические предикторы тяжести течения и эффективности фармакотерапии COVID-19 / И. Н. Шишиморов, О. В. Магницкая, Ю. В. Пономарева // Фармация и фармакология. – 2021. – Т. 9, № 3. – С. 174–184.Shishimorov I. N., Magnitskaya O. V., Ponomareva Yu. V. Genetic predictors of the severity of the course and effectiveness of COVID-19 pharmacotherapy. Farmatsiya i farmakologiya [Pharmacy and pharmacology], 2021, vol. 9, no. 3, pp. 174–184 (in Russian).Роль ренин-ангиотензиновой системы и ангиотензинпревращающего фермента 2 типа в развитии и течении вирусной инфекции СОVID-19 у пациентов с сахарным диабетом / О. К. Викулова [и др.] // Сахар. диабет. – 2020. – Т. 23, № 3. – С. 242–249.Vikulova O. K., Zuraeva Z. T., Nikankina L. V., Shestakova M. V. The role of renin-angiotensin system and. Sakharnyi diabet [Diabetes mellitus], 2020, vol. 23, no. 3, pp. 242–249 (in Russian).Genome-wide analysis provides genetic evidence that ACE2 influences COVID-19 risk and yields risk scores associated with severe disease / J. E. Horowitz [et al.] // Nat. Genet. ‒ 2022. – Vol. 54, N 4. – P. 382–392. https://doi.org/10.1038/s41588-021-01006-7Horowitz J. E., Kosmicki J. A., Damask A., Sharma D., Roberts G. H. L., Justice A. E. [et al.]. Genome-wide analysis provides genetic evidence that ACE2 influences COVID-19 risk and yields risk scores associated with severe disease. Nature Genetics, 2022, vol. 54, no. 4, pp. 382–392. https://doi.org/10.1038/s41588-021-01006-7The relationship between angiotensinogen gene polymorphisms and essential hypertension in a Northern Han Chinese population / H. Li [et al.] // Angiology. – 2014. – Vol. 65, N 7. – P. 614–619. https://doi.org/10.1177/0003319713491309Li Hdu Zh., Zhang L., Wu T., Deng Zh., Li J., Cong M., Liu J., Qiu Ch. Angiology. The relationship between angiotensinogen gene polymorphisms and essential hypertension in a Northern Han Chinese population. Angiology, 2014, vol. 65, no. 7, pp. 614–619. https://doi.org/10.1177/0003319713491309Linkage of blood pressure, obesity and diabetes mellitus with angiotensinogen gene (AGT 704T>C/rs699) polymorphism in hypertensive patients / Y. Repchuk [et al.] // Bratisl. Lek. Listy. – 2021. – Vol. 122, N 10. – P. 715–720. https://doi.org/10.4149/BLL_2021_114Repchuk Y., Sydorchuk L. P., Sydorchuk A. R., Fedonyuk L. Y., Kamyshnyi O., Korovenkova O. [et al.]. Linkage of blood pressure, obesity and diabetes mellitus with angiotensinogen gene (AGT 704T>C/rs699) polymorphism in hypertensive patients. Bratislavské lekárske listy, 2021, vol. 122, no. 10, pp. 715–720. https://doi.org/10.4149/BLL_2021_114Association between angiotensinogen (AGT), angiotensin-converting enzyme (ACE) and angiotensin-II receptor 1 (AGTR1) polymorphisms and COVID-19 infection in the southeast of Iran: a preliminary case-control study / H. R. Kouhpayeh [et al.] // Transl. Med. Commun. – 2021. – Vol. 6, N 1. – Art. 26. https://doi.org/10.1186/s41231-021-00106-0Kouhpayeh H. R., Tabasi F., Dehvari M., Naderi M., Bahari Gh., Khalili T., Clark C., Ghavami S., Taheri M. Association between angiotensinogen (AGT), angiotensin-converting enzyme (ACE) and angiotensin-II receptor 1 (AGTR1) polymorphisms and COVID-19 infection in the southeast of Iran: a preliminary case-control study. Translational Medicine Communications, 2021, vol. 6, no. 1, art. 26. https://doi.org/10.1186/s41231-021-00106-0Angiotensin system polymorphisms’ in SARS-CoV-2 positive patients: Assessment between symptomatic and asymptomatic patients: A pilot study / C. Cafiero [et al.] // Pharmgenomics Pers. Med. – 2021. – Vol. 27, N 14. – P. 621–629. https://doi.org/10.2147/PGPM.S303666Cafiero C., Rosapepe F., Palmirotta R., Re A., Ottaiano M. P., Benincasa G. [et al.]. Angiotensin system polymorphisms’ in SARS-CoV-2 positive patients: Assessment between symptomatic and asymptomatic patients: A pilot study. Pharmacogenomics and Personalized Medicine, 2021, vol. 27, no. 14, pp. 621–629. https://doi.org/10.2147/PGPM.S303666Angiotensin II type 1 receptor gene polymorphisms in human essential hypertension / A. Bonnardeaux [et al.] // Hypertension. – 1994. – Vol. 24, N 1. – P. 63–69. https://doi.org/10.1161/01.hyp.24.1.63Bonnardeaux A., Davies E., Jeunemaitre X., Féry I., Charru A., Clauser E., Tiret L., Cambien F., Corvol P., Soubrier F. Angiotensin II type 1 receptor gene polymorphisms in human essential hypertension. Hypertension, 1994, vol. 24, no. 1, pp. 63–69. https://doi.org/10.1161/01.hyp.24.1.63Allele С (rs5186) of at1r is associated with the severity of COVID-19 in the Ukrainian population / O. Izmailova [et al.] // Infect. Genet. Evol. – 2022. – Vol. 98. https://doi.org/10.1016/j.meegid.2022.105227Izmailova O., Shlykova O., Vatsenko A., Ivashchenko D., Dudchenko M., Koval T., Kaidashev I. Allele С (rs5186) of at1r is associated with the severity of COVID-19 in the Ukrainian population. Infection, Genetics and Evolution, 2022, vol. 98. https://doi.org/10.1016/j.meegid.2022.105227Геногеография в России и мире snp-маркеров гена lztfl1, ассоциированных с тяжелым течением COVID-19 / Е. В. Балановская [и др.] // Вестн. Рос. гос. мед. ун-та. – 2022. – № 5. – C. 31‒40. https://doi.org/10.24075/vrgmu.2022.047Balanovskaya E. V., Gorin I. O., Petrushenko V. S., Chernevskiy D. K., Koshe S. M., Temirbulatov I. I., Pylev V. Yu., Agdzhoyan A. T. Geographic distribution of the LZTFL1 SNP markers associated with severe COVID-19 in Russia and worldwide. Vestnik Rossiyskogo gosudarstvennogo meditsinskogo universiteta [Bulletin of Russian State Medical University], 2022, no. 5, pp. 30–39 (in Russian). https://doi.org/10.24075/brsmu.2022.047Василевский, И. В. Генетические факторы человека, связанные с восприимчивостью к инфекции SARSCoV-2 и тяжестью заболевания COVID-19 / И. В. Василевский // Здравоохранение. – 2022. – № 4. – С. 20–30.Vasilevskii I. V. Human genetic factors associated with susceptibility to SARS-CoV-2 infection and severity of COVID-19 disease. Zdravookhranenie [Healthcare], 2022, no. 4, pp. 20–30 (in Russian).Severity of coronavirus disease 19: Profile of inflammatory markers and ACE (rs4646994) and ACE2 (rs2285666) gene polymorphisms in Iraqi patients / Z. S. Mahmood [et al.] // Meta Gene. – 2022. – Vol. 31. – Art. 101014. https://doi.org/10.1016/j.mgene.2022.101014Mahmood Z. S., Fadhil H. Y., Abdul Hussein T. A., Ad’hiah A. H. Severity of coronavirus disease 19: Profile of inflammatory markers and ACE (rs4646994) and ACE2 (rs2285666) gene polymorphisms in Iraqi patients. Meta Gene, 2022, vol. 31, art. 101014. https://doi.org/10.1016/j.mgene.2022.101014Strong association of angiotensin converting enzyme-2 gene insertion/deletion polymorphism with susceptibility to SARS-CoV-2, hypertension, coronary artery disease and COVID-19 disease mortality / M. M. Mir [et al.] // J. Pers. Med. – 2021. – Vol. 11, N 11. – Art. 1098. https://doi.org/10.3390/jpm11111098Mir M. M., Mir R., Alghamdi M. A. A., Alsayed B. A., Wani J. I., Alharthi M. H., AL-Shahrani A. M. Strong association of angiotensin converting enzyme-2 gene insertion/deletion polymorphism with susceptibility to SARS-CoV-2, hypertension, coronary artery disease and COVID-19 disease mortality. Journal of Personalized Medicine, 2021, vol. 11, art. 1098. https://doi.org/10.3390/jpm11111098Mapping the human genetic architecture of COVID-19 / COVID-19 host genetics initiative // Nature. – 2021. – Vol. 600, N 7889. – P. 472–477. https://doi.org/10.1038/s41586-021-03767-xCOVID-19 host genetics initiative. Mapping the human genetic architecture of COVID-19. Nature, 2021, vol. 600, no. 7889, pp. 472–477. https://doi.org/10.1038/s41586-021-03767-xAge-dependent impact of the major common genetic risk factor for COVID-19 on severity and mortality [Electronic resource] / T. Nakanishi [et al.] // medRxiv. – 2021. – Mode of access: https://doi.org/10.1101/2021.03.07.21252875. – Date of access: 10.10.2024.Nakanishi T., Pigazzini S., Degenhardt F., Cordioli M., Butler-Laporte G., Maya-Miles D. [et al.]. Age-dependent impact of the major common genetic risk factor for COVID-19 on severity and mortality. medRxiv, 2021. Available at: https://doi.org/10.1101/2021.03.07.21252875 (accessed 10.10.2024).

The authors declare that there are no conflicts of interest present.