persmedРоссийский журнал персонализированной медициныRussian Journal for Personalized Medicine2782-38062782-3814ФОНД АЛМАЗОВА10.18705/2782-3806-2022-2-3-47-60persmed-57Research ArticleФАРМАКОГЕНЕТИКА И ФАРМАКОГЕНОМИКАPHARMACOGENETICS AND PHARMACOGENOMICSПОЛИМОРФНЫЕ ВАРИАНТЫ RS1004467 И RS11191548 ГЕНА CYP17A1 СВЯЗАНЫ С РАННИМ ГИПОЛИПИДЕМИЧЕСКИМ ОТВЕТОМ НА ТЕРАПИЮ РОЗУВАСТАТИНОМPOLYMORPHISMS RS1004467 AND RS11191548 AT CYP17A1 ARE ASSOCIATED WITH EARLY HYPOLIPIDEMIC RESPONSE TO ROSUVASTATIN THERAPYКононовС. И.KononovS. I.

Кононов Станислав Игоревич, к.м.н., ассистент кафедры внутренних болезней № 2

ул. Карла Маркса, д. 3, Курск, 305041

Kononov Stanislav I., candidate of medical sciences, assistant lecturer of the Department of Internal Medicine N 2

Karl Marx str., 3, Kursk, 305041

ck325@yandex.ruАзароваЮ. Э.AzarovaY. E.

Азарова Юлия Эдуардовна, к.м.н., доцент кафедры биохимии, заведующий лабораторией биохимической генетики и метаболомики НИИ генетической и молекулярной эпидемиологии 

ул. Карла Маркса, д. 3, Курск, 305041

Azarova Yulia E., candidate of medical sciences, associate professor of the Department of Biochemistry; head of Laboratory of Biochemical Genetics and Metabolomics, Research Institute for Genetic and Molecular Epidemiology

Karl Marx str., 3, Kursk, 305041

КлёсоваЕ. Ю.KlyosovaE. Y.

Клёсова Елена Юрьевна, ассистент кафедры биологии, медицинской генетики и экологии, младший научный сотрудник лаборатории биохимической генетики и метаболомики НИИ генетической и  молекулярной эпидемиологии

ул. Карла Маркса, д. 3, Курск, 305041

Klyosova Elena Yu., assistant lecturer of the Department of Biology, Medical Genetics and Ecology; junior researcher of Laboratory of Biochemical Genetics and Metabolomics, Research Institute for Genetic and Molecular Epidemiology

Karl Marx str., 3, Kursk, 305041

БыкановаМ. А.BykanovaM. A.

Быканова Марина Алексеевна, к.б.н., ассистент кафедры биологии, медицинской генетики и экологии, научный сотрудник лаборатории геномных исследований НИИ генетической и молекулярной эпидемиологии

ул. Карла Маркса, д. 3, Курск, 305041

Bykanova Marina A., candidate of biological sciences, assistant lecturer of the Department of Biology, Medical Genetics and Ecology; researcher of Laboratory of Genomic Research, Research Institute for Genetic and Molecular Epidemiology

Karl Marx str., 3, Kursk, 305041

КононоваИ. Н.KononovaI. N.

Кононова Ирина Николаевна, врач-кардиолог

Курск

Kononova Irina N., cardiologist

Kursk

ПолониковА. В.PolonikovA. V.

Полоников Алексей Валерьевич, д.м.н., директор НИИ генетической и молекулярной эпидемиологии, профессор кафедры биологии, медицинской генетики и экологии

ул. Карла Маркса, д. 3, Курск, 305041

Polonikov Alexey V., doctor of medical sciences, professor of the Department of Biology, Medical Genetics and Ecology; Head of Research Institute for Genetic and Molecular Epidemiology

Karl Marx str., 3, Kursk, 305041

Федеральное государственное бюджетное образовательное учреждение высшего образования «Курский государственный медицинский университет» Министерства здравоохранения Российской ФедерацииРоссияFederal State Budget Educational Establishment of Higher Education “Kursk State Medical University” Ministry of Health Care of Russian FederationRussian FederationОбластное бюджетное учреждение здравоохранения «Курская городская клиническая больница скорой медицинской помощи»РоссияRegional Budget Health Care Establishment “Kursk City Clinical Hospital of Emergency Medical Care”Russian Federation202213072022234760Copyright © Кононов С.И., Азарова Ю.Э., Клёсова Е.Ю., Быканова М.А., Кононова И.Н., Полоников А.В., 20222022Кононов С.И., Азарова Ю.Э., Клёсова Е.Ю., Быканова М.А., Кононова И.Н., Полоников А.В.Kononov S.I., Azarova Y.E., Klyosova E.Y., Bykanova M.A., Kononova I.N., Polonikov A.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://persmed.elpub.ru/jour/article/view/57

Актуальность. Полиморфные варианты гена CYP17A1 известны своей связью с риском развития ишемической болезни сердца (ИБС), артериальной гипертензии (АГ) и дислипидемии, уровнями половых гормонов, однако до настоящего времени не исследовались в контексте фармакогенетики. Цель. Изучить связь полиморфных вариантов rs1004467 и rs11191548 гена CYP17A1 с эффективностью терапии розувастатином в отношении динамики изменения липидов плазмы крови и толщины комплекса интима-медиа (ТИМ) общей сонной артерии, а также исследовать ассоциации данных полиморфизмов с риском развития ИБС и АГ в российской популяции. Материалы и методы. В фармакогенетическое исследование включались 116 пациентов с ИБС: стабильной стенокардией напряжения, длительность наблюдения — 12 месяцев; в генетико-ассоциативное: 749 пациентов с ИБС и 737 — с АГ. Генотипирование выполнено по технологии iPLEX на геномном масс-спектрометре MassARRAY-4. Результаты. Оба исследованных полиморфизма не были ассоциированы с риском развития ИБС и АГ. Наиболее значимые ассоциации с ослабленной динамикой снижения ХС ЛНП наблюдались через 1 месяц терапии (у гомозигот по минорному аллелю обоих полиморфизмов, p = 0,0002), с динамикой триглицеридов — через 6 месяцев терапии (у гетерозигот по rs1004467 и rs11191548, p = 0,0015 и 0,0013 соответственно). Ослабление регресса ТИМ за 6 месяцев наблюдения было ассоциировано с вариантом rs11191548 (p = 0,034). Заключение. В работе впервые установлены ассоциации полиморфных вариантов rs1004467 и rs11191548 гена CYP17A1 с эффективностью применения розувастатина, которые были наиболее значимы в раннем периоде терапии.

Background. Polymorphisms of the CYP17A1 gene are known for their association with the risk of coronary artery disease (CAD), and essential hypertension (EH), dyslipidemia, and with the levels of sex hormones. However, pharmacogenetics aspects of these polymorphisms have not so far been investigated. Objective. To study the association of rs1004467 and rs11191548 variants at CYP17A1 with the effectiveness of rosuvastatin therapy in terms of change in plasma lipids and carotid intima-media thickness (CIMT), and the association with the risk of CAD and EH in Russians. Design and methods. The pharmacogenetics study included 116 patients with CAD, stable angina pectoris, observation period was 12 months; genetic association study — 749 patients with CAD, 737 EH patients. Genotyping was performed using the MassARRAY-4 system. Results. Both CYP17A1 polymorphisms were not associated with CAD and EH risk. The most significant associations with the attenuated decrease in LDL-C were observed in 1 month of therapy (in variant homozygotes of both polymorphisms, p = 0,0002), and with triglyceride level change in 6 months (in heterozygotes of rs1004467 and rs11191548, p = 0,0015 и 0,0013, respectively). Attenuated CIMT regression in 6 months was associated with rs11191548 variant (p = 0,034). Conclusion. We have found for the first time the associations of rs1004467 and rs11191548 of CYP17A1 with the effectiveness of rosuvastatin therapy, and the associations were the strongest in the early period of treatment.

ишемическая болезнь сердцакомплекс интима-медиалипопротеиды низкой плотностиполиморфизмрозувастатинтриглицеридыфармакогенетикахолестеринCYP17A1carotid intima-media thicknesscholesterolcoronary artery diseaseCYP17A1low-density lipoproteinspharmacogeneticspolymorphismrosuvastatintriglyceridesReferencesМирзаев К.Б., Федоринов Д.С., Иващенко Д.В., и др. Мультиэтнический анализ кардиологических фармакогенетических маркеров генов цитохрома Р450 и мембранных транспортеров в российской популяции. Рациональная Фармакотерапия в Кардиологии. 2019;15(3):393–406.Mirzaev KB, Fedorinov DS, Ivashchenko DV, et al. Multi-Ethnic Analysis of Cardiac Pharmacogenetic Markers of Cytochrome p450 and Membrane Transporters Genes in the Russian Population. Rational Pharmacotherapy in Cardiology. 2019;15(3):393–406. In RussianSCORE2 working group and ESC Cardiovascular risk collaboration. SCORE2 risk prediction algorithms: new models to estimate 10-year risk of cardiovascular disease in Europe. Eur Heart J. 2021;42(25):2439–2454.SCORE2 working group and ESC Cardiovascular risk collaboration. SCORE2 risk prediction algorithms: new models to estimate 10-year risk of cardiovascular disease in Europe. Eur Heart J. 2021;42(25):2439–2454.Tabara Y, Kohara K, Kita Y, et al. Common variants in the ATP2B1 gene are associated with susceptibility to hypertension: the Japanese Millennium Genome Project. Hypertension. 2010;56(5):973–80.Tabara Y, Kohara K, Kita Y, et al. Common variants in the ATP2B1 gene are associated with susceptibility to hypertension: the Japanese Millennium Genome Project. Hypertension. 2010;56(5):973–80.Liu C, Li H, Qi Q, et al. Common variants in or near FGF5, CYP17A1 and MTHFR genes are associated with blood pressure and hypertension in Chinese Hans. J Hypertens. 2011 Jan;29(1):70–5. DOI:10.1097/HJH.0b013e32833f60ab. PMID:20852445.Liu C, Li H, Qi Q, et al. Common variants in or near FGF5, CYP17A1 and MTHFR genes are associated with blood pressure and hypertension in Chinese Hans. J Hypertens. 2011 Jan;29(1):70–5. DOI:10.1097/HJH.0b013e32833f60ab. PMID:20852445.Huber M, Lezius S, Reibis R, et al. A Single Nucleotide Polymorphism near the CYP17A1 Gene Is Associated with Left Ventricular Mass in Hypertensive Patients under Pharmacotherapy. Int J Mol Sci. 2015;16(8):17456–68.Huber M, Lezius S, Reibis R, et al. A Single Nucleotide Polymorphism near the CYP17A1 Gene Is Associated with Left Ventricular Mass in Hypertensive Patients under Pharmacotherapy. Int J Mol Sci. 2015;16(8):17456–68.Hamrefors V, Sjögren M, Almgren P, et al. Pharmacogenetic implications for eight common blood pressure-associated single-nucleotide polymorphisms. J Hypertens. 2012;30(6):1151–60.Hamrefors V, Sjögren M, Almgren P, et al. Pharmacogenetic implications for eight common blood pressure-associated single-nucleotide polymorphisms. J Hypertens. 2012;30(6):1151–60.Dai CF, Xie X, Yang YN, et al. Relationship between CYP17A1 genetic polymorphism and coronary artery disease in a Chinese Han population. Lipids Health Dis. 2015;14:16.Dai CF, Xie X, Yang YN, et al. Relationship between CYP17A1 genetic polymorphism and coronary artery disease in a Chinese Han population. Lipids Health Dis. 2015;14:16.Dai CF, Xie X, Ma YT, et al. Haplotype analyses of CYP17A1 genetic polymorphisms and coronary artery disease in a Uygur population. J Renin Angiotensin Aldosterone Syst. 2015;16(2):389–398.Dai CF, Xie X, Ma YT, et al. Haplotype analyses of CYP17A1 genetic polymorphisms and coronary artery disease in a Uygur population. J Renin Angiotensin Aldosterone Syst. 2015;16(2):389–398.Zhang N, Chen H, Jia J, et al. The CYP17A1 gene polymorphisms are associated with hypercholesterolemia in Han Chinese. J Gene Med. 2019;21(8):e3102.Zhang N, Chen H, Jia J, et al. The CYP17A1 gene polymorphisms are associated with hypercholesterolemia in Han Chinese. J Gene Med. 2019;21(8):e3102.Никулина С.Ю., Шульман В.А., Чернова А.А. и др. Роль однонуклеотидного полиморфизма гена СYP17A в развитии инсульта. Рациональная Фармакотерапия в Кардиологии 2018;14(4):488–493.Nikulina SY, Shulman VA, Chernova AA, et al. Role of Single Nucleotide Polymorphism of СУР17А Gene in the Development of Stroke. Rational Pharmacotherapy in Cardiology. 2018;14(4):488–493. In RussianКанаева М.Д., Глотов А.С., Вашукова Е.С. и др. Исследование генетической предрасположенности к развитию артериальной гипертензии у детей Северо-Западного региона России. Экологическая генетика. 2013;11(2):34–40.Kanaeva MD, Glotov AS, Vashukova YeS, et al. Research of genetic markers in susceptibility to arterial hypertension in Russian Northwest Region children. Ecological genetics. 2013;11(2):34–40. In RussianКиселева А.В., Климушина М.В., Тюпаева С.А. и др. Вклад генетических маркеров и производственных факторов в развитие артериальной гипертонии у мужчин в организованной когорте работников машиностроительного завода. Российский кардиологический журнал. 2017;10(150):55–60.Kiseleva AV, Klimushina МV, Tyupaeva SА, et al. Contribution of genetic markers and production factors in the development of arterial hypertension in men in an organized workers cohort of machine-building plant. Russ J Cardiol. 2017;10(150):55–60. In RussianZhang J, Yang M, Luan P, et al. Associations Between Cytochrome P450 (CYP) Gene SingleNucleotide Polymorphisms and Second-to-Fourth Digit Ratio in Chinese University Students. Med Sci Monit. 2021;27:e930591.Zhang J, Yang M, Luan P, et al. Associations Between Cytochrome P450 (CYP) Gene SingleNucleotide Polymorphisms and Second-to-Fourth Digit Ratio in Chinese University Students. Med Sci Monit. 2021;27:e930591.Solodilova MA, Medvedeva MV, Bykanova MA, et al. Polymorphism of the VEGFA gene, smoking and coronary heart disease: the significance of geneenvironmental interactions for disease susceptibility. Res. Results Biomed. 2020;6(3):350–366.Solodilova MA, Medvedeva MV, Bykanova MA, et al. Polymorphism of the VEGFA gene, smoking and coronary heart disease: the significance of geneenvironmental interactions for disease susceptibility. Res. Results Biomed. 2020;6(3):350–366.Zvyagina MV, Mal GS, Bushueva OY, et al. Estimating the effectiveness of hypolipidemic therapy with rosuvastatin in patients with coronary heart disease depending on the genotype of lipoprotein lipase. Eksp. Klin. Farmakol. 2016;79(1):15–19.Zvyagina MV, Mal GS, Bushueva OY, et al. Estimating the effectiveness of hypolipidemic therapy with rosuvastatin in patients with coronary heart disease depending on the genotype of lipoprotein lipase. Eksp. Klin. Farmakol. 2016;79(1):15–19.Polonikov A, Kharchenko A, Bykanova M, et al. Polymorphisms of CYP2C8, CYP2C9 and CYP2C19 and risk of coronary heart disease in Russian population. Gene. 2017;627: 451–459.Polonikov A, Kharchenko A, Bykanova M, et al. Polymorphisms of CYP2C8, CYP2C9 and CYP2C19 and risk of coronary heart disease in Russian population. Gene. 2017;627: 451–459.Polonikov AV, Vialykh EK, Churnosov MI, et al. The C718T polymorphism in the 3’-untranslated region of glutathione peroxidase-4 gene is a predictor of cerebral stroke in patients with essential hypertension. Hypertens. Res. 2012:35(5):507–512.Polonikov AV, Vialykh EK, Churnosov MI, et al. The C718T polymorphism in the 3’-untranslated region of glutathione peroxidase-4 gene is a predictor of cerebral stroke in patients with essential hypertension. Hypertens. Res. 2012:35(5):507–512.Балахонова Т.В., Трипотень М.И., Погорелова О.А. Ультразвуковые методы оценки толщины комплекса интима-медиа артериальной стенки. SonoAce-Ultrasound. 2010;21:57–63.Balakhonova TV, Tripoten’ MI, Pogorelova OA. Ultrasonic methods for assessing the thickness of the intima-media complex of the arterial wall. SonoAceUltrasound. 2010;21:57–63. In RussianPignoli P, Tremoli E, Poli A, et al. Intimal plus medial thickness of the arterial wall: a direct measurement with ultrasound imaging. Circulation. 1986;74(6):1399–1406.Pignoli P, Tremoli E, Poli A, et al. Intimal plus medial thickness of the arterial wall: a direct measurement with ultrasound imaging. Circulation. 1986;74(6):1399–1406.German CA, Sinsheimer JS, Klimentidis YC, et al. Ordered multinomial regression for genetic association analysis of ordinal phenotypes at Biobank scale. Genetic Epidemiology. 2020;44(3):248–260.German CA, Sinsheimer JS, Klimentidis YC, et al. Ordered multinomial regression for genetic association analysis of ordinal phenotypes at Biobank scale. Genetic Epidemiology. 2020;44(3):248–260.Wei BL, Yin RX, Liu CX, et al. CYP17A1- ATP2B1 SNPs and Gene-Gene and Gene-Environment Interactions on Essential Hypertension. Front Cardiovasc Med. 2021;8:720884.Wei BL, Yin RX, Liu CX, et al. CYP17A1- ATP2B1 SNPs and Gene-Gene and Gene-Environment Interactions on Essential Hypertension. Front Cardiovasc Med. 2021;8:720884.Poniah P, Mohamed Z, Apalasamy YD, et al. Genetic polymorphisms in the androgen metabolism pathway and risk of prostate cancer in low incidence Malaysian ethnic groups. Int J Clin Exp Med. 2015;10(8):8.Poniah P, Mohamed Z, Apalasamy YD, et al. Genetic polymorphisms in the androgen metabolism pathway and risk of prostate cancer in low incidence Malaysian ethnic groups. Int J Clin Exp Med. 2015;10(8):8.Solé X, Guinó E, Valls J, et al. SNPStats: a web tool for the analysis of association studies. Bioinformatics. 2006;22(15):1928–1929.Solé X, Guinó E, Valls J, et al. SNPStats: a web tool for the analysis of association studies. Bioinformatics. 2006;22(15):1928–1929.Uhlén M, Fagerberg L, Hallström BM, et al. Tissue-based map of the human proteome. Science. 2015;347(6220):1260419.Uhlén M, Fagerberg L, Hallström BM, et al. Tissue-based map of the human proteome. Science. 2015;347(6220):1260419.Ortega I, Cress AB, Wong DH, et al. Simvastatin reduces steroidogenesis by inhibiting Cyp17a1 gene expression in rat ovarian theca-interstitial cells. Biol Reprod. 2012;86(1):1–9.Ortega I, Cress AB, Wong DH, et al. Simvastatin reduces steroidogenesis by inhibiting Cyp17a1 gene expression in rat ovarian theca-interstitial cells. Biol Reprod. 2012;86(1):1–9.1000 Genomes Project Consortium. A global reference for human genetic variation. Nature. 2015;526(7571):68–74.1000 Genomes Project Consortium. A global reference for human genetic variation. Nature. 2015;526(7571):68–74.Bunevicius A. The association of digit ratio (2D:4D) with cancer: A systematic review and metaanalysis. Dis Markers. 2018;2018:7698193.Bunevicius A. The association of digit ratio (2D:4D) with cancer: A systematic review and metaanalysis. Dis Markers. 2018;2018:7698193.Zhang N, Jia J, Ding Q, et al. Common variant rs11191548 near the CYP17A1 gene is associated with hypertension and the serum 25(OH) D levels in Han Chinese. J Hum Genet. 2018;63(6):731–37.Zhang N, Jia J, Ding Q, et al. Common variant rs11191548 near the CYP17A1 gene is associated with hypertension and the serum 25(OH) D levels in Han Chinese. J Hum Genet. 2018;63(6):731–37.Sokalska A, Stanley SD, Villanueva JA, et al. Comparison of effects of different statins on growth and steroidogenesis of rat ovarian theca-interstitial cells. Biol Reprod. 2014;90(2):44.Sokalska A, Stanley SD, Villanueva JA, et al. Comparison of effects of different statins on growth and steroidogenesis of rat ovarian theca-interstitial cells. Biol Reprod. 2014;90(2):44.Sun J, Wang D, Guo L, et al. Androgen Receptor Regulates the Growth of Neuroblastoma Cells in vitro and in vivo. Front Neurosci. 2017;11:116.Sun J, Wang D, Guo L, et al. Androgen Receptor Regulates the Growth of Neuroblastoma Cells in vitro and in vivo. Front Neurosci. 2017;11:116.Allott EH, Howard LE, Cooperberg MR, et al. Serum lipid profile and risk of prostate cancer recurrence: Results from the SEARCH database. Cancer Epidemiol Biomarkers Prev. 2014;23:2349–2356.Allott EH, Howard LE, Cooperberg MR, et al. Serum lipid profile and risk of prostate cancer recurrence: Results from the SEARCH database. Cancer Epidemiol Biomarkers Prev. 2014;23:2349–2356.Munir MT, Ponce C, Powell CA, et al. The contribution of cholesterol and epigenetic changes to the pathophysiology of breast cancer. J Steroid Biochem Mol Biol. 2018;183:1–9.Munir MT, Ponce C, Powell CA, et al. The contribution of cholesterol and epigenetic changes to the pathophysiology of breast cancer. J Steroid Biochem Mol Biol. 2018;183:1–9.Hashimoto M, Kobayashi K, Yamazaki M, et al. Cyp3a deficiency enhances androgen receptor activity and cholesterol synthesis in the mouse prostate. J Steroid Biochem Mol Biol. 2016;163:121–128.Hashimoto M, Kobayashi K, Yamazaki M, et al. Cyp3a deficiency enhances androgen receptor activity and cholesterol synthesis in the mouse prostate. J Steroid Biochem Mol Biol. 2016;163:121–128.Hu Z, Cheng C, Wang Y, et al. Synergistic Effect of Statins and Abiraterone Acetate on the Growth Inhibition of Neuroblastoma via Targeting Androgen Receptor. Front Oncol. 2021;11:595285.Hu Z, Cheng C, Wang Y, et al. Synergistic Effect of Statins and Abiraterone Acetate on the Growth Inhibition of Neuroblastoma via Targeting Androgen Receptor. Front Oncol. 2021;11:595285.GTEx Consortium. The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science. 2020;369(6509):1318–1330.GTEx Consortium. The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science. 2020;369(6509):1318–1330.Liu CJ, Fu X, Xia M, et al. miRNASNP-v3: a comprehensive database for SNPs and disease-related variations in miRNAs and miRNA targets. Nucleic Acids Res. 2021;49(D1):D1276–D1281.Liu CJ, Fu X, Xia M, et al. miRNASNP-v3: a comprehensive database for SNPs and disease-related variations in miRNAs and miRNA targets. Nucleic Acids Res. 2021;49(D1):D1276–D1281.

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