phgenomicsФармакогенетика и фармакогеномикаPharmacogenetics and Pharmacogenomics2588-05272686-8849LLC "Izdatelstvo OKI"10.37489/2588-0527-0004HVFULCphgenomics-353Research ArticleКЛИНИЧЕСКАЯ ФАРМАКОГЕНЕТИКАCLINICAL PHARMACOGENETICSВклад полиморфных локусов генов в фармакорезистентность пациентов с шизофрениейThe contribution of polymorphic gene loci to the pharmacoresistance of patients with schizophreniahttps://orcid.org/0009-0001-5159-3796ГолубеваТ. С.GolubevaT. S.

Голубева Татьяна Сергеевна — к. б. н., доцент, зав. отделом 

Минск

 

Tatyana S. Golubeva — Cand. Sci. (Bio), Associate professor, Head of the Department of Republican 

Minsk

tatyana.gol2011@yandex.byhttps://orcid.org/0000-0002-9972-2120КаминскаяЮ. М.KaminskayaJ. M.

Каминская Юлия Михайловна — к. м. н., доцент, директор 

Минск

Julia M. Kaminskaya — Cand. Sci. (Med), Associate Professor, Director 

Minsk

Yu.m.kaminskaya@mail.ruhttps://orcid.org/0009-0004-7055-0451ГолоенкоИ. М.HalayenkaI. M.

Голоенко Инесса Михайловна — к. б. н., доцент, ведущий научный сотрудник 

Минск

Inessa M. Halayenka — Cand. Sci. (Biology), Associate Professor, Leading Researcher 

Minsk

halayenkai@mail.ruhttps://orcid.org/0009-0002-1588-3531СергеевГ. В.SergeevG. V.

Сергеев Геннадий Валерьевич — к. х. н., зав. лабораторией 

Минск

Gennady V. Sergeev — Cand. Sci. (Chemistry), Head of the laboratory

Minsk

gvserg@iboch.byhttps://orcid.org/0000-0002-4272-0108ГребеньН. Ф.HrebenN. F.

Гребень Наталия Федеровна — старший научный сотрудник 

Минск

Natalia F. Hreben — Senior Researcher of the Department 

Minsk

grenat810@gmail.comhttps://orcid.org/0009-0007-0449-0974ОбъедковВ. Г.ObedkovV. G.

Объедков Виктор Георгиевич — к. м. н., доцент кафедры психиатрии, наркологии, психотерапии и медицинской психологии с курсом повышения квалификации и переподготовки 

Минск

Victor G. Obedkov — Cand. Sci. (Med), Associate Professor of the Department of Psychiatry, Narcology, Psychotherapy and Medical Psychology with advanced training and retraining course 

Minsk

ObyedkovVG@gmail.comБокутьО. С.BokutO. S.

Бокуть Ольга Сергеевна — младший научный сотрудник 

Минск

Olga S. Bokut — junior research assistant 

Minsk

volha.bokuts@gmail.comhttps://orcid.org/0000-0003-4448-8098ГайдукевичИ. В.HaidukevichI. V.

Гайдукевич Ирина Викторовна — к. х. н., старший научный сотрудник 

Минск

Irina V. Haidukevich — Cand. Sci. (Chemistry), Senior Researcher 

Minsk

ihaidukevich@gmail.comhttps://orcid.org/0000-0001-5147-8192ДокукинаТ. В.DakukinaT. V.

Докукина Татьяна Васильевна — д. м. н., доцент, ведущий научный сотрудник 

Минск

Tatyana V. Dakukina — Dr. Sci. (Med), Associate Professor, Leading Researcher 

Minsk

polak0208@mail.ruГУ «Республиканский научно-практический центр психического здоровья»БеларусьRepublican Research and Practice Center for Mental HealthBelarusГНУ «Институт биоорганической химии Национальной академии наук Беларуси»БеларусьInstitute of Bioorganic Chemistry of National Academy of Sciences of BelarusBelarusУО «Белорусский государственный медицинский университет»БеларусьBelarusian State Medical UniversityBelarus202624052026012434Copyright © Голубева Т.С., Каминская Ю.М., Голоенко И.М., Сергеев Г.В., Гребень Н.Ф., Объедков В.Г., Бокуть О.С., Гайдукевич И.В., Докукина Т.В., 20262026Голубева Т.С., Каминская Ю.М., Голоенко И.М., Сергеев Г.В., Гребень Н.Ф., Объедков В.Г., Бокуть О.С., Гайдукевич И.В., Докукина Т.В.Golubeva T.S., Kaminskaya J.M., Halayenka I.M., Sergeev G.V., Hreben N.F., Obedkov V.G., Bokut O.S., Haidukevich I.V., Dakukina T.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.pharmacogenetics-pharmacogenomics.ru/jour/article/view/353Актуальность

Актуальность. Несмотря на то, что применение антипсихотических препаратов по-прежнему остаётся одним из наиболее эффективных методов лечения шизофрении, 20–30 % пациентов неадекватно реагируют на фармакотерапию. Эта неэффективность может быть обусловлена генетической изменчивостью, которая влияет на метаболизм лекарств, побочные реакции и эффективность лечения, а также на взаимодействие генов и окружающей среды.

Цель

Цель. Изучить связь ряда полиморфных локусов генов с фармакорезистентностью (ФР) пациентов с шизофренией, жителей Беларуси.

Материалы и методы

Материалы и методы. В исследование был включен 161 пациент с шизофренией. В основную группу вошло 104 пациента с отсутствием улучшения психического состояния на фоне приёма адекватных доз двух и более антипсихотиков (включая атипичные антипсихотики) на протяжении не менее 6–8 недель; в группу сравнения — 57 пациентов с положительной динамикой ответа на фармакологическое лечение шизофрении. Фармакогенетическое тестирование проводили с использованием стандартных методов выделения нуклеиновых кислот, ПЦР-анализа. Проводилось генотипирование по 19 полиморфным локусам 15 генов (CYP2D6, CYP2C9, CYP2C19, CYP1A2; MDR1, ANKK1, HTR1А, HTR2A, SLC6A4, HTR2C, COMT, MAOA, BDNF, DRD2, UGT1A1). Статистическая обработка клинических данных и данных генотипирования проводилась с использованием программы SPSS Statistics 20.0. В качестве показателя связи между аллелями и генотипами с риском развития фармакорезистентности были использованы отношение шансов (ОШ) и 95 % доверительный интервал (ДИ).

Результаты

Результаты. Сравнение частот генотипов и аллелей полиморфных локусов генов в исследованных группах пациентов с шизофренией позволило выявить связь полиморфных генетических локусов с фармакорезистентностью у носителей генотипов AG (CYP2D6, rs3892097) (χ2=6,647; р=0,01); СС (HTR1A, rs6295) (χ2=5,522; р=0,019) и аллелей А (CYP2D6, rs3892097) (χ2=4,124; р=0,042), G (COMT, rs4680) (χ2=9,006; р=0,003). Дальнейший анализ обнаружил повышение показателей риска ФР при сочетании этих аллелей с другими локусами генов. Повышенный риск развития ФР имели пациенты с фармакогенетическими профилями: А-/A(CYP2D6*4 / CYP1A2), (OШ 2,926; ДИ 1,206–7,102); А-/A-/T(CYP2D6*4 / CYP1A2 / MDR1), (OШ 4,833; ДИ 1,753–13,328); G-/L(COMT / SLC6A4), (OШ 3,172; ДИ 1,500–6,709); G-/LL (COMT / SLC6A4), (OШ 6,923; ДИ 1,900–25,227); G-/LL/T(COMT / SLC6A4 / MDR1), (OШ 11,143; ДИ 2,415–51,414); CC/T(HTR1А / MDR1), (OШ 2,564; ДИ 1,120–5,873).

Заключение

Заключение. Исследование с использованием фармакогенетического тестирования жителей Беларуси, больных шизофренией, выявило значимую связь риска ФР с полиморфными локусами генов CYP2D6 (rs3892097), HTR1A (rs6295), COMT (rs4680). Повышенный риск ФР наблюдался при сочетании выявленных аллелей с полиморфными локусами генов CYP1A2 (rs762551), MDR1 (rs1045642), SLC6A4 (5-HTTLPR). Описаны фармакогенетические профили риска развития ФР при терапии антипсихотиками у лиц, страдающих шизофренией.

Relevance

Relevance. Despite the use of antipsychotic drugs is still one of the most effective treatment methods of schizophrenia, the 20–30 % of patients do not respond adequately to pharmacotherapy. This inefficacy may stem from genetic variability, which influences drug metabolism, adverse reactions, and treatment response, alongside gene-environment interactions. This study aimed to investigate the association between polymorphic gene loci and pharmacoresistant schizophrenia among Belarusian patients.

Objective

Objective. To study the relationship of a number of polymorphic gene loci with pharmacoresistance (FR) in patients with schizophrenia, residents of Belarus.

Methods

Methods. The study included 161 people with schizophrenia. The main group included 104 patients with no improvement when treating with two or more antipsychotics (including an atypical antipsychotic) for 6 to 8 weeks; the comparison group included 57 patients with positive response to pharmacological treatment of schizophrenia. Pharmacogenetic testing was performed using standard methods of nucleic acid isolation and PCR analysis. 19 polymorphic loci in 15 genes (CYP2D6, CYP2C9, CYP2C19, CYP1A2; MDR1, ANKK1, HTR1A, HTR2A, SLC6A4, HTR2C, COMT, MAOA, BDNF,

DRD2, UGT1A1) were genotyped. Statistical processing of clinical and genotyping data was carried out using the SPSS Statistics 20.0 program. The odds ratio (OR) and 95 % confidence interval (CI) were used as an indicator of the relationship between alleles and genotypes with the risk of developing PR.

Results

Results. Comparison of the genotypes and alleles frequencies in the studied groups of patients with schizophrenia revealed an association of PR in carriers of alleles — A (CYP2D6, rs3892097) (χ2=4.124; p=0.042), G (COMT, rs4680) (χ2=9.006; p=0.003); AG genotype (CYP2D6, rs3892097) (χ2=6,647; р=0,01), CC genotype (HTR1A, rs6295) (χ2=5.522; p=0.019). Further analysis revealed an increase in the risk of PR when these alleles were combined with other gene loci. Patients with pharmacogenetic profiles A-/A(CYP2D6 / CYP1A2), (OR 2.926; CI 1.206–7.102); A-/B-/T(CYP2D6 / CYP1A2 / MDR1), (OR 4.833) had an increased risk of developing FR; CI 1,753–13,328); G-/L(COMT / SLC6A4), (OR 3,172; CI 1,500–6,709); G-/LL (COMT / SLC6A4), (OR 6,923; CI 1,900–25,227); G-/LL/T(COMT / SLC6A4 / MDR1), (OR =11.143; CI 2.415–51.414); CC/T(HTR1A / MDR1), (OR 2.564; CI 1.120–5.873).

Conclusion

Conclusion. A study using pharmacogenetic testing of residents of Belarus with schizophrenia revealed a significant association of the risk of PR with polymorphic loci of the genes CYP2D6 (rs3892097), HTR1A (rs6295), COMT (rs4680). An increased risk of PR was observed when the identified alleles were combined with polymorphic loci of the CYP1A2 (rs762551), MDR1 (rs1045642), and SLC6A4 (5-HTTLPR) genes. Pharmacogenetic risk profiles for the development of PR during antipsychotic therapy in patients with schizophrenia are described.

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