actabiomedicaActa Biomedica ScientificaActa Biomedica Scientifica2541-94202587-9596Scientific Centre for Family Health and Human Reproduction Problems10.29413/ABS.2020-5.3.2actabiomedica-2362Research ArticleГЕНЕТИКА, ПРОТЕОМИКА И МЕТАБОЛОМИКАGENETICS, PROTEOMICS AND METABOLOMICSФармакогенетические аспекты в терапии сахарного диабета 2-го типаPharmacogenetic Aspects of Type 2 Diabetes Treatmenthttps://orcid.org/0000-0001-8035-8288ПоздняковН. О.PozdnyakovN. O.

Поздняков Николай Олегович – кандидат медицинских наук, ассистент кафедры клинической фармакологии

150000, г. Ярославль, ул. Революционная, 5 

Nikolay O. Pozdnyakov – Cand. Sc. (Med.), Teaching Assistant of the Department of Clinical Pharmacology

Revolutsionnaya str. 5, Yaroslavl 150000

pozdnyakov.niko@yandex.ruhttps://orcid.org/0000-0002-2139-6847КаграманянИ. Н.KagarmanyanI. N.

Каграманян Игорь Николаевич – доктор медицинских наук, директор

109004, г. Москва, ул. Александра Солженицына, 28, стр. 1

Igor N. Kagramanyan – Dr. Sc. (Med.), Director

Alexander Solzhenitsyn str. 28, build. 1, Moscow 109004

kirova.yulia@mail.ruhttps://orcid.org/0000-0001-6657-3950МирошниковА. Е.MiroshnikovA. E.

Мирошников Алексей Евгеньевич – кандидат медицинских наук, ассистент кафедры клинической фармакологии

150000, г. Ярославль, ул. Революционная, 5 

Alexei E. Miroshnikov – Cand. Sc. (Med), Teaching Assistant of the Department of Clinical Pharmacology

Revolutsionnaya str. 5, Yaroslavl 150000 

miraleff@mail.ruhttps://orcid.org/0000-0001-6365-5467ЕмельяновЕ. С.EmelyanovE. S.

Емельянов Евгений Сергеевич – кандидат медицинских наук, врач-эндокринолог

150030, г. Ярославль, Суздальское шоссе, 39

Evgeny S. Emelyanov – Cand. Sc. (Med.), Endocrinologist 

Suzdal Highway 39, Yaroslavl 150030

9109703511@mail.ruhttps://orcid.org/0000-0002-0779-7003ГруздеваА. А.GruzdevaA. A.

Груздева Анна Андреевна – кандидат медицинских наук, заведующая кардиологическим отделением первичного сосудистого центра

156002, г. Кострома, ул. Спасокукоцкого, 29/62

Anna A. Gruzdeva – Cand. Sc. (Med.), Head of the Cardiology Department of the Primary Vascular Center

Spasokukotskiy str. 29/62, Kostroma 156002

gruzdeva-anna@mail.ruhttps://orcid.org/0000-0001-6994-7153СироткинаА. М.SirotkinaA. M.

Сироткина Альфия Михайловна – кандидат медицинских наук, заведующая кафедрой терапии педиатрического факультета

150000, г. Ярославль, ул. Революционная, 5 

Alfiya M. Sirotkina – Cand. Sc. (Med.), Head of the Department of Therapy of Pediatric Faculty

Revolutsionnaya str. 5, Yaroslavl 150000 

a.sirotkina@mail.ruhttps://orcid.org/0000-0002-0119-6290ДуханинаИ. А.DukhaninaI. A.

Духанина Инесса Александровна – сотрудник кафедры клинической фармакологии

150000, г. Ярославль, ул. Революционная, 5 

Inessa A. Dukhanina – Officer at the Department of Clinical Pharmacology

Revolutsionnaya str. 5, Yaroslavl 150000 

duk.inessa27@mail.ruhttps://orcid.org/0000-0002-2439-0985МилкинаА. А.MilkinaA. A.

Милкина Анна Анатольевна – врач-терапевт

150030, г. Ярославль, Суздальское шоссе, 21

Anna A. Milkina – Primary Care Physician

Suzdal Highway 21, Yaroslavl 150030

annamilkina@bk.ruhttps://orcid.org/0000-0002-6684-4199ХохловА. А.KhokhlovA. A.

Хохлов Александр Александрович – кандидат медицинских наук, ассистент кафедры клинической фармакологии

150000, г. Ярославль, ул. Революционная, 5 

Alexander A. Khokhlov – Cand. Sc. (Med.), Teaching Assistant at the Department of Clinical Pharmacology

Revolutsionnaya str. 5, Yaroslavl 150000 

aa_khokhlov@cphinvest.ruhttps://orcid.org/0000-0002-8826-4590ПоздняковС. О.PozdnyakovS. O.

Поздняков Станислав Олегович – кандидат медицинских наук, ассистент кафедры нервных болезней

150000, г. Ярославль, ул. Революционная, 5

Stanislav O. Pozdnyakov – Cand. Sc. (Med.), Teaching Assistant at the Department of Nervous Diseases

Revolutsionnaya str. 5, Yaroslavl 150000 

sopozdnyakov@yandex.ruФГБОУ ВО «Ярославский государственный медицинский университет» Минздрава РоссииYaroslavl State Medical UniversityИнститут лидерства и управления здравоохранениемInstitute of Leadership and Health ManagementГБУЗ Ярославской области «Клиническая больница № 2»Clinical Hospital N 2ОГБУЗ «Окружная больница Костромского округа № 1»District Hospital N 1 of the Kostroma DistrictЧУЗ «Клиническая больница «РЖД-Медицина» города Ярославль»Clinical Hospital “RZhD-Meditsina” of Yaroslavl202013072020531323Copyright © Поздняков Н.О., Каграманян И.Н., Мирошников А.Е., Емельянов Е.С., Груздева А.А., Сироткина А.М., Духанина И.А., Милкина А.А., Хохлов А.А., Поздняков С.О., 20202020Поздняков Н.О., Каграманян И.Н., Мирошников А.Е., Емельянов Е.С., Груздева А.А., Сироткина А.М., Духанина И.А., Милкина А.А., Хохлов А.А., Поздняков С.О.Pozdnyakov N.O., Kagarmanyan I.N., Miroshnikov A.E., Emelyanov E.S., Gruzdeva A.A., Sirotkina A.M., Dukhanina I.A., Milkina A.A., Khokhlov A.A., Pozdnyakov S.O.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.actabiomedica.ru/jour/article/view/2362

Значимую роль в развитии заболевания и в эффективности фармакотерапии сахарного диабета 2-го типа играют генетические факторы. Представляют интерес полиморфизмы генов, как ответственных за метаболизм (гены цитохрома P450), транспортировку препаратов (SLC22A1), так и за фармакодинамический ответ (TCF7L2, KCNJ11). В работе проанализирована роль полиморфизмов генов KCNJ11, TCF7L2, SLC22A1, SLC22A3, CYP2C9, CYP2C8, PPARγ в эффективности фармакотерапии сахарного диабета 2-го типа. Аллель Т полиморфизма гена KCNJ11 rs2285676 и аллель G полиморфизма rs5218 ассоциированы с ответом на терапию иДПП-4, а наличие аллеля А полиморфизма rs5210 выступает предиктором плохого ответа терапию иДПП-4. Оценивалось значение полиморфизма rs7903146 гена TCF7L2 у пациентов с сахарным диабетом 2-го типа, принимающих линаглиптин. Линаглиптин значимо снижал уровень HbA1c при всех трёх генотипах rs7903146 (CC: –0,82 %; СТ: –0,77 %; TT: –0,57 %). Значимо меньший эффект от терапии наблюдался при генотипе ТТ. Изучен полиморфизм rs622342 гена SLC22A1 и его связь с эффективностью метформина. Исследования показали, что носители варианта АА имели среднее снижение HbA1c на 0,53 %, гетерозиготные пациенты – снижение на 0,32 %, а носители минорного варианта СС имели увеличение на 0,2 % уровня HbA1c. Отмечено значимое влияние полиморфизмов CYP2C9 на фармакокинетические параметры препаратов сульфонилмочевины. Носительство аллеля *2 значимо снижает метаболизм глибенкламида: гомозиготные носители имели клиренс на 90 % ниже, чем гомозиготные носители дикого варианта. Исследования подтвердили связь аллельных вариантов Thr394Thr и Gly482Ser гена PPARγ с более высокой эффективностью препарата росиглитазон. В настоящей статье представлены различные полиморфизмы генов, способных влиять как на кинетику препарата, так и на фармакодинамический ответ. Именно персонализированный поход, основанный, в том числе, на знании вариантов полиморфизмов, позволит выбрать наиболее эффективный препарат с транспарентной кинетикой для каждого конкретного пациента.

In this article, we analyze the role of different variants of the KCNJ11, TCF7L2, SLC22A1, SLC22A3, CYP2C9, CYP2C8, PPARγ genes polymorphisms in efficacy of diabetes mellitus pharmacotherapy. T allele of the KCNJ11 rs2285676 gene polymorphism and G allele of KCNJ11 rs5218 gene polymorphism are associated with the response to IDPP-4 therapy; the presence of KCNJ11 gene rs5210 polymorphism A allele is a predictor of poor response. The effect of rs7903146 polymorphism of TCF7L2 gene was evaluated on the response to treatment of patients taking linagliptin. Linagliptin significantly reduced HbA1c levels for all three rs7903146 genotypes (CC: –0.82 %; CT: –0.77 %; TT: –0.57 %). A significantly smaller effect of therapy was observed with the genotype with ТТ. The rs622342 polymorphism of SLC22A1 gene was studied in effectiveness of metformin. The researches demonstrated that carriers of variant AA had an average decrease of HbA1c of 0.53 %, heterozygous – decrease of 0.32 %, and carriers of a minor variant of SS had an increase of 0.2 % in the level of HbA1c. A significant effect of CYP2C9 polymorphisms on the pharmacokinetic parameters of PSM was noted. When studying the kinetics of glibenclamide, it was found that carriage of the allele *2 significantly reduces glibenclamide metabolism: homozygous carriers had clearance 90 % lower than homozygous carriers of the wild variant. The studies confirmed the association of the allelic variants of Thr394Thr and Gly482Ser of PPARγ gene with higher efficacy of the rosiglitazone. The data obtained from the analysis of the association of the Pro12Ala polymorphism of PPARγ gene and the response to therapy is contradictory. Thus the personalized approach, based on the knowledge of polymorphism options, will allow choosing the most effective drug with transparent kinetics for each individual patient.

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