evrazkarЕвразийский Кардиологический ЖурналEurasian heart journal2225-16852305-0748Евразийская ассоциация кардиологов10.38109/2225-1685-2017-1-24-31evrazkar-6Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL PAPERSОСОБЕННОСТИ РАСПРЕДЕЛЕНИЯ ПОЛИМОРФИЗМОВ ГЕНОВ МЕТАБОЛИЗМА И ТРАНСПОРТА СТАТИНОВ В ПЕЧЕНИ У БОЛЬНЫХ ИБС ЭТНИЧЕСКИХ УЗБЕКОВ С НЕПЕРЕНОСИМОСТЬЮ СИМВАСТАТИНАDISTRIBUTION OF POLYMORPHISMS OF GENES OF STATINS METABOLISM AND TRANSPORT IN THE LIVER IN PATIENTS WITH CORONARY ARTERY DISEASE ETHNIC UZBEKS WITH SIMVASTATIN INTOLERANCEШекА. Б.ShekA. B.

Д.м.н., руководитель лаборатории ИБС, заместитель директора по научным вопросам

100052, г. Ташкент, Мирзо-Улугбекский, улица Осиё, дом 4,

тел. +998-90-321-99-67, факс: +998-71-234-16-67

E-mail: shek-999@mail.ru

MD, Head of CAD Laboratory, Deputy Director for Scientific Affairs o

100052, Tashkent, Mirzo-Ulugbek Street Osie, house 4

cardiocenter@mail.ruКурбановР. Д.KurbanovR. D.

Д.м.н., профессор, директор

100052, г. Ташкент, Мирзо-Улугбекский, улица Осиё, дом 4,

тел. +998-71-237-38-16

MD, Professor, Director 

100052, Tashkent, Mirzo-Ulugbek Street Osie, house 4

cardiocenter@mail.ruАбдуллаеваГ. Ж.AbdullayevaG. J.

К.м.н., старший научный сотрудник лаборатории АГ с группой молекулярногенетических исследований 

100052, г. Ташкент, Мирзо-Улугбекский, улица Осиё, дом 4,

тел. +998-71-237-38-16

PhD, senior scientist with the group AG molecular genetic studies 

100052, Tashkent, Mirzo-Ulugbek Street Osie, house 4

guzal@pochta.ruНагайА. В.NagaiA. V.

К.б.н., научный сотрудник лаборатории АГ с группой молекулярно-генетических исследований

100052, г. Ташкент, Мирзо-Улугбекский, улица Осиё, дом 4

тел. +998-71-237-38-16

PhD, Researcher, Laboratory AG with a group of molecular genetic studies 

100052, Tashkent, Mirzo-Ulugbek Street Osie, house 4

alexsan1984@mail.ruАбдуллаевА. А.AbdullaevA. A.

Д.м.н., директор

102151, Узбекистан, Ташкентская обл., Кибрайский р-н, п/о Юкори-юз

тел. +998-71-264-22-30

MD, director

102151, Uzbekistan, Tashkent region., Kibray district, post office Yukori-skid

igebr_anruz@genetika.uzАхмедоваШ. С.AhmedovaS. S.

К.м.н., научный сотрудник лаборатории ИБС 

100052, г. Ташкент, Мирзо-Улугбекский, улица Осиё, дом 4

тел. +998-71- 237-34-15

PhD, researcher of CAD Laboratory

100052, Tashkent, Mirzo-Ulugbek Street Osie, house 4

pashechka78@mail.ruХошимовШ. У.HoshimovS. U.

К.м.н., научный сотрудник лаборатории ИБС

00052, г. Ташкент, Мирзо-Улугбекский, улица Осиё, дом 4,

тел. +998-71-237-34-15

shavkat.cardiolog@mail.ruЗияеваА. В.ZiyaevaA. V.

К.м.н., научный сотрудник лаборатории ИБС

100052, г. Ташкент, Мирзо-Улугбекский, улица Осиё, дом 4,

тел. +998-71-237-34-15

PhD, researcher of CAD Laboratory

100052, Tashkent, Mirzo-Ulugbek Street Osie, house 4

ziyayeva.69@mail.ruАО Республиканский специализированный центр кардиологииУзбекистанJSC Republican Specialized Center of CardiologyUzbekistanИнститут Генетики и Экспериментальной биологии растений АН РУзУзбекистанInstitute of Genetics and Experimental Biology of Plants of the Academy of Sciences of UzbekistanUzbekistan201730032017012431Copyright © Шек А.Б., Курбанов Р.Д., Абдуллаева Г.Ж., Нагай А.В., Абдуллаев А.А., Ахмедова Ш.С., Хошимов Ш.У., Зияева А.В., 20172017Шек А.Б., Курбанов Р.Д., Абдуллаева Г.Ж., Нагай А.В., Абдуллаев А.А., Ахмедова Ш.С., Хошимов Ш.У., Зияева А.В.Shek A.B., Kurbanov R.D., Abdullayeva G.J., Nagai A.V., Abdullaev A.A., Ahmedova S.S., Hoshimov S.U., Ziyaeva 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://www.heartj.asia/jour/article/view/6Актуальность

Актуальность. Известно, что лечение статинами в большинстве случаев безопасно и хорошо переносится, однако у отдельных пациентов наблюдаются побочные эффекты, связанные с их влиянием на мышцы или печень - главная причина отмены лечения. Принадлежность к азиатской национальности является одним из предрасполагающих факторов развития статин-ассоциированных побочных эффектов.

Цель

Цель. Изучить возможное влияние полиморфизма генов CYP3A5 (6986A>G), CYP2C9 (430C>T), CYP2C9 (1075A>C), SLCO1B1 (521T>C) и BCRP (ABCG2, 421C>A) на возникновение непереносимости симвастатина у больных ишемической болезнью сердца, этнических узбеков.

Материал и методы

Материал и методы. В проспективное исследование по методу «случай-контроль» были включены 100 больных с хронической ишемической болезнью сердца (ИБС). Группу «случай» составили 50 пациентов, у которых при назначении начальной дозы симвастатина 10-20 мг/сут были зарегистрированы клинические симптомы «непереносимости» - 37 с клиническими симптомами побочного влияния на печень, сопровождавшимися повышением уровня трансаминаз в 3 и более раза и 13 с миопатией, сопровождавшейся повышением уровня общей креатинфосфокиназы (КФК) в 3 и более раз. У 4 больных с побочным влиянием на печень, наряду с повышением ферментов, одновременно отмечалось повышение уровня КФК. В группу «контроль» были включены 50 пациентов с хронической ИБС, при условии переносимости лечения симвастатином 20-40 мг и отсутствии побочных эффектов в течение 1 года и более. Изучаемые группы были сопоставимы по полу, возрасту, клиническому течению заболевания, не имели исходных нарушений функции почек и печени. Группу сравнения составили здоровые этнические узбеки (n=41) сопоставимого возраста и пола, с отсутствием семейного анамнеза ИБС. Генотипирование было выполнено PCR-RFLP методом.

Результаты

Результаты. Распределение изучаемых генотипов у больных (n=100) и здоровых лиц (n=41) во всех случаях (за исключением CYP2C9*2 у больных) соответствовало равновесному распределению Харди-Вайнберга. При сравнении распространённости наиболее часто встречающихся гомозиготных генотипов с вариантными, оказалось, что в группе «случай» преобладали генотип *3/*3 гена CYP3A5 (ОШ 9,33; 95% ДИ 3,37-25,9; Р=0,0001) и вариантный генотип СA гена BCRP (ОШ 3,22; 95% ДИ 1,25-8,30; Р=0,024).

Заключение

Заключение. Генотипы *3/*3 гена CYP3A5 (6986A>G) и CA гена BCRP (ABCG2, 421C>A) в большей степени ассоциировались с вызванными статинами побочными эффектами у больных ИБС этнических узбеков.

Background

Background. It is well-known that in majority of cases treatment with statins can be safe and well tolerated, but in some patients observed statin-induced adverse liver or muscle symptoms - the main reasons for statin discontinuation. Asian ethnicity - is one of the predisposing factors for statin-associated adverse effects.

Objective

Objective. To study possible effects of CYP3A5 (6986A>G), CYP2C9 (430C>T), CYP2C9 (1075A>C), SLCO1B1 (521T>C) and BCRP (ABCG2, 421C>A) genetic polymorphism on simvastatin tolerance and safety in ethnic Uzbek patients with Coronary Artery Disease (CAD).

Material and methods

Material and methods. The prospective case-control research included 100 patients with CAD. Group "case" were 50 patients who demonstrated statin-induced adverse liver effects (transaminase level increases 3 times and more - in 37 cases) or statin-induced elevations in serum CK (of >3*UNL - in 4 cases) at treatment with simvastatin with the dose of 20 mg/day for 3 months of treatment and 13 with myopathy, associated with increased levels of total creatine phosphokinase (CPK) 3 times or more. In 4 patients with adverse effects on the liver, along with an increase in the enzymes, while there was an increase of CPK levels. Control group contained 50 patient with CAD treated with simvastatin with the dose of 20-40 mg/day for one year without side effects. The both groups of patients were similar in gender, age, original index of kidney function and serum CK level. The comparison group consisted of healthy ethnic Uzbeks (n = 41) of comparable age and sex, with the absence of a family history of coronary artery disease. The research was performed by means of PCR-RFLP method.

Results

Results. As a whole, all genotypes (except for CYP2C9 * 2 in patients) were in Hardy-Weinberg equilibrium. Among patients with simvastatin intolerance, compared to the control group, the following genotypes were observed more frequently with high level of confidence: CYP3A5 *3/*3, compared to genotype variants *1/*3 and *1/*1 (OR 9.33; 95% CI 3,37-25,9; P = 0.0001) and BCRP CA (patients with BCRP CC genotype were not observed among those examined) (OR 3.22; 95% CI 1,258,30, P = 0.024).

Conclusions

Conclusions. Genotypes CYP3A5 *3/*3 (6986A>G) and BCRP CA (ABCG2, 421C>A) are accompanied with the increase of statin-induced adverse effects in ethnic Uzbek patients with Coronary artery disease.

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