aterosklerozАтеросклерозAteroscleroz2078-256X2949-3633НИИТПМ-филиал ИЦиГ СО РАН10.52727/2078-256X-2026-22-1-84-98ateroskleroz-1175Research ArticleОБЗОРЫ ЛИТЕРАТУРЫLITERATURE REVIEWSМолекулярно-генетические детерминанты рефрактерной гиперхолестеринемииMolecular genetic determinants of refractory hypercholesterolemiahttps://orcid.org/0000-0002-4596-8950ШестакА. Г.ShestakA. G.

Анна Геннадьевна Шестак, канд. биол. наук, старший научный сотрудник отдела клинической и предиктивной генетики Центра предиктивной генетики, фармакогенетики и персонализированной терапии

119435, г. Москва, Абрикосовский пер., 2 

Anna G. Shestak, senior researcher at the department of clinical and predictive genetics 

2, Abrikosovsky per., Moscow, 119435 

anna.shestak87@gmail.comhttps://orcid.org/0009-0003-5979-0094ДорофееваО. Д.DorofeevaO. D.

Ольга Дмитриевна Дорофеева, студентка 

630090, г. Новосибирск, ул. Пирогова, 1 

Olga D. Dorofeeva, student 

1, Pirogov st., Novosibirsk, 630090 

olia.dorofeeva@gmail.comhttps://orcid.org/0000-0002-8828-0259ШироковаН. С.ShirokovaN. S.

Нина Сергеевна Широкова, младший научный сотрудник лаборатории молекулярной генетики человека 

630090, г. Новосибирск, пр. Академика Лаврентьева,10 

Nina S. Shirokova, junior researcher at the laboratory of human molecular genetics 

10, Lavrentyeva ave., Novosibirsk, 630090 

shirokovans97@mail.ruhttps://orcid.org/0000-0002-0403-545XИванощукД. Е.IvanoshchukD. E.

Динара Евгеньевна Иванощук, младший научный сотрудник лаборатории молекулярной генетики человека 

630090, г. Новосибирск, пр. Академика Лаврентьева,10 

630089, г. Новосибирск, ул. Бориса Богаткова, 175/1 

Dinara E. Ivanoshchuk, junior researcher at the laboratory of human molecular genetics 

175/1, Boris Bogatkov st., Novosibirsk, 630089 

dinara@bionet.nsc.ruФедеральное государственное бюджетное научное учреждение «Российский научный центр хирургии имени академика Б.В. Петровского»РоссияPetrovsky National Research Center of SurgeryRussian FederationФедеральное государственное автономное образовательное учреждение высшего образования «Новосибирский национальный исследовательский государственный университет»РоссияNovosibirsk State UniversityRussian FederationФедеральное государственное бюджетное научное учреждение «Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук»РоссияInstitute of Cytology and Genetics, Siberian Branch of Russian Academy of SciencesRussian FederationФедеральное государственное бюджетное научное учреждение «Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук» ; Научно-исследовательский институт терапии и профилактической медицины – филиал Федерального государственного бюджетного научного учреждения «Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук»РоссияInstitute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences ; Research Institute of Internal and Preventive Medicine – Branch of Institute of Cytology and Genetics Siberian Branch of the Russian Academy of SciencesRussian Federation2026020420262218498Copyright © Шестак А.Г., Дорофеева О.Д., Широкова Н.С., Иванощук Д.Е., 20262026Шестак А.Г., Дорофеева О.Д., Широкова Н.С., Иванощук Д.Е.Shestak A.G., Dorofeeva O.D., Shirokova N.S., Ivanoshchuk D.E.This work is licensed under a Creative Commons Attribution 4.0 License.https://ateroskleroz.elpub.ru/jour/article/view/1175

Цель обзора – анализ современных данных о молекулярно-генетических механизмах формирования устойчивости (рефрактерности) к липидснижающей терапии с акцентом на роль редких функционально значимых генетических вариантов в формировании индивидуального ответа на лечение.

Материал и методы

Материал и методы. Проведен анализ публикаций, представленных в базах данных PubMed и elibrary.ru, за период с 2019 по 2024 г. Поиск выполнен по ключевым словам: «рефрактерность к гиполипидемической терапии», «резистентность к гиполипидемической терапии», «резистентность к статинам», «непереносимость статинов». Отобрано и проанализировано 68 источников, соответствующих критериям поиска.

Результаты

Результаты. В обзоре рассмотрена роль генетических вариантов в генах LDLR, APOB, PCSK9, LDLRAP1, NPC1L1, HMGCR, SLCO1B1, CYP3A4, ABCB1 и LPL в формировании вариабельности эффективности и переносимости гиполипидемической терапии. Показано, что редкие и функционально значимые патогенные варианты, особенно в генах LDLR-зависимого клиренса, являются ключевым фактором развития рефрактерной гиперхолестеринемии и ограничивают достижение целевых уровней холестерина липопропротеинов низкой плотности даже при использовании комбинированных схем лечения.

Заключение

Заключение. Генетическая гетерогенность гиперхолестеринемии определяет необходимость персонализированного подхода к диагностике и выбору липидснижающей терапии. Дальнейшие исследования должны быть направлены на изучение спектра молекулярных маркеров резистентности и внедрение новых фармакогенетических стратегий в клиническую практику.

Objective

Objective. This review aims to synthesize and analyse available evidence on molecular genetic mechanisms associated with inadequate response (refractoriness) to lipid-lowering therapy, with a particular emphasis on rare, functionally relevant genetic variants contributing to interindividual variability in treatment efficacy and tolerability.

Material and methods

Material and methods. A narrative literature review was conducted using PubMed and elibrary.ru, covering publications from 2019 to 2024. The search strategy included the following terms (and related keywords): «refractory to lipid-lowering therapy», «resistance to lipid-lowering therapy», «statin resistance», «intolerance to statins». In total, 68 sources were included in the qualitative synthesis.

Results

Results. The review summarizes reported associations between genetic variation in LDLR, APOB, PCSK9, LDLRAP1, NPC1L1, HMGCR, SLCO1B1, CYP3A4, ABCB1, and LPL and variability in lipid-lowering response and tolerability. Evidence across clinical and mechanistic studies suggests that rare pathogenic variants affecting LDLR-mediated LDL clearance are frequently linked to attenuated LDL-C lowering and reduced likelihood of achieving guideline-recommended LDL-C targets, representing a key factor in the development of refractory hypercholesterolemia even with combination treatment regimens.

Conclusions

Conclusions. The genetic heterogeneity of hypercholesterolemia highlights the need for a personalized approach to diagnosis and selection of lipid-lowering therapy. Further studies should prioritize expanding and clinically validating molecular markers of insufficient response and integrating pharmacogenetic and rare-variant information into routine clinical decision-making.

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