Молекулярно-генетические детерминанты рефрактерной гиперхолестеринемии

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. 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. 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. 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.

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