Molecular genetic determinants of refractory hypercholesterolemia
https://doi.org/10.52727/2078-256X-2026-22-1-84-98
Abstract
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. 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. 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. 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.
Supporting agencies: This research was conducted with the financial support of the State Budget Project FWNR- 2024-0004.
About the Authors
A. G. Shestak
Petrovsky National Research Center of Surgery
Russian Federation
Russian Federation
Anna G. Shestak, senior researcher at the department of clinical and predictive genetics
2, Abrikosovsky per., Moscow, 119435
O. D. Dorofeeva
Novosibirsk State University
Russian Federation
Russian Federation
Olga D. Dorofeeva, student
1, Pirogov st., Novosibirsk, 630090
N. S. Shirokova
Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences
Russian Federation
Russian Federation
Nina S. Shirokova, junior researcher at the laboratory of human molecular genetics
10, Lavrentyeva ave., Novosibirsk, 630090
D. E. Ivanoshchuk
Institute 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 Sciences
Russian Federation
Russian Federation
Dinara E. Ivanoshchuk, junior researcher at the laboratory of human molecular genetics
175/1, Boris Bogatkov st., Novosibirsk, 630089
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For citations:
Shestak A.G., Dorofeeva O.D., Shirokova N.S., Ivanoshchuk D.E. Molecular genetic determinants of refractory hypercholesterolemia. Ateroscleroz. 2026;22(1):84-98. (In Russ.) https://doi.org/10.52727/2078-256X-2026-22-1-84-98
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