Prevalence and penetrance of pathogenic and likely pathogenic LDLR and APOB gene variants linked to familial hypercholesterolemia and an increased risk of ischemic heart disease

Irina Dzhumaniiazova^1*Aleksei N. Meshkov^2,3Veronika Erema¹Marat V. Ezhov²Elena A. Zelenova¹Ulyana V. Chubykina²Daria Kashtanova¹Michail V. Ivanov¹Lorena R. Matkava¹Olga I. Blinova¹Natalia A. Kumar¹A. Y. Fedorov¹H. U. Ibragimova²T. A. Lavrikova²Y. O. Aksenova²T. M. Gurciev²N. V. Gomyranova²Y. S. Vorobeva²Z. B. Hasanova²Vladimir Sergeevich Yudin¹Valentin V. Makarov¹Anton Keskinov¹Sergey A. Kraevoy¹Sergey A. Boytsov²Sergey M. Yudin¹Veronika Skvortsova⁴

• ¹Federal State Budgetary Institution «Centre for Strategic Planning and Management of Biomedical Health Risks» of the Federal medical and biological agency, Moscow, Russia
• ²National Medical Research Center for Cardiology, Ministry of Health of the Russian Federation, Moscow, Moscow Oblast, Russia
• ³Federal State Institution 'National Medical Research Center for Preventive Medicine' of the Ministry of Healthcare of the Russian Federation, Moscow, Moscow Oblast, Russia
• ⁴Federal medical and biologicl agency, Moscow, Russia

Background. Familial hypercholesterolemia is a common disease. Its monogenic form is associated with an increased risk of premature ischemic heart disease. Assessing the prevalence and penetrance of pathogenic and likely pathogenic variants linked to familial hypercholesterolemia can inform the viability of routine genetic testing of the population for predisposition to the monogenic form of the disease. Methods. In this study, genetic data from 4,856 inpatients with various cardiovascular diseases were examined for pathogenic and likely pathogenic variants in the PCSK9, APOB, and LDLR genes. The examination involved clinical, instrumental and laboratory evaluations. All participants underwent whole-genome DNA sequencing of blood leukocytes. Results. A total of 1.77% of inpatients were found to carry pathogenic or likely pathogenic variants in the LDLR and APOB genes. There were no carriers of such variants in the PCSK9 gene. Carriers of pathogenic or likely pathogenic variants faced a 1.3 times higher risk of ischemic heart disease [95% CI 1.18-1.46; p=5*10-7], after adjusting for sex and age. Additionally, they presented with significantly higher levels of total cholesterol and LDL-C (p=0.00032 and p=0.0123, respectively). Conclusion. This study, representing the first investigation of FH genetic screening in a hospitalized population in Russia, found familial hypercholesterolemia to be significantly underdiagnosed. Only 10.5% of carriers of pathogenic or likely pathogenic variants in the LDLR and APOB genes had a prior diagnosis of familial hypercholesterolemia. This provides molecular evidence for low FH diagnosis rates in Eastern European populations and advances the development of cost-effective-oriented screening strategies. This finding highlights the need for routine genetic screening of younger individuals for familial hypercholesterolemia. However, further research is required to assess the clinical applicability and cost-effectiveness of this approach.