Dzhumaniiazova I K, Meshkov A N, Daniel V V, Ezhov M V, Zelenova E A, Chubykina U V, Kashtanova D A, Ivanov M V, Matkava L R, Blinova O I, Kumar N A, Fedorov A Y, Ibragimova H U, Lavrikova T A, Aksenova Y O, Gurciev T M, Gomyranova N V, Vorobeva Y S, Hasanova Z B, Yudin V S, Makarov V V, Keskinov A A, Kraevoy S A, Boytsov S A, Yudin S M, Skvortsova V I
Federal State Budgetary Institution «Centre for Strategic Planning and Management of Biomedical Health Risks» of the Federal Medical and Biological Agency, Moscow, Russia.
Federal State Budgetary Institution National Medical Research Centre of Cardiology Named After Academician E.I. Chazov of the Ministry of Health of the Russian Federation, Moscow, Russia.
Front Genet. 2025 Aug 25;16:1589014. doi: 10.3389/fgene.2025.1589014. eCollection 2025.
Familial hypercholesterolemia (FH) is a prevalent hereditary disorder, with its monogenic form linked to an elevated risk of early-onset ischemic heart disease. Evaluating the prevalence and penetrance of pathogenic and likely pathogenic variants associated with this disorder would provide valuable information supporting routine FH screening of the general population. Such informed screening would facilitate early identification of at-risk individuals, enabling timely intervention and management.
We analyzed genetic data from 4,856 individuals with various cardiovascular conditions for pathogenic and likely pathogenic variants in the PCSK9, APOB, and LDLR genes. The evaluation included comprehensive clinical assessments, instrumental examinations, and laboratory tests. All genetic data were obtained through the whole-genome sequencing of blood leukocytes.
A total of 1.77% of participants carried pathogenic or likely pathogenic variants in the LDLR or APOB genes, and none in the PCSK9 gene. After adjusting for sex and age, the risk of ischemic heart disease was 1.3 times higher in carriers of pathogenic or likely pathogenic variants [95% CI 1.18-1.46; = 5*10-7]. Additionally, the carriers presented with significantly higher levels of total cholesterol and LDL-C ( = 0.00032 and = 0.0123, respectively).
FH remains significantly underdiagnosed. Only 10.5% of carriers of pathogenic or likely pathogenic variants in the LDLR and APOB genes had a prior diagnosis of FH. Our findings suggest low diagnostic rates for this disorder in Eastern European populations and highlight the need for routine genetic screening of younger individuals. However, further research is needed to assess the clinical applicability and cost-effectiveness of such screening programs.
家族性高胆固醇血症（FH）是一种常见的遗传性疾病，其单基因形式与早发性缺血性心脏病风险升高有关。评估与该疾病相关的致病性和可能致病性变异的患病率和外显率，将为支持普通人群常规FH筛查提供有价值的信息。这种明智的筛查将有助于早期识别高危个体，从而实现及时干预和管理。
我们分析了4856名患有各种心血管疾病个体的基因数据，以寻找PCSK9、APOB和LDLR基因中的致病性和可能致病性变异。评估包括全面的临床评估、仪器检查和实验室检测。所有基因数据均通过血液白细胞全基因组测序获得。
共有1.77%的参与者在LDLR或APOB基因中携带致病性或可能致病性变异，而在PCSK9基因中未发现此类变异。在调整性别和年龄后，致病性或可能致病性变异携带者患缺血性心脏病的风险高1.3倍[95%置信区间1.18 - 1.46；P = 5×10⁻⁷]。此外，携带者的总胆固醇和低密度脂蛋白胆固醇水平显著更高（分别为P = 0.00032和P = 0.0123）。
FH的诊断仍明显不足。在LDLR和APOB基因中携带致病性或可能致病性变异的携带者中，只有10.5%曾被诊断为FH。我们的研究结果表明，东欧人群中该疾病的诊断率较低，并强调了对年轻人进行常规基因筛查的必要性。然而，需要进一步研究来评估此类筛查项目的临床适用性和成本效益。
