Genetic architecture of familial hypercholesterolemia: a cohort of St. Petersburg residents

Aim. To determine the frequency of pathogenic and likely pathogenic variants associated with familial hypercholesterolemia (FH) with assessment of the proportion of polygenic FH according to the 6-SNP genetic risk score (GRS) among patients diagnosed with possible/probable/definite FH in St. Petersburg.

Material and methods. This study tested a hybrid targeted panel for gene diagnostics of hereditary dyslipidemias, including an expanded list of genes associated with monogenic dyslipidemias and a number of single-nucleotide variants associated with polygenic hypercholesterolemia and cardiovascular risk. Genetic testing was performed on 125 patients.

Results. A total of 26 pathogenic and likely pathogenic variants in the LDLR gene were identified in 38 patients, while 6 variants of uncertain clinical significance in the LDLR gene — in 7 patients, and a pathogenic variant 10580G>A (p.Arg3527G) in the APOB gene — in 6 patients. The highest detection rate of causal genetic variants (66,7%) was observed, as expected, in the subgroup of patients with definite FH. Patients with a high polygenic risk of hypercholesterolemia predominated in the subgroups diagnosed with possible and probable FH.

Conclusion. The use of an expanded next-generation sequencing (NGS) panel, including genes for hereditary dyslipidemias, as well as loci for calculating the GRS, may be critical for differential diagnosis, determining the etiology of hypercholesterolemia, and personalizing treatment approaches.

1. Meshkov AN, Ershova AI, Kiseleva AV, et al. The prevalence of heterozygous familial hypercholesterolemia in selected regions of the Russian Federation: The FH-ESSE-RF study. Journal of Personalized Medicine. 2021;11(6):464. doi:10.3390/jpm11060464.

2. Sturm AC, Knowles JW, Gidding SS, et al. Clinical genetic testing for familial hypercholesterolemia: JACC scientific expert panel. Journal of the American College of Cardiology. 2018;72(6):662-80. doi:10.1016/j.jacc.2018.05.044.

3. Meshkov A, Ershova A, Kiseleva A, et al. The LDLR, APOB, and PCSK9 variants of index patients with familial hypercholesterolemia in Russia. Genes. 2021;12(1):66. doi:10.3390/genes12010066.

4. Miroshnikova VV, Pchelina SN, Donnikov MYu, et al. The NGS panel for genetic testing in cardiology: from the evaluation of disease risk to pharmacogenetics. Pharmacogenetics and Pharmacogenomics. 2023;(1):7-19. (In Russ.) doi:10.37489/2588-0527-2023-1-7-19.

5. Medeiros AM, Alves AC, Miranda B, et al. Unraveling the genetic background of individuals with a clinical familial hypercholesterolemia phenotype. Journal of Lipid Research. 2024;65(2):100490. doi:10.1016/j.jlr.2023.100490.

6. Rieck L, Bardey F, Grenkowitz T, et al. Mutation spectrum and polygenic score in German patients with familial hypercholesterolemia. Clinical genetics. 2020;98(5):457-67. doi:10.1111/cge.13826.

7. Miroshnikova VV, Romanova OV, Ivanova ON, et al. Identification of novel variants in the LDLR gene in Russian patients with familial hypercholesterolemia using targeted sequencing. Biomedical Reports. 2021;14(1):15. doi:10.3892/br.2020.1391.

8. Miroshnikova VV, Vasiluev PA, Linkova SV, et al. Pediatric Patients with Sitosterolemia: Next-Generation Sequencing and Biochemical Examination in Clinical Practice. Journal of Personalized Medicine. 2023;13(10):1492. doi:10.3390/jpm13101492.

9. Boytsov SA, Pogosova NV, Ansheles AA, et al. Cardiovascular prevention 2022. Russian national guidelines. Russian Journal of Cardiology. 2023;28(5):5452. (In Russ.) doi:10.15829/1560-4071-2023-5452. EDN: EUDWYG.

10. Khera AV, Chaffin M, Aragamet KG, et al. Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. Nature genetics. 2018;50(9):1219-24. doi:10.1038/s41588-018-0183-z.

11. Meshkov AN, Kiseleva AV, Ershova AI, et al. ANGPTL3, ANGPTL4, APOA5, APOB, APOC2, APOC3, LDLR, PCSK9, LPL gene variants and coronary artery disease risk. Russian Journal of Cardiology. 2022;27(10):5232. (In Russ.) doi:10.15829/1560-4071-2022-5232. EDN: FAKGMM.

12. Futema M, Shah S, Cooper JA, et al. Refinement of variant selection for the LDL cholesterol genetic risk score in the diagnosis of the polygenic form of clinical familial hypercholesterolemia and replication in samples from 6 countries. Clinical chemistry. 2015;61(1):231- 8. doi:10.1373/clinchem.2014.231365.

13. Blokhina AV, Ershova AI, Kiseleva AV, et al. Clinical and biochemical features of atherogenic hyperlipidemias with different genetic basis: A comprehensive comparative study. Plos one. 2024;19(12): e0315693. doi:10.1371/journal.pone.0315693.

14. Vasilyev V, Zakharova F, Bogoslovskay T, Mandelshtam M. Familial hypercholesterolemia in Russia: three decades of genetic studies. Frontiers in genetics. 2020;11:550591. doi:10.3389/fgene.2020.550591.

15. Guo J, Gao Y, Li X, et al. Systematic prediction of familial hypercholesterolemia caused by low-density lipoprotein receptor missense mutations. Atherosclerosis. 2019;281:1-8. doi:10.1016/j.atherosclerosis.2018.12.003.