Molecular diagnostics of familial hypercholesterolemia in Russia: yesterday, today and tomorrow

Abstract

Familial hypercholesterolemia is a severe hereditary disease leading to the development of atherosclerosis and its complications in the form of angina pectoris, myocardial infarction, cerebral stroke, or even leading to sudden death. Since the description of the disease, the concept of it has undergone significant evolution. First, it became clear that the prevalence of this disease was significantly higher than originally thought (1:300 for heterozygous familial hypercholesterolemia and not as 1:500 as estimated earlier). Secondly, it has been established that it is not based on the pathology of the low-density lipoprotein receptor gene alone, but includes at least four monogenic forms (defects of the APOB, PCSK9, ARH genes) and may also have a multigenic nature. Thirdly, with the development of DNA analysis methods from the initially available Southern hybridization to next generation DNA sequencing, the exceptional molecular heterogeneity of familial hypercholesterolemia became obvious and, accordingly, the need to establish national spectra of mutations leading to the development of familial hypercholesterolemia was established. Researchers have moved from characterizing individual mutations to creating national registries and databases. Finally, research into the genetics of familial hypercholesterolemia has led to the emergence of new classes of cholesterol-lowering drugs. In Russia, molecular diagnostics of familial hypercholesterolemia has also undergone significant changes since the beginning of the study of familial hypercholesterolemia in 1987 and to the present, consideration of these changes formed the basis of this review.

Keywords

hypercholesterolemia / molecular diagnostics / low density lipoprotein receptor / coronary heart disease

References

[1] Goldstein JL, Hobbs HH, Brown MS. Familial hypercholesterolemia. The Metabolic and Molecular Bases of Inherited Disease. Scriver C, Beaudet A, Sly W, Valle D, editors. New York: McGraw-Hill; 2001. P. 2863–2913.

[2] Goldstein J.L., Hobbs H.H., Brown M.S. Familial hypercholesterolemia. The Metabolic and Molecular Bases of Inherited Disease. Scriver C, Beaudet A, Sly W, Valle D, editors. New York: McGraw-Hill, 2001. P. 2863–2913.

[3] Sjouke B, Kusters DM, Kindt I, et al. Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome. Eur Heart J. 2015;36(9):560–565. doi: 10.1016/S0735-1097(14)62053-2

[4] Sjouke B., Kusters D.M., Kindt I., et al. Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome // Eur Heart J. 2015. Vol. 36, N 9. P. 560–565. doi: 10.1016/S0735-1097(14)62053-2

[5] Defesche JC, Gidding SS, Harada-Shiba M, et al. Familial hypercholesterolaemia. Nat Rev Dis Primers. 2017;3:17093. doi: 10.1038/nrdp.2017.93

[6] Defesche J.C., Gidding S.S., Harada-Shiba M., et al. Familial hypercholesterolaemia // Nat Rev Dis Primers. 2017. Vol. 3. P. 17093. doi: 10.1038/nrdp.2017.93

[7] Sarraju A, Knowles JW. Genetic testing and risk scores: impact on familial hypercholesterolemia. Front Cardiovasc Med. 2019;6:5. doi: 10.3389/fcvm.2019.00005

[8] Sarraju A., Knowles J.W. Genetic testing and risk scores: impact on familial hypercholesterolemia // Front Cardiovasc Med. 2019. Vol. 6. P. 5. doi: 10.3389/fcvm.2019.00005

[9] Seftel HC, Baker SG, Jenkins T, Mendelsohn D. Prevalence of familial hypercholesterolemia in Johannesburg Jews. Am J Med Genet. 1989;34(4):545–547. doi: 10.1002/ajmg.1320340418

[10] Seftel H.C., Baker S.G., Jenkins T., Mendelsohn D. Prevalence of familial hypercholesterolemia in Johannesburg Jews // Am J Med Genet. 1989. Vol. 34, N 4. P. 545–547. doi: 10.1002/ajmg.1320340418

[11] Marks D, Thorogood M, Neil HA, Humphries SE. A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia. Atherosclerosis. 2003;168(1):1–14. doi: 10.1016/s0021-9150(02)00330-1

[12] Marks D., Thorogood M., Neil H.A., Humphries S.E. A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia // Atherosclerosis. 2003. Vol. 168, N 1. P. 1–14. doi: 10.1016/s0021-9150(02)00330-1

[13] Steyn K, Goldberg YP, Kotze MJ, et al. Estimation of the prevalence of familial hypercholesterolaemia in a rural Afrikaner community by direct screening for three Afrikaner founder low density lipoprotein receptor gene mutations. Hum Genet. 1996;98(4):479–484. doi: 10.1007/s004390050243

[14] Steyn K., Goldberg Y.P., Kotze M.J., et al. Estimation of the prevalence of familial hypercholesterolaemia in a rural Afrikaner community by direct screening for three Afrikaner founder low density lipoprotein receptor gene mutations // Hum Genet. 1996. Vol. 98, N 4. P. 479–484. doi: 10.1007/s004390050243

[15] Marais AD, Firth JC, Blom DJ. Familial hypercholesterolemia in South Africa. Semin Vasc Med. 2004;4(1):93–95. doi: 10.1055/s-2004-822991

[16] Marais A.D., Firth J.C., Blom D.J. Familial hypercholesterolemia in South Africa // Semin Vasc Med. 2004. Vol. 4, N 1. P. 93–95. doi: 10.1055/s-2004-822991

[17] Moorjani S, Roy M, Gagné C, et al. Homozygous familial hypercholesterolemia among French Canadians in Québec Province. Arteriosclerosis. 1989;9(2):211–216. doi: 10.1161/01.atv.9.2.211

[18] Moorjani S., Roy M., Gagné C., et al. Homozygous familial hypercholesterolemia among French Canadians in Québec Province // Arteriosclerosis. 1989. Vol. 9, N 2. P. 211–216. doi: 10.1161/01.atv.9.2.211

[19] Der Kaloustian VM, Naffah J, Loiselet J. Genetic diseases in Lebanon. Am J Med Genet. 1980;7(2):187–203. doi: 10.1002/ajmg.1320070212

[20] Der Kaloustian V.M., Naffah J., Loiselet J. Genetic diseases in Lebanon // Am J Med Genet. 1980. Vol. 7, N 2. P. 187–203. doi: 10.1002/ajmg.1320070212

[21] Karpov YuA, Kukharchuk VV, Boytsov SA, et al. Consensus statement of the Russian National Atherosclerosis Society (RNAS). Familial hypercholesterolemia in Russia: outstanding issues in diagnosis and management. Journal of atherosclerosis and dyslipidemias. 2015;(2(19)):5–16. EDN: UAPQET

[22] Карпов Ю.А., Кухарчук В.В., Бойцов С.А. и др. Заключение совета экспертов Национального общества по изучению атеросклероза (НОА). Семейная гиперхолестеринемия в Российской Федерации: нерешенные проблемы диагностики и лечения // Атеросклероз и дислипидемии. 2015. № 2(19). С. 5–16. EDN: UAPQET

[23] Ershova AI, Meshkov AN, Bazhan SS, et al. The prevalence of familial hypercholesterolemia in the West Siberian region of the Russian Federation: a substudy of the ESSE-RF. PLoS One. 2017;12(7):e0181148. doi: 10.1016/j.atherosclerosis.2017.06.592

[24] Ershova A.I., Meshkov A.N., Bazhan S.S., et al. The prevalence of familial hypercholesterolemia in the West Siberian region of the Russian Federation: a substudy of the ESSE-RF // PLoS One. 2017. Vol. 12, N 7. P. e0181148. doi: 10.1016/j.atherosclerosis.2017.06.592

[25] Umans-Eckenhausen MA, Defesche JC, Sijbrands EJ, et al. Review of first 5 years of screening for familial hypercholesterolaemia in the Netherlands. Lancet. 2001;357(9251):165–168. doi: 10.1016/s0140-6736(00)03587-x

[26] Umans-Eckenhausen M.A., Defesche J.C., Sijbrands E.J., et al. Review of first 5 years of screening for familial hypercholesterolaemia in the Netherlands // Lancet. 2001. Vol. 357, N 9251. P. 165–168. doi: 10.1016/s0140-6736(00)03587-x

[27] Muller C. Angina pectoris in hereditary xanthomatosis. Nutr Rev. 1987;45(4):113–115. doi: 10.1111/j.1753-4887.1987.tb02723.x

[28] Muller C. Angina pectoris in hereditary xanthomatosis // Nutr Rev. 1987. Vol. 45, N 4. P. 113–115. doi: 10.1111/j.1753-4887.1987.tb02723.x

[29] Khachadurian AK. The inheritance of essential familial hypercholesterolemia. Am J Med. 1964;37:402–407. doi: 10.1016/0002-9343(64)90196-2

[30] Khachadurian A.K. The inheritance of essential familial hypercholesterolemia // Am J Med. 1964. Vol. 37. P. 402–407. doi: 10.1016/0002-9343(64)90196-2

[31] Brown MS, Goldstein JL. Familial hypercholesterolemia: defective binding of lipoproteins to cultured fibroblasts associated with impaired regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. Proc Natl Acad Sci USA. 1974;71(3):788–792. doi: 10.1073/pnas.71.3.788

[32] Brown M.S., Goldstein J.L. Familial hypercholesterolemia: defective binding of lipoproteins to cultured fibroblasts associated with impaired regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity // Proc Natl Acad Sci USA. 1974. Vol. 71, N 3. P. 788–792. doi: 10.1073/pnas.71.3.788

[33] Südhof TC, Goldstein JL, Brown MS, Russell DW. The LDL receptor gene: a mosaic of exons shared with different proteins. Science. 1985;228(4701):815–822. doi: 10.1126/science.2988123

[34] Südhof T.C., Goldstein J.L., Brown M.S., Russell D.W. The LDL receptor gene: a mosaic of exons shared with different proteins // Science. 1985. Vol. 228, N 4701. P. 815–822. doi: 10.1126/science.2988123

[35] Law SW, Lackner KJ, Hospattankar AV, et al. Human apolipoprotein B-100: cloning, analysis of liver mRNA, and assignment of the gene to chromosome 2. Proc Natl Acad Sci USA. 1985;82(24):8340–8344. doi: 10.1073/pnas.82.24.8340

[36] Law S.W., Lackner K.J., Hospattankar A.V., et al. Human apolipoprotein B-100: cloning, analysis of liver mRNA, and assignment of the gene to chromosome 2 // Proc Natl Acad Sci USA. 1985. Vol. 82, N 24. P. 8340–8344. doi: 10.1073/pnas.82.24.8340

[37] Vega GL, Grundy SM. In vivo evidence for reduced binding of low density lipoproteins to receptors as a cause of primary moderate hypercholesterolemia. J Clin Invest. 1986;78(5):1410–1414. doi: 10.1172/jci112729

[38] Vega G.L., Grundy S.M. In vivo evidence for reduced binding of low density lipoproteins to receptors as a cause of primary moderate hypercholesterolemia // J Clin Invest. 1986. Vol. 78, N 5. P. 1410–1414. doi: 10.1172/jci112729

[39] Innerarity TL, Weisgraber KH, Arnold KS, et al. Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding. Proc Natl Acad Sci USA. 1987;84(19):6919–6923. doi: 10.1073/pnas.84.19.6919

[40] Innerarity T.L., Weisgraber K.H., Arnold K.S., et al. Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding // Proc Natl Acad Sci USA. 1987. Vol. 84, N 19. P. 6919–6923. doi: 10.1073/pnas.84.19.6919

[41] Soria LF, Ludwig EH, Clarke HR, et al. Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100. Proc Natl Acad Sci USA. 1989;86(2):587–591. doi: 10.1073/pnas.86.2.587

[42] Soria L.F., Ludwig E.H., Clarke H.R., et al. Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100 // Proc Natl Acad Sci USA. 1989. Vol. 86, N 2. P. 587–591. doi: 10.1073/pnas.86.2.587

[43] Alves AC, Etxebarria A, Soutar AK, et al. Novel functional APOB mutations outside LDL-binding region causing familial hypercholesterolaemia. Hum Mol Genet. 2014;23(7):1817–1828. doi: 10.1093/hmg/ddt573

[44] Alves A.C., Etxebarria A., Soutar A.K., et al. Novel functional APOB mutations outside LDL-binding region causing familial hypercholesterolaemia // Hum Mol Genet. 2014. Vol. 23, No. 7. P. 1817–1828. doi: 10.1093/hmg/ddt573

[45] Garcia CK, Wilund K, Arca M, et al. Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein. Science. 2001;292(5520):1394–1398. doi: 10.1126/science.1060458

[46] Garcia C.K., Wilund K., Arca M., et al. Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein // Science. 2001. Vol. 292, N 5520. P. 1394–1398. doi: 10.1126/science.1060458

[47] Seidah NG, Benjannet S, Wickham L, et al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc Natl Acad Sci USA. 2003;100(3):928–933. doi: 10.1073/pnas.0335507100

[48] Seidah N.G., Benjannet S., Wickham L., et al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation // Proc Natl Acad Sci USA. 2003. Vol. 100, N 3. P. 928–933. doi: 10.1073/pnas.0335507100

[49] Abifadel M, Varret M, Rabès JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34(2):154–156. doi: 10.1038/ng1161

[50] Abifadel M., Varret M., Rabès J.P., et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia // Nat Genet. 2003. Vol. 34, N 2. P. 154–156. doi: 10.1038/ng1161

[51] Mandelshtam MYu, Vasilyev VB. Monogenic hypercholesterolemias: new genes, new drug targets. Russian Journal of Genetics. 2008;44(10):1134–1140. EDN: LLCFZZ doi: 10.1134/s1022795408100025

[52] Мандельштам М.Ю., Васильев В.Б. Моногенные гиперхолестеринемии: новые гены, новые мишени для лечения // Генетика. 2008. Т. 44, № 10. С. 1309–1316. EDN: LLCFZZ doi: 10.1134/s1022795408100025

[53] Marduel M, Ouguerram K, Serre V, et al. Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation. Hum Mutat. 2013;34(1):83–87. doi: 10.1002/humu.22215

[54] Marduel M., Ouguerram K., Serre V., et al. Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation // Hum Mutat. 2013. Vol. 34, N 1. P. 83–87. doi: 10.1002/humu.22215

[55] Awan Z, Choi HY, Stitziel N, et al. APOE p.Leu167del mutation in familial hypercholesterolemia. Atherosclerosis. 2013;231(2):218–222. doi: 10.1016/j.atherosclerosis.2013.09.007

[56] Awan Z., Choi H.Y., Stitziel N., et al. APOE p.Leu167del mutation in familial hypercholesterolemia // Atherosclerosis. 2013. Vol. 231, N 2. P. 218–222. doi: 10.1016/j.atherosclerosis.2013.09.007

[57] Wintjens R, Bozon D, Belabbas K, et al. Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France. J Lipid Res. 2016;57(3):482–491. doi: 10.1194/jlr.p055699

[58] Wintjens R., Bozon D., Belabbas K., et al. Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France // J Lipid Res. 2016. Vol. 57, N 3. P. 482–491. doi: 10.1194/jlr.p055699

[59] Abifadel M, Boileau C. Genetic and molecular architecture of familial hypercholesterolemia. J Intern Med. 2023;293:144–165. doi: 10.1111/joim.13577

[60] Abifadel M., Boileau C. Genetic and molecular architecture of familial hypercholesterolemia // J Intern Med. 2023. Vol. 293. P. 144–165. doi: 10.1111/joim.13577

[61] Talmud PJ, Shah S, Whittall R, et al. Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study. Lancet. 2013;381(9874):1293–1301. doi: 10.1016/s0140-6736(12)62127-8

[62] Talmud P.J., Shah S., Whittall R., et al. Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study // Lancet. 2013. Vol. 381, N 9874. P. 1293–1301. doi: 10.1016/s0140-6736(12)62127-8

[63] Shakhtshneider E, Ivanoshchuk D, Orlov P, et al. Analysis of the Ldlr, Apob, Pcsk9 and Ldlrap1 genes variability in patients with familial hypercholesterolemia in West Siberia using targeted high throughput resequencing. Atherosclerosis. 2019;287:e285. doi: 10.1016/j.atherosclerosis.2019.06.883

[64] Shakhtshneider E., Ivanoshchuk D., Orlov P., et al. Analysis of the Ldlr, Apob, Pcsk9 and Ldlrap1 genes variability in patients with familial hypercholesterolemia in West Siberia using targeted high throughput resequencing // Atherosclerosis. 2019. Vol. 287, P. e285. doi: 10.1016/j.atherosclerosis.2019.06.883

[65] 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. Biomed Rep. 2021;14(1):15. doi: 10.3892/br.2020.1391

[66] Miroshnikova V.V., Romanova O.V., Ivanova O.N., et al. Identification of novel variants in the LDLR gene in Russian patients with familial hypercholesterolemia using targeted sequencing // Biomed Rep. 2021. Vol. 14, N 1. P. 15. doi: 10.3892/br.2020.1391

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

[68] Meshkov A., Ershova A., Kiseleva A., et al. The LDLR, APOB, and PCSK9 variants of index patients with familial hypercholesterolemia in Russia // Genes (Basel). 2021. Vol. 12, N 1. P. 66. doi: 10.3390/genes12010066

[69] Shakhtshneider E, Ivanoshchuk D, Timoshchenko O, et al. Analysis of rare variants in genes related to lipid metabolism in patients with familial hypercholesterolemia in Western Siberia (Russia). J Pers Med. 2021;11(11):1232. doi: 10.3390/jpm11111232

[70] Shakhtshneider E., Ivanoshchuk D., Timoshchenko O., et al. Analysis of rare variants in genes related to lipid metabolism in patients with familial hypercholesterolemia in Western Siberia (Russia) // J Pers Med. 2021. Vol. 11, N 11. P. 1232. doi: 10.3390/jpm11111232

[71] Andersen LH, Miserez AR, Ahmad Z, Andersen RL. Familial defective apolipoprotein B-100: a review. J Clin Lipidol. 2016;10(6):1297–1302. doi: 10.1016/j.jacl.2016.09.009

[72] Andersen L.H., Miserez A.R., Ahmad Z., Andersen R.L. Familial defective apolipoprotein B-100: a review // J Clin Lipidol. 2016. Vol. 10, N 6. P. 1297–1302. doi: 10.1016/j.jacl.2016.09.009

[73] Ezhov MV, Barbarash OL, Voevoda MI, et al. Organization of lipid centers operation in the Russian Federation — new opportunities. Russian Journal of Cardiology. 2021;26(6):16–23. EDN: UGKJTQ doi: 10.15829/1560-4071-2021-4489

[74] Ежов М.В., Барбараш О.Л., Воевода М.И. и др. Организация работы липидных центров в Российской Федерации — новые возможности // Российский кардиологический журнал. 2021. Т. 26, № 6. С. 16–23. EDN: UGKJTQ doi: 10.15829/1560-4071-2021-4489

[75] Hamasaki M, Sakane N, Hara K, Kotani K. LDL-cholesterol and PCSK9 in patients with familial hypercholesterolemia: influence of PCSK9 variants under lipid-lowering therapy. J Clin Lab Anal. 2021;35(11):e24056. doi: 10.1002/jcla.24056

[76] Hamasaki M., Sakane N., Hara K., Kotani K. LDL-cholesterol and PCSK9 in patients with familial hypercholesterolemia: influence of PCSK9 variants under lipid-lowering therapy // J Clin Lab Anal. 2021. Vol. 35, N 11. P. e24056. doi: 10.1002/jcla.24056

[77] Mandelshtam MYu, Lipovetskii BM, Schvartsman AL, Gaitskhoki VS. Molecular heterogeneity of familial hypercholesterolemia in the St. Petersburg population. Russian Journal of Genetics. 1995;31(4):447–452. (In Russ.)

[78] Мандельштам М.Ю., Липовецкий Б.М., Шварцман А.Л., Гайцхоки В.С. Молекулярная гетерогенность семейной гиперхолестеринемии в популяции жителей Санкт-Петербурга // Генетика. 1995. Т. 31, № 4. С. 521–527.

[79] Mandelshtam MJ, Lipovetskyi BM, Schwartzman AL, Gaitskhoki VS. A novel deletion in the low-density lipoprotein receptor gene in a patient with familial hypercholesterolemia from Petersburg. Hum Mutat. 1993;2(4):256–260. doi: 10.1002/humu.1380020404

[80] Mandelshtam M.J., Lipovetskyi B.M., Schwartzman A.L., Gaitskhoki V.S. A novel deletion in the low-density lipoprotein receptor gene in a patient with familial hypercholesterolemia from Petersburg // Hum Mutat. 1993. Vol. 2, N 4. P. 256–260. doi: 10.1002/humu.1380020404

[81] Zakharova FM, Damgaard D, Mandelshtam MY, et al. Familial hypercholesterolemia in St-Petersburg: the known and novel mutations found in the low density lipoprotein receptor gene in Russia. BMC Med Genet. 2005;6:6. doi: 10.1186/1471-2350-6-6

[82] Zakharova F.M., Damgaard D., Mandelshtam M.Y., et al. Familial hypercholesterolemia in St-Petersburg: the known and novel mutations found in the low density lipoprotein receptor gene in Russia // BMC Med Genet. 2005. Vol. 6. P. 6. doi: 10.1186/1471-2350-6-6

[83] Komarova TYu, Korneva VA, Kuznetsova TYu, et al. Familial hypercholesterolemia mutations in Petrozavodsk: no similarity to St. Petersburg mutation spectrum. BMC Med Genet. 2013;14:128. doi: 10.1186/1471-2350-14-128

[84] Komarova T.Yu., Korneva V.A., Kuznetsova T.Yu., et al. Familial hypercholesterolemia mutations in Petrozavodsk: no similarity to St. Petersburg mutation spectrum // BMC Med Genet. 2013. Vol. 14. P. 128. doi: 10.1186/1471-2350-14-128

[85] Korneva VA, Kuznetsova TYu, Bogoslovskaya TYu, et al. Cholesterol levels in genetically determined familial hypercholesterolaemia in Russian Karelia. Cholesterol. 2017;2017:9375818. doi: 10.1155/2017/9375818

[86] Korneva V.A., Kuznetsova T.Yu., Bogoslovskaya T.Yu., et al. Cholesterol levels in genetically determined familial hypercholesterolaemia in Russian Karelia // Cholesterol. 2017. Vol. 2017. P. 9375818. doi: 10.1155/2017/9375818

[87] Vasilyev VB, Zakharova FM, Bogoslovskaya TYu, Mandelshtam MYu. Analysis of the low density lipoprotein receptor gene (LDLR) mutation spectrum in Russian familial hypercholesterolemia. Vavilov Journal of Genetics and Breeding. 2022;26(3):319–326. EDN: HPHVJV doi: 10.18699/vjgb-22-38

[88] Васильев В.Б., Захарова Ф.М., Богословская Т.Ю., Мандельштам М.Ю. Анализ спектра мутаций гена рецептора низкой плотности (LDLR) при семейной гиперхолестеринемии в России // Вавиловский журнал генетики и селекции. 2022. № 26(3). С. 319–326. EDN: HPHVJV doi: 10.18699/vjgb-22-38

[89] Meshkov AN, Malyshev PP, Kukharchuk VV. Familial hypercholesterolemia in Russia: genetic and phenotypic characteristics. Terapevticheskiy Arkhiv. 2009;81(9):23–28. EDN: KZRAHZ

[90] Мешков А.Н., Малышев П.П., Кухарчук В.В. Семейная гиперхолестеринемия в России: генетическая и фенотипическая характеристика // Терапевтический архив. 2009. Т. 81, № 9. С. 23–28. EDN: KZRAHZ

[91] Malyshev PP, Meshkov AN, Kotova LA, Kukharchuk VV. Familial defect of apolipoprotein В-100: molecular disease basis and clinico-biochemical characteristics of the patients. Cardiovascular Therapy and Prevention. 2007;6(6):40–45. EDN: IJWXGL

[92] Малышев П.П., Мешков А.Н., Котова Л.А., Кухарчук В.В. Семейный дефект аполипопротеина В-100: молекулярная основа заболевания и клинико-биохимические особенности пациентов // Кардиоваскулярная терапия и профилактика. 2007. Т.6, № 6. С. 40–45. EDN: IJWXGL

[93] Voevoda MI, Kulikov IV, Shakhtshneider EV, et al. The spectrum of mutations in the low-density lipoprotein receptor gene in the Russian population. Russian Journal of Genetics. 2008;44(10):1191–1194. EDN: LLCFYB doi: 10.1134/s1022795408100074

[94] Воевода М.И., Куликов И.В., Шахтшнейдер Е.В. и др. Спектр мутаций гена рецептора липопротеинов низкой плотности в Российской популяции // Генетика. 2008. Т. 44, № 10. С. 1374–1378. EDN: JSJRHJ

[95] Semenova AE, Sergienko IV, García-Giustiniani D, et al. Verification of underlying genetic cause in a cohort of Russian patients with familial hypercholesterolemia using targeted next generation sequencing. J Cardiovasc Dev Dis. 2020;7(2):16. doi: 10.3390/jcdd7020016

[96] Semenova A.E., Sergienko I.V., García-Giustiniani D., et al. Verification of underlying genetic cause in a cohort of Russian patients with familial hypercholesterolemia using targeted next generation sequencing // J Cardiovasc Dev Dis. 2020. Vol. 7, N 2. P. 16. doi: 10.3390/jcdd7020016

[97] Vasilyev V, Zakharova F, Bogoslovskaya T, Mandelshtam M. Familial hypercholesterolemia in Russia: Three decades of genetic studies. Front Genet. 2020;11:550591. doi: 10.3389/fgene.2020.550591

[98] Vasilyev V., Zakharova F., Bogoslovskaya T., Mandelshtam M. Familial hypercholesterolemia in Russia: Three decades of genetic studies // Front Genet. 2020. Vol. 11. P. 550591. doi: 10.3389/fgene.2020.550591

[99] 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. J Pers Med. 2021;11(6):464. doi: 10.3390/jpm11060464

[100] Meshkov A.N., Ershova A.I., Kiseleva A.V., et al. The prevalence of heterozygous familial hypercholesterolemia in selected regions of the Russian Federation: The FH-ESSE-RF study // J Pers Med. 2021. Vol. 11, N 6. P. 464. doi: 10.3390/jpm11060464

[101] Chakir Kh, Skobeleva NA, Shevtsov SP, et al. Two novel slavic point mutations in the low-density lipoprotein receptor gene in patients with familial hypercholesterolemia from St. Petersburg, Russia. Mol Genet Metab. 1998;63(1):31–34. doi: 10.1006/mgme.1997.2614

[102] Chakir Kh., Skobeleva N.A., Shevtsov S.P., et al. Two novel slavic point mutations in the low-density lipoprotein receptor gene in patients with familial hypercholesterolemia from St. Petersburg, Russia // Mol Genet Metab. 1998. Vol. 63, N 1. P. 31–34. doi: 10.1006/mgme.1997.2614

[103] Mandelshtam M, Chakir K, Shevtsov S, et al. Prevalence of Lithuanian mutation among St. Petersburg Jews with familial hypercholesterolemia. Hum Mutat. 1998;12(4):255–258. doi: 10.1002/(sici)1098-1004(1998)12:4<255::aid-humu6>3.0.co;2-e

[104] Mandelshtam M., Chakir K., Shevtsov S., et al. Prevalence of Lithuanian mutation among St. Petersburg Jews with familial hypercholesterolemia // Hum Mutat. 1998. Vol. 12, N 4. P. 255–258. doi: 10.1002/(sici)1098-1004(1998)12:4<255::aid-humu6>3.0.co;2-e

[105] Patent RU 2022621118/18.05.2022. Bull. No. 5. Mandelstam MYu, Zakharova FM, Bogoslovskaya TYu, Vasiliev VB. List of mutations in the low-density lipoprotein receptor gene found in patients with familial hypercholesterolemia in Russia. (In Russ.) EDN: FFCVVP

[106] Патент RU 2022621118/18.05.2022. Бюл. № 5. Мандельштам М.Ю., Захарова Ф.М., Богословская Т.Ю., Васильев В.Б. Перечень мутации в гене рецептора липопротеинов низкой плотности, обнаруженных у пациентов с семейной гиперхолестеринемией в России. EDN: FFCVVP

[107] Patent RU 2022620667/29.03.2022. Bull. No. 4. Mandelshtam MYu, Zakharova FM, Bogoslovskaya TYu, Vasilyev VB. List of polymorphisms in the low-density lipoprotein receptor gene found in patients with familial hypercholesterolemia in Russia. (In Russ.) EDN: FULUHN

[108] Патент RU 2022620667/29.03.2022. Бюл. № 4. Мандельштам М.Ю., Захарова Ф.М., Богословская Т.Ю., Васильев В.Б. Перечень полиморфизмов в гене рецептора липопротеинов низкой плотности, обнаруженных у пациентов с семейной гиперхолестеринемией в России. EDN: FULUHN

[109] El Khoury P, Elbitar S, Ghaleb Y, et al. PCSK9 Mutations in familial hypercholesterolemia: from a groundbreaking discovery to anti-PCSK9 therapies. Curr Atheroscler Rep. 2017;19(12):49. doi: 10.1007/s11883-017-0684-8

[110] El Khoury P., Elbitar S., Ghaleb Y., et al. PCSK9 Mutations in familial hypercholesterolemia: from a groundbreaking discovery to anti-PCSK9 therapies // Curr Atheroscler Rep. 2017. Vol. 19, N 12. P. 49. doi: 10.1007/s11883-017-0684-8

[111] Raal FJ, Honarpour N, Blom DJ, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385(9965):341–350. doi: 10.1016/s0140-6736(14)61374-x

[112] Raal F.J., Honarpour N., Blom D.J., et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial // Lancet. 2015. Vol. 385, N 9965. P. 341–350. doi: 10.1016/s0140-6736(14)61374-x

[113] Blom DJ, Harada-Shiba M, Rubba P, et al. Efficacy and safety of Alirocumab in adults with homozygous familial hypercholesterolemia: The ODYSSEY HoFH Trial. J Am Coll Cardiol. 2020;76(2):131–142. doi: 10.1016/j.jacc.2020.05.027

[114] Blom D.J., Harada-Shiba M., Rubba P., et al. Efficacy and safety of Alirocumab in adults with homozygous familial hypercholesterolemia: The ODYSSEY HoFH Trial // J Am Coll Cardiol. 2020. Vol. 76, N 2. P. 131–142. doi: 10.1016/j.jacc.2020.05.027

[115] Hovingh GK, Lepor NE, Kallend D, et al. Inclisiran durably lowers low-density lipoprotein cholesterol and proprotein convertase subtilisin/kexin type 9 expression in homozygous familial hypercholesterolemia: The ORION-2 pilot study. Circulation. 2020;141(22):1829–1831. doi: 10.1161/circulationaha.119.044431

[116] Hovingh G.K., Lepor N.E., Kallend D., et al. Inclisiran durably lowers low-density lipoprotein cholesterol and proprotein convertase subtilisin/kexin type 9 expression in homozygous familial hypercholesterolemia: The ORION-2 pilot study // Circulation. 2020. Vol. 141, N 22. P. 1829–1831. doi: 10.1161/circulationaha.119.044431

[117] Ray KK, Bays HE, Catapano AL, et al. Safety and efficacy of Bempedoic acid to reduce LDL cholesterol. N Engl J Med. 2019;380(11):1022–1032. doi: 10.1056/nejmoa1803917

[118] Ray K.K., Bays H.E., Catapano A.L., et al. Safety and efficacy of Bempedoic acid to reduce LDL cholesterol // N Engl J Med. 2019. Vol. 380, N 11. P. 1022–1032. doi: 10.1056/nejmoa1803917

[119] Tibuakuu M, Blumenthal RS, Martin SS. Bempedoic Acid for LDL-C lowering: what do we know? [Internet]. American College of Cardiology; Aug 10, 2020. Available from: https://www.acc.org/latest-in-cardiology/articles/2020/08/10/08/21/bempedoic-acid-for-ldl-c-lowering. Accessed: 29 Feb 2024.

[120] Tibuakuu M., Blumenthal R.S., Martin S.S. Bempedoic Acid for LDL-C lowering: what do we know? [Электронный ресурс] // American College of Cardiology. Aug 10, 2020. Режим доступа: https://www.acc.org/latest-in-cardiology/articles/2020/08/10/08/21/bempedoic-acid-for-ldl-c-lowering. Дата обращения: 29.02.2024.

[121] Arca M, Minicocci I, Maranghi M. The angiopoietin-like protein 3: a hepatokine with expanding role in metabolism. Curr Opin Lipidol. 2013;24(4):313–320. doi: 10.1097/mol.0b013e3283630cf0

[122] Arca M., Minicocci I., Maranghi M. The angiopoietin-like protein 3: a hepatokine with expanding role in metabolism // Curr Opin Lipidol. 2013. Vol. 24, N 4. P. 313–320. doi: 10.1097/mol.0b013e3283630cf0

[123] Musunuru K, Pirruccello JP, Do R, et al. Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N Engl J Med. 2010;363(23):2220–2227. doi: 10.1056/nejmoa1002926

[124] Musunuru K., Pirruccello J.P., Do R., et al. Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia // N Engl J Med. 2010. Vol. 363, N 23. P. 2220–2227. doi: 10.1056/nejmoa1002926

[125] Dewey FE, Gusarova V, Dunbar RL, et al. Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. N Engl J Med. 2017;377(3):211–221. doi: 10.1056/nejmoa1612790

[126] Dewey F.E., Gusarova V., Dunbar R.L., et al. Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease // N Engl J Med. 2017. Vol. 377, N 3. P. 211–221. doi: 10.1056/nejmoa1612790

[127] Stitziel NO, Khera AV, Wang X, et al. ANGPTL3 Deficiency and protection against coronary artery disease. J Am Coll Cardiol. 2017;69(16):2054–2063. doi: 10.1016/j.jacc.2017.02.030

[128] Stitziel N.O., Khera A.V., Wang X., et al. ANGPTL3 Deficiency and protection against coronary artery disease // J Am Coll Cardiol. 2017. Vol. 69, N 16. P. 2054–2063. doi: 10.1016/j.jacc.2017.02.030

[129] Chilazi M, Sharma G, Blumenthal RS, Martin SS. Angiopoietin-like 3 (ANGPTL3) — a novel therapeutic target for treatment of hyperlipidemia [Internet]. American College of Cardiology; Jan 06, 2021. Available from: https://www.acc.org/latest-in-cardiology/articles/2021/01/06/13/01/angiopoietin-like-3-angptl3. Accessed: 29 Feb 2024.

[130] Chilazi M., Sharma G., Blumenthal R.S., Martin S.S. Angiopoietin-like 3 (ANGPTL3) — a novel therapeutic target for treatment of hyperlipidemia [Электронный ресурс] // American College of Cardiology. Jan 06, 2021. Режим доступа: https://www.acc.org/latest-in-cardiology/articles/2021/01/06/13/01/angiopoietin-like-3-angptl3. Дата обращения: 29.02.2024.

[131] Raal FJ, Hovingh GK, Catapano AL. Familial hypercholesterolemia treatments: Guidelines and new therapies. Atherosclerosis. 2018;277:483–492. doi: 10.1016/j.atherosclerosis.2018.06.859

[132] Raal F.J., Hovingh G.K., Catapano A.L. Familial hypercholesterolemia treatments: Guidelines and new therapies // Atherosclerosis. 2018. Vol. 277. P. 483–492. doi: 10.1016/j.atherosclerosis.2018.06.859

[133] Konstantinov VO. Familial hypercholesterolemia: Three “under” (understood, underdiagnosed, and undertreated) disease. In: Cardiovascular Risk Factors in Pathology. IntechOpen. doi: 10.5772/intechopen.93042

[134] Sadykova DI, Galimova LF. Familial hypercholesterolemia in children: clinic, diagnostics, treatment. Russian bulletin of perinatology and pediatrics. 2017;62:(5):119–123. EDN: XCWDXR doi: 10.21508/1027-4065-2017-62-5-119-123

[135] Садыкова Д.И., Галимова Л.Ф. Семейная гиперхолестеринемия у детей: клинические проявления, диагностика, лечение // Российский вестник перинатологии и педиатрии. 2017. Т. 62, № 5. С. 119–123. EDN: XCWDXR doi: 10.21508/1027-4065-2017-62-5-119-123

[136] Galimova LF, Sadykova DI, Slastnikova E., Usova NE. Diagnosis of familial hypercholesterolemia in children: cascade screening from theory to practice. Cardiovascular Therapy and Prevention. 2020;19(3):191–196. EDN: VYMTKN doi: 10.15829/1728-8800-2020-2348

[137] Галимова Л.Ф., Садыкова Д.И., Сластникова Е.С., Усова Н.Э. Диагностика семейной гиперхолестеринемии у детей: каскадный скрининг от теории к практике // Кардиоваскулярная терапия и профилактика. 2020 Т. 19, № 3. C. 191–196. EDN: VYMTKN doi: 10.15829/1728-8800-2020-2348

[138] Zakharova IN, Osmanov IM, Pshenichnikova II, et al. Hypercholesterolemia in children and adolescents: focus on the familial variant. Medical council. 2021;(17):294–299. EDN: AGKVPC doi: 10.21518/2079-701X-2021-17-294-299

[139] Захарова И.Н., Османов И.М., Пшеничникова И.И. и др. Гиперхолестеринемия у детей и подростков: фокус на семейный вариант // Медицинский совет. 2021. № 17. С. 294–299. EDN: AGKVPC doi: 10.21518/2079-701X-2021-17-294-299

[140] Yezhov MV, Bliznyuk SA, Tmoyan NA, et al. Register of patients with familial hypercholesterolemia and patients of very high cardiovascular risk with lipid-lowering therapy underperformance (RENESSANS). Russian Journal of Cardiology. 2019;24(5):7–13. EDN: ZGREKR doi: 10.15829/1560-4071-2019-5-7-13

[141] Ежов М.В., Близнюк С.А., Тмоян Н.А. и др. Регистр пациентов с семейной гиперхолестеринемией и пациентов очень высокого сердечно-сосудистого риска с недостаточной эффективностью проводимой гиполипидемической терапии (РЕНЕССАНС) // Российский кардиологический журнал. 2019. Т. 24, № 5. С. 7–13. EDN: ZGREKR doi: 10.15829/1560-4071-2019-5-7-13

[142] Ezhov MV, Sergienko IV, Rozhkova TА, et al. Diagnosis and treatment of family hypercholesterinemia (russian guidelines). The Bulletin of Contemporary Clinical Medicine. 2017;10(2):72–79. EDN: YKOSDZ doi: 10.20969/VSKM.2017.10(2).72-79

[143] Ежов М.В., Сергиенко И.В., Рожкова Т.А. и др. Диагностика и лечение семейной гиперхолестеринемии (российские рекомендации) // Вестник современной клинической медицины. 2017. Т. 10, № 2. С. 72–79. EDN: YKOSDZ doi: 10.20969/VSKM.2017.10(2).72-79

[144] Pogoda T, Metelskaya V, Perova N, Limborska S. Detection of the apoB-3500 mutation in a Russian family with coronary heart disease. Hum Hered. 1998;48(5):291–292. doi: 10.1159/000022819

[145] Pogoda T., Metelskaya V., Perova N., Limborska S. Detection of the apoB-3500 mutation in a Russian family with coronary heart disease // Hum Hered. 1998. Vol. 48, N 5. P. 291–292. doi: 10.1159/000022819

[146] Krapivner SR, Malyshev PP, Poltaraus AB, et al. A case of familial hypercholesterolemia caused by a novel mutation D461Y in the low density lipoprotein receptor gene. Kardiologiia. 2001;41(1):92–94. EDN: MOTAFT

[147] Крапивнер С.Р., Малышев П.П., Полтараус А.Б. и др. Случай семейной гиперхолестеринемии, вызванный новой мутацией D461Y в гене рецептора липопротеинов низкой плотности // Кардиология. 2001. Т. 41, № 1. С. 92–94. EDN: MOTAFT

[148] Shakhtshneider EV, Makarenkova KV, Astrakova KS, et al. Targeted next-generation sequencing of PCSK9 gene in patients with familial hypercholesterolemia in Russia. Kardiologiia. 2017;57(6):46–51. EDN: YUEIUX doi: 10.18565/cardio.2017.6.46-51

[149] Шахтшнейдер Е.В., Макаренкова К.В., Астракова К.С. и др. Таргетное секвенирование гена PCSK9 пациентов с семейной гиперхолестеринемией в России // Кардиология. 2017. Т. 57, № 6. С. 46–51. EDN: YUEIUX doi: 10.18565/cardio.2017.6.46-51

RIGHTS & PERMISSIONS

Eco-Vector