Analysis of lipid metabolism gene variants in individuals aged 25–44 years with contrasting LDL cholesterol levels
https://doi.org/10.52727/2078-256X-2025-21-3-237-247
Abstract
The increasing prevalence of low-density lipoprotein (LDL) hypercholesterolemia and its associated diseases among young people is a major public health concern in many countries. The aim of this study was to identify rare functionally significant variants in coding regions and adjacent splice sites of genes associated with elevated LDL cholesterol (LDL-C) levels in men and women aged 25–44 years.
Methods. A population-based sample was stratified by deciles according to LDL-C concentration. The study included 146 individuals with LDL-C <2.1 mmol/L (first decile) and 158 individuals with LDL-C ≥ 4.2 mmol/L (tenth decile). Targeted high-throughput sequencing was performed.
Results. In the sample of young adults, 0.07 % had LDL-C levels >8.5 mmol/L, 0.13 % had levels ranging from 6.5 to 8.4 mmol/L, and 2.25 % had levels between 5.0 and 6.4 mmol/L. Participants in the first and tenth LDL-C deciles differed in the spectrum of variants in lipid metabolism genes. Functionally significant variants associated with LDL hypercholesterolemia were identified in individuals with LDL-C ≥4.2 mmol/L in the coding regions of the LDLR and APOB genes, as well as in ABCA1, LCAT, LIPA, LIPC, and LPA.
Conclusions. Rare functionally significant variants in coding regions and adjacent splice sites of genes associated with elevated LDL-C levels were identified in young men and women.
Keywords
low-density lipoprotein hypercholesterolemia,
young age,
targeted sequencing technology,
rare variants in lipid metabolism genes,
familial hypercholesterolemia
Supporting agencies: The study was carried out within the framework of the main topic of state assignment No. FWNR-2024-0004.
About the Authors
A. N. Spiridonov
Research Institute of Internal and Preventive Medicine – Branch of the Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences
Russian Federation
Russian Federation
Aleksandr N. Spiridonov, graduate student "Cardiology"
175/1, Boris Bogatkov st., Novosibirsk, 630089
D. E. Ivanoshchuk
Research Institute of Internal and Preventive Medicine – Branch of the Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences
Russian Federation
Russian Federation
Dinara E. Ivanoshchuk, researcher at the laboratory of molecular genetic investigations of internal diseases
175/1, Boris Bogatkov st., Novosibirsk, 630089
E. V. Kashtanova
Research Institute of Internal and Preventive Medicine – Branch of the Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences
Russian Federation
Russian Federation
Elena V. Kashtanova, doctor of biological sciences, head of the laboratory of clinical biochemical and hormonal studies of therapeutic diseases
175/1, Boris Bogatkov st., Novosibirsk, 630089
E. V. Shakhtshneider
Research Institute of Internal and Preventive Medicine – Branch of the Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences
Russian Federation
Russian Federation
Elena V. Shakhtshneider, doctor of medical sciences, leadering researcher in the laboratory of the molecular genetic investigations of internal disease
175/1, Boris Bogatkov st., Novosibirsk, 630089
References
1. World Health Organization. Noncommunicable diseases. Available at: https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death
2. Roth G.A., Mensah G.A., Johnson C.O., Addolorato G., Ammirati E., Baddour L.M., Barengo N.C., Beaton A.Z., Benjamin E.J., Benziger C.P., Bonny A., Brauer M., Brodmann M., Cahill T.J., Carapetis J., Catapano A.L., Chugh S.S., Cooper L.T., Coresh J., Criqui M. Global burden of cardiovascular diseases and risk factors, 1990–2019: Update From the GBD 2019 Study. J. Am. Coll. Cardiol., 2020; 76 (25): 2982–3021. doi: 10.1016/j.jacc.2020.11.010
3. Banderali G., Capra M.E., Biasucci G., Stracquadaino R., Viggiano C., Pederiva C. Detecting familial hypercholesterolemia in children and adolescents: potential and challenges. Ital. J. Pediatr., 2022; 48 (1): 115. doi: 10.1186/s13052-022-01257-y
4. Stone N.J., Smith S.C. Jr, Orringer C.E., Rigotti N.A., Navar A.M., Khan S.S., Jones D.W., Goldberg R., Mora S., Blaha M., Pencina M.J., Grundy S.M. Managing atherosclerotic cardiovascular risk in young adults: JACC State-of-the-Art Review. J. Am. Coll. Cardiol., 2022; 79 (8): 819–836. doi: 10.1016/j.jacc.2021.12.016
5. Cohen H., Stefanutti C.; The Mighty Medic Satellite Research Group for Pediatric Dyslipidemia. Current approach to the diagnosis and treatment of heterozygote and homozygous FH children and adolescents. Curr. Atheroscler. Rep., 2021; 23 (6): 30. doi: 10.1007/s11883-021-00926-3
6. Hajar R. Risk factors for coronary artery disease: historical perspectives. Heart Views, 2017; 18 (3): 109–114. doi: 10.4103/HEARTVIEWS.HEARTVIEWS_106_17
7. Bauersachs R., Zeymer U., Brière J.B. Burden of coronary artery disease and peripheral artery disease: a literature review. Cardiovasc. Ther., 2019; 2019: 8295054. doi: 10.1155/2019/8295054
8. Korneva V., Kuznetsova T., Julius U. The role of cumulative LDL cholesterol in cardiovascular disease development in patients with familial hypercholesterolemia. J. Pers. Med., 2022; 12 (1): 71. doi: 10.3390/jpm12010071
9. van der Laan S.W., Harshfield E.L., Hemerich D. From lipid locus to drug target through human genomics. Cardiovasc. Res., 2018; 114 (9): 1258–1270. doi: 10.1093/cvr/cvy120
10. Mgliara G., Baccolini V., Rosso A., d’Andrea E. Familial hypercholesterolemia: a systematic review of guidelines on genetic testing and patient management. Front. Public Health., 2017; 5: 252. doi: 10.3389/fpubh.2017.00252
11. Brown E.E., Sturm A.C., Cuchel M. Genetic testing in dyslipidemia: A scientific statement from the National Lipid Association. Atherosclerosis, 2020; 14 (4): 398–413. doi: 10.1016/j.jacl.2020.04.011
12. Ramasamy I. Update on the molecular biology of dyslipidemias. Clin. Chim. Acta, 2016; 454: 143–185. doi: 10.1016/j.cca.2015.10.033
13. García-Giustiniani D., Stein R. Genetics of dyslipidemia. Arq. Bras. Cardiol., 2016; 106 (5): 434–438. doi: 10.5935/abc.20160074
14. Meshkov A., Ershova A., Kiseleva A. The LDLR, APOB, and PCSK9 variants of index patients with familial hypercholesterolemia in Russia. Genes, 2021; 12 (1): 66–83. doi: 10.3390/genes12010066
15. Liu D.J., Peloso G.M., Yu H. Exome-wide association study of plasma lipids in >300,000 individuals. Nat. Genet., 2017; 49 (12): 1758–1766. doi: 10.1038/ng.3977
16. Peloso G.M., Auer P.L., Bis J.C. Association of lowfrequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks. Am. J. Hum. Genet., 2014; 94 (2): 223–232. doi: 10.1016/j.ajhg.2014.01.009
17. Vasilyev V., Zakharova F., Bogoslovskaya T. Familial hypercholesterolemia in Russia: Three decades of genetic studies. Front. Genet., 2020; 11: 550591. doi: 10.3389/fgene.2020.550591
18. Sambrook J., Russell D.W. Purification of nucleic acids by extraction with phenol:chloroform. CSH Protocols, 2006; 2006 (1): pdb.prot4455. doi: 10.1101/pdb.prot4455
19. Richards S., Aziz N., Bale S., Bick D., Das S., Gastier-Foster J., Grody W.W., Hegde M., Lyon E., Spector E., Voelkerding K., Rehm H.L., ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med., 2015; 17 (5): 405–424. doi: 10.1038/gim.2015.30
20. World Health Organization. Familial hypercholesterolaemia – report of a second WHO consultation. Geneva: WHO; 1999. Available at: https://apps.who.int/iris/handle/10665/66346
21. GnomAD: Genome Aggregation Database. Available at: https://gnomad.broadinstitute.org
22. Rutkowska L., Sałacińska K., Salachna D. Identification of new genetic determinants in pediatric patients with familial hypercholesterolemia using a custom NGS panel. Genes (Basel), 2022; 13 (6): 999. doi: 10.3390/genes13060999
23. Latkovskis G., Rescenko-Krums R., Nesterovics G. Genetic characteristics of Latvian patients with familial hypercholesterolemia: the first analysis from genome-wide sequencing. J. Clin. Med., 2023; 12 (15): 5160. doi: 10.3390/jcm12155160
24. Tada H., Nohara A., Usui S. Validation of the 2022 clinical diagnostic criteria of familial hypercholesterolemia in Japan. J. Atheroscler. Thromb., 2024; 31 (5): 550–558. doi: 10.5551/jat.64549
25. Abifadel M., Boileau C. Genetic and molecular architecture of familial hypercholesterolemia. J. Int. Med., 2023; 293 (2): 144–165. doi: 10.1111/joim.13577
26. Burnett J.R., Hooper A.J., Hegele R.A. APOB-related familial hypobetalipoproteinemia. Seattle (WA): Seattle: University of Washington, 2021. 16 p.
27. Alves A.C., Etxebarria A., Soutar A.K., Martin C., Bourbon M. Novel functional APOB mutations outside LDL-binding region causing familial hypercholesterolaemia. Hum. Mol. Genet., 2014; 23 (7): 1817–1828. doi: 10.1093/hmg/ddt573
28. Rabès J.P., Varret M., Devillers M. R3531C mutation in the apolipoprotein B gene is not sufficient to cause hypercholesterolemia. Arterioscler. Thromb. Vasc. Biol., 2000; 20 (10): e76–e82. doi: 10.1161/01.atv.20.10.e76
29. Vandrovcova J., Thomas E.R., Atanur S.S. The use of next-generation sequencing in clinical diagnosis of familial hypercholesterolemia. Genet. Med., 2013; 15 (12): 948–957. doi: 10.1038/gim.2013.55
30. Arnaboldi L., Ossoli A., Giorgio E. LIPA gene mutations affect the composition of lipoproteins: enrichment in ACAT-derived cholesteryl esters. Atherosclerosis, 2020; 297: 8–15. doi: 10.1016/j.atherosclerosis.2020.01.026
31. Mayanskiy N., Brzhozovskaya E., Pushkov A. A kinetic assay of total lipase activity for detecting lysosomal acid lipase deficiency (LAL-D) and the molecular characterization of 18 LAL-D patients from Russia. JIMD Reports, 2019; 48 (1): 75–82. doi: 10.1002/jmd2.12050
32. Lipiński P., Ługowska A., Zakharova E.Y. Diagnostic algorithm for cholesteryl ester storage disease: clinical presentation in 19 Polish patients. J. Pediatr. Gastroenterol. Nutr., 2018; 67 (4): 452–457. doi: 10.1097/MPG.0000000000002084
33. Dron J.S., Wang J., McIntyre A.D., Iacocca M.A., Robinson J.F., Ban M.R., Cao H., Hegele R.A. Six years’ experience with LipidSeq: clinical and research learnings from a hybrid, targeted sequencing panel for dyslipidemias. BMC Med. Genomics, 2020; 13 (1): 23. doi: 10.1186/s12920-020-0669-2
34. Geller A.S., Polisecki E.Y., Diffenderfer M.R., Asztalos B.F., Karathanasis S.K., Hegele R.A., Schaefer E.J. Genetic and secondary causes of severe HDL deficiency and cardiovascular disease. J. Lipid Res., 2018; 59 (12): 2421–2435. doi: 10.1194/jlr.M088203
35. Cohen J.C., Kiss R.S., Pertsemlidis A., Marcel Y.L., McPherson R., Hobbs H.H. Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science, 2004; 305 (5685): 869–872. doi: 10.1126/science.1099870
36. Michaeli D.T., Michaeli J.C., Albers S., Boch T., Michaeli T. Established and emerging lipid-lowering drugs for primary and secondary cardiovascular prevention. Am. J. Cardiovasc. Drugs, 2023; 23 (5): 477–495. doi: 10.1007/s40256-023-00594-5
37. Liao J., Yang L., Zhou L., Zhao H., Qi X., Cui Y., Ouyang D. The NPC1L1 gene exerts a notable impact on the reduction of low-density lipoprotein cholesterol in response to hyzetimibe: a factorial-designed clinical trial. Front. Pharmacol., 2022; 13: 755469. doi: 10.3389/fphar.2022.755469
38. Weinglass A.B., Kohler M., Schulte U., Liu J., Nketiah E.O., Thomas A., Schmalhofer W., Williams B., Bildl W., McMasters D.R., Dai K., Beers L., McCann M.E., Kaczorowski G.J., Garcia M.L. Extracellular loop C of NPC1L1 is important for binding to ezetimibe. Proc. Natl. Acad. Sci. USA, 2008; 105 (32): 11140–11145. doi: 10.1073/pnas.0800936105
39. Shyamala N., Gundapaneni K.K., Galimudi R.K., Tupurani M.A., Padala C., Puranam K., Kupsal K., Kummari R., Gantala S.R., Nallamala K.R., Sahu S.K., Hanumanth S.R. PCSK9 genetic (rs11591147) and epigenetic (DNA methylation) modifications associated with PCSK9 expression and serum proteins in CAD patients. J. Gene Med., 2021; 23 (8): e3346. doi: 10.1002/jgm.3346
40. Lacaze P., Riaz M., Sebra R., Hooper A.J., Pang J., Tiller J., Polekhina G., Tonkin A., Reid C., Zoungas S., Murray A.M., Nicholls S., Watts G., Schadt E., McNeil J.J. Protective lipid-lowering variants in healthy older individuals without coronary heart disease. Open Heart, 2021; 8 (2): e001710. doi: 10.1136/openhrt-2021-001710
41. Grimaudo S., Bartesaghi S., Rametta R., Marra F., Mancina R.M., Pihlajamäki J., Kakol-Palm D., Andréasson A.C., Dongiovanni P., Fracanzani A.L., Lori G., Männistö V., Pellegrini G., Bohlooly M., Pennisi G., Pipitone R.M., Spagnuolo R., Craxì A., Lindén D., Valenti L. PCSK9 rs11591147 R46L lossof-function variant protects against liver damage in individuals with NAFLD. Liver Int., 2021; 41 (2): 321–332. doi: 10.1111/liv.14711
42. Khoramipour K., Chamari K., Hekmatikar A.A., Ziyaiyan A., Taherkhani S., Elguindy N.M., Bragazzi N.L. Adiponectin: structure, physiological functions, role in diseases, and effects of nutrition. Nutrients, 2021; 13(4): 1180. doi: 10.3390/nu13041180
43. Achari A.E., Jain S.K. Adiponectin, a therapeutic target for obesity, diabetes, and endothelial dysfunction. Int. J. Mol. Sci., 2017; 18 (6): 1321. doi: 10.3390/ijms18061321
44. Heimbürger S.M.N., Hoe B., Nielsen C.N., Bergman N.C., Skov-Jeppesen K., Hartmann B., Holst J.J., Dela F., Overgaard J., Størling J., Vilsbøll T., Dejgaard T.F., Havelund J.F., Gorshkov V., Kjeldsen F., Færgeman N.J., Madsen M.R., Christensen M.B., Knop F.K. GIP affects hepatic fat and brown adipose tissue thermogenesis but not white adipose tissue transcriptome in type 1 diabetes. J. Clin. Endocrinol. Metab., 2022; 107 (12): 3261–3274. doi: 10.1210/clinem/dgac542
45. Lindquist P., Gasbjerg L.S., Mokrosinski J., Holst J.J., Hauser A.S., Rosenkilde M.M. The location of missense variants in the human GIP gene is indicative for natural selection. Front. Endocrinol. (Lausanne), 2022; 13: 891586. doi: 10.3389/fendo.2022.891586
46. Fahed A.C., Natarajan P. Clinical applications of polygenic risk score for coronary artery disease through the life course. Atherosclerosis, 2023; 386: 117356. doi: 10.1016/j.atherosclerosis.2023.117356
47. Safarova M.S., Klee E.W., Baudhuin L.M., Winkler E.M., Kluge M.L., Bielinski S.J., Olson J.E., Kullo I.J. Variability in assigning pathogenicity to incidental findings: insights from LDLR sequence linked to the electronic health record in 1013 individuals. Eur. J. Hum. Genet., 2017; 25 (4): 410–415. doi: 10.1038/ejhg.2016.193
48. Wang J., Dron J.S., Ban M.R., Robinson J.F., McIntyre A.D., Alazzam M., Zhao P.J., Dilliott A.A., Cao H., Huff M.W. Polygenic versus monogenic causes of hypercholesterolemia ascertained clinically. Arterioscler. Thromb. Vasc. Biol., 2016; 36 (12): 2439–2445. doi: 10.1161/ATVBAHA.116.308027
49. Khalil Y.A., Rabès J.P., Boileau C., Varret M. APOE gene variants in primary dyslipidemia. Atherosclerosis, 2021; 328: 11–22. doi: 10.1016/j.atherosclerosis.2021.05.007
50. Daneshpour M.S., Hedayati M., Sedaghati-Khayat B., Guity K., Zarkesh M., Akbarzadeh M., Javanrooh N., Zadeh-Vakili A., Azizi F. Genetic identification for non-communicable disease: findings from 20 years of the Tehran Lipid and Glucose Study. Int. J. Endocrinol. Metab., 2018; 16 (4): e84744. doi: 10.5812/ijem.84744
51. Melendez Q.M., Krishnaji S.T., Wooten C.J., Lopez D. Hypercholesterolemia: the role of PCSK9. Arch. Biochem. Biophys., 2017; 625–626: 39–53. doi: 10.1016/j.abb.2017.06.001
52. Kheirkhah A., Schachtl-Riess J.F., Lamina C., di Maio S., Koller A., Schönherr S., Coassin S., Forer L., Sekula P., Gieger C. Meta-GWAS on PCSK9 concentrations reveals associations of novel loci outside the PCSK9 locus in white populations. Atherosclerosis, 2023; 386: 117384. doi: 10.1016/j.atherosclerosis.2023.117384
53. Gai M.T., Adi D., Chen X.C., Liu F., Xie X., Yang Y.N., Gao X.M., Ma X., Fu Z.Y., Ma Y.T., Chen B.D. Polymorphisms of rs2483205 and rs562556 in the PCSK9 gene are associated with coronary artery disease and cardiovascular risk factors. Sci. Rep., 2021; 11 (1): 11450. doi: 10.1038/s41598-021-90975-0
54. Borén J., Chapman M.J., Krauss R.M., Packard C.J., Bentzon J.F., Binder C.J., Daemen M.J., Demer L.L., Hegele R.A., Nicholls S.J. Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights. Eur. Heart. J., 2020; 41: 2313–2330. doi: 10.1093/eurheartj/ehz962
55. Sniderman A.D., Thanassoulis G., Glavinovic T. Apolipoprotein B particles and cardiovascular disease: a narrative review. JAMA Cardiology, 2019; 4 (12): 1287–1295. doi: 10.1001/jamacardio.2019.3780
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Spiridonov A.N., Ivanoshchuk D.E., Kashtanova E.V., Shakhtshneider E.V. Analysis of lipid metabolism gene variants in individuals aged 25–44 years with contrasting LDL cholesterol levels. Ateroscleroz. 2025;21(3):237-247. (In Russ.) https://doi.org/10.52727/2078-256X-2025-21-3-237-247
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