Associations of ANRIL rs1333049 and LPA rs10455872 with clinical markers of vascular damage in patients with hereditary dyslipidemias under 44 years of age

Aim. To study the impact of ANRIL rs1333049 and LPA rs10455872 polymorphisms on the clinical status of patients with heterozygous familial hypercholesterolemia (FH) and hyperlipoproteinemia(a) (hyperLP(a)).

Material and methods. A total of 171 patients aged 3 to 44 years were examined. Lipid profile, apolipoprotein B (apoB), and lipoprotein(a) (LP(a)) were determined using chemiluminescence immunoassay on the Roche Cobas 8000 automated modular analyzer. Single-nucleotide variant (SNV) carriage was determined using polymerase chain reaction (PCR) on a Rotor-Gene 6000 system with TaqMan allelic discrimination technology and Applied Biosystems fluorescent probes for LPA rs10455872 (A/G) and ANRIL rs1333049 (C/G). Genotype frequency distributions corresponded to Hardy-Weinberg equilibrium. Extracranial vessel ultrasound was assessed taking into account age-specific references.

Results. A study of relationship between the ANRIL rs1333049 and LPA rs10455872 in patients with FH and hyperLA revealed that the CG genotype of ANRIL rs1333049 directly correlates with apoB levels and intima-media thickness (IMT) in both target groups. An influence of the AG genotype of LPA rs10455872 on apoB, LP(a), and IMT levels was revealed in patients with FH and hyperLA(a). The mean age at onset of coronary events was 35 years. The incidence of myocardial infarction was 2,5 times higher in the FH group than in the LP(a) group.

Conclusion. In patients with FH and hyperLA(a), a predominance of the ANRIL CG genotype is associated with high apoB, IMT, and the incidence of coronary events. The AG genotype of LPA rs10455872 is associated with high LP(a) levels, increased IMT, and the risk of early myocardial infarction.

1. . Kukharchuk VV, Ezhov MV, Sergienko IV, et al. Diagnosis and correction of lipid metabolism disorders in order to prevent and treat of atherosclerosis Russian recommendations VII revision. Atherosclerosis and dyslipidemia. 2020;1(38):7-40. (In Russ.) doi:10.34687/2219-8202.JAD.2020.01.0002.

2. Chubykina UV, Ezhov MV, Afanasyeva OI, et al. Prevalence of familial hypercholesterolemia and hyperlipoproteinemia(a) in patients with premature acute coronary syn drome. Russian Journal of Cardiology. 2022;27(6):5041. (In Russ.) doi:10.15829/1560-4071-2022-5041. EDN: YNDJHY.

3. Drapkina OM, Shalnova SA, Imaeva AE, et al. Epidemiology of Cardiovascular Diseases in Regions of Russian Federation. Third survey (ESSE-RF 3). Rationale and study design. Cardiovascular Therapy and Prevention. 2022;21(5):3246. (In Russ.) doi:10.15829/1728-8800-2022-3246. EDN: EZUGUW.

4. Emelyanchik VS, Marilovtseva OV, Khomchenkov RV, et al. Lipoprotein(a) in the diagnosis of cardiovascular risk. The values of lipoprotein (a) and apolipoprotein B in the adult population of Krasnoyarsk. Russian Journal of Cardiology. 2023;28(7):5499. (In Russ.) doi:10.15829/1560-4071-2023-5499. EDN: FJFJYU.

5. Pavlova AV, Asekritova AS, Kylbanova ES, et al. Definite hederitary familial hypercholesterolemia in Yakytia. Vestnik of North-Eastern Federal University. Medical Sciences. 2022;(4):51-8. (In Russ.) doi:10.25587/SVFU.2022.29.4.005.

6. Ivanova ON, Vasiliev PA, Zakharova EYu. Molecular bases of primary monogenic dyslipidemia. Medical Genetics. 2020;19(12):4-17. (In Russ.) doi:10.25557/2073-7998.2020.12.4-17.

7. Shakhtschneider EV, Ivanoshchuk DE, Voevoda MI. Modern methods of molecular genetic diagnosis of familial hypercholesterolemia. Atherosclerosis. 2021;17(3):54. (In Russ.) doi:10.52727/2078-256X-2021-17-3-54-54.

8. Tzveova R, Naydenova, G, Yaneva-Sirakova T, et al. Association study of polymorphic variants in 9p21 locus and the manifestation of coronary artery disease in Bulgarians. Acta Medica Bulgaric. 2025;52(1):29-40. doi:10.2478/AMB-2025-0005.

9. Xu B, Xu Z, Chen Y, et al. Genetic and epigenetic associations of ANRIL with coronary artery disease and risk factors. BMC Med Genomics. 2021;14(1):240. doi:10.1186/s12920-021-01094-8.

10. Ahmed W, Ali IS, Riaz M, et al. Association of ANRIL polymorphism (rs1333049: C>G) with myocardial infarction and its pharmacogenomic role in hypercholesterolemia. Gene. 2013;515(2):416-20. doi:10.1016/j.gene.2012.12.044.

11. Gareev I, Kudriashov V, Sufianov A, et al. The role of long non-coding RNA ANRIL in the development of atherosclerosis. Noncoding RNA Res. 2022;7(4):212-6. doi:10.1016/j.ncrna.2022.09.002.

12. Liu X, Wang TT, Li Y, et al. High density lipoprotein from coronary artery disease patients caused abnormal expression of long non-coding RNAs in vascular endothelial cells. Biochem Biophys Res Commun. 2017;487(3):552-9. doi:10.1016/j.bbrc.2017.04.082.

13. Holdt LM, Teupser D. Long Noncoding RNA ANRIL: Lnc-ing Genetic Variation at the Chromosome 9p21 Locus to Molecular Mechanisms of Atherosclerosis. Front Cardiovasc Med. 2018;5:145. doi:10.3389/fcvm.2018.00145.

14. Hu L, Su G, Wang X. The roles of ANRIL polymorphisms in coronary artery disease: a meta-analysis. Biosci Rep. 2019;39(12):BSR20181559. doi:10.1042/BSR20181559.

15. Semaev S, Shakhtshneider E, Shcherbakova L, et al. Association of Common Variants of APOE, CETP, and the 9p21.3 Chromosomal Region with the Risk of Myocardial Infarction: A Prospective Study. Int J Mol Sci. 2023;24(13):10908. doi:10.3390/ijms241310908.

16. Kaur N, Singh J, Reddy S. ANRIL rs1333049 C/G polymorphism and coronary artery disease in a North Indian population — Gender and age specific associations. Genet Mol Biol. 2020;43(1):e20190024. doi:10.1590/1678-4685-GMB-2019-0024.

17. Dyussenbayev A. Age Periods of Human Life. Advances in Social Sciences Research Journal. 2017;4:258-63. doi:10.14738/assrj.46.2924.

18. Paré G, Çaku A, McQueen M, et al. Lipoprotein(a) Levels and the Risk of Myocardial Infarction Among 7 Ethnic Groups. Circulation. 2019;139(12):1472-82. doi:10.1161/CIRCULATIONAHA.118.034311.

19. Patel AP, Wang M, Pirruccello JP, et al. Lp(a) (Lipoprotein[a]) Concentrations and Incident Atherosclerotic Cardiovascular Disease: New Insights From a Large National Biobank. Arterioscler Thromb Vasc Biol. 2021;41(1):465-74. doi:10.1161/ATVBAHA.120.315291.

20. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41(1):111-88. doi:10.1093/eurheartj/ehz455.

21. Bots ML, Evans GW, Tegeler CH, et al. Carotid Intima-media Thickness Measurements: Relations with Atherosclerosis, Risk of Cardiovascular Disease and Application in Randomized Controlled Trials. Chin Med J (Engl). 2016;129(2):215-26. doi:10.4103/0366-6999.173500.

22. Zhang C, Ni J, Chen Z. Apolipoprotein B Displays Superior Predictive Value Than Other Lipids for Long-Term Prognosis in Coronary Atherosclerosis Patients and Particular Subpopulations: A Retrospective Study. Clin Ther. 2022;44(8):1071-92. doi:10.1016/j.clinthera.2022.06.010.

23. Homma S, Troxclair DA, Zieske AW, et al. Histological changes and risk factor associations in type 2 atherosclerotic lesions (fatty streaks) in young adults. Atherosclerosis. 2011;219(1):184-90. doi:10.1016/j.atherosclerosis.2011.07.022.

24. Behbodikhah J, Ahmed S, Elyasi A, et al. Apolipoprotein B and Cardiovascular Disease: Biomarker and Potential Therapeutic Target. Metabolites. 2021;11(10):690. doi:10.3390/metabo11100690.

25. López-Melgar B, Fernández-Friera L, Oliva B, et al. Subclinical Atherosclerosis Burden by 3D Ultrasound in Mid-Life: The PESA Study. J Am Coll Cardiol. 2017;70(3):301-13. doi:10.1016/j.jacc.2017.05.033.

26. Deniz MF, Guven B, Ebeoglu AO, et al. Screening for Subclinical Atherosclerosis in Patients with Familial Hypercholesterolemia: Insights and Implications. Journal of Clinical Medicine. 2025;14(2):656. doi:10.3390/jcm14020656.

27. Sadykova DI, Galimova LF, Slastnikova ES. Diagnostic Characteristics of Familial Hypercholesterolemia in Children. Pediatric pharmacology. 2020;17(2):124-8. (In Russ.) doi:10.15690/pf.v17i2.2098.

28. Emelyanchik EYu, Korchagin EE, Yanin VN, et al. Regional lipid centre: structure, tasks, prospects. Siberian Medical Review. 2024;(4):94-100. (In Russ.) doi:10.20333/25000136-2024-4-94-100.