Generate QR code
Open Access
Subscription Access
Polymorphism of the APOΕ gene, rs7412 C>T (Arg158Cys) and rs429358 T>C (Cys112Arg), in indigenous populations of Eastern and Southern Siberia
https://doi.org/10.25557/2073-7998.2025.03.50-68
Abstract
Apolipoprotein E is involved in lipid metabolism and many other important processes in the body. Polymorphism in the APOΕ gene has a huge impact on the risk of developing and severity of such serious diseases as Alzheimer’s disease, type III hyperproteinemia, cardiovascular, oncological and many others. Therefore, the importance of studying this polymorphism in human populations is undoubted. This paper presents the frequency of occurrence of APOΕ genotypes and its polymorphic variants ε2, ε3, ε4 in 8 populations of indigenous peoples living in Eastern and Southern Siberia (Yakuts, Buryats, Teleuts, Dolgans, Nganasans, Russians). Inter-population comparisons have been made between the populations studied by us and some of the world’s populations.
Keywords
apolipoprotein E,
cholesterol,
LDL,
rs7412 C > T and rs429358 T > C,
ε2,
ε3,
ε4,
neurodegenerative diseases,
atherosclerosis,
hyperproteinemia III,
indigenous peoples of Siberia
Supporting agencies: The study was carried out within the framework of the state assignment for the Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences (No. FWNR-2022-0021).
About the Authors
R. P. Tiis
Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences
Russian Federation
Russian Federation
10, Prospekt Lavrentyeva, Novosibirsk, 630090
L. E. Tabikhanova
Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences
Russian Federation
Russian Federation
10, Prospekt Lavrentyeva, Novosibirsk, 630090
D. V. Lichman
Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences
Russian Federation
Russian Federation
10, Prospekt Lavrentyeva, Novosibirsk, 630090
E. N. Voronina
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences
Russian Federation
Russian Federation
8, Prospekt Lavrentyeva, Novosibirsk, 630090
L. P. Osipova
Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences
Russian Federation
Russian Federation
10, Prospekt Lavrentyeva, Novosibirsk, 630090
M. L. Filipenko
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences
Russian Federation
Russian Federation
8, Prospekt Lavrentyeva, Novosibirsk, 630090
References
1. Mahley R.W. Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders. J. Mol. Med. 2016;94:739-746. doi: 10.1007/s00109-016-1427-y.
2. Rall S.C. Jr., Weisgraber K.H., Mahley R.W. Human apolipoprotein E: the complete amino acid sequence. J. Biol. Chem. 1982; 257:4171-4178.
3. Mahley R.W., Rall S.C. Apolipoprotein E: far more than a lipid transport protein. Annu. Rev. Genomics Hum. Genet. 2000;(1):507–537.
4. Kockx M., Traini M., Kritharides L. Cell-specific production, secretion, and function of apolipoprotein E. Journal of Molecular Medicine. 2018; https://doi.org/10.1007/s00109-018-1632-y
5. Blum C.B.. Type III hyperlipoproteinemia: still worth considering? Prog. Cardiovasc. Dis. 2016;59: 119-124.
6. Rebeck G.W., Reiter J.S., Strickland D.K., Hyman B.T. Apolipoprotein E in sporadic Alzheimer’s disease: allelic variation and receptor interactions. Neuron. 1993;11(4): 575-580.
7. Han X., Cheng H., Fryer J., et al. Novel role for apolipoprotein E in the central nervous system. Modulation of sulfatide content. J. Biol. Chem. 2003;278:8043–8051.
8. Potapov A.A., Yusupova M.M., Tenedieva V.D. et al. Klinicheskoye i prognosticheskoye znacheniye geneticheskikh markorov gena APOE pri cherepno-mozgovoy travme [Clinical and prognostic significance of genetic markers of APOE gene in traumatic brain injury]. Voprosy neyrokhirurgii im. N. N. Burdenko [Burdenko’s Journal of Neurosurgery]. 2010; 3:54-62. (In Russ.)
9. Harmony J.A.K., Akeson A.L., McCarthy B.M.., et al. Immunoregulation by plasma lipoproteins. In Biochemistry and Biology of Plasma Lipoproteins, ed. AM Scanu, AA Spector, New York: Marcel Dekker. 1986;403–452.
10. Trommsdorff M., Borg J.P., Margolis B., Herz J. Interaction of cytosolic adaptor proteins with neuronal apolipoprotein E receptors and the amyloid precursor protein. J. Biol. Chem. 1998;273:33556–60.
11. Shakibaei M., Frevert U.. Dual interaction of the malaria circumsporozoite protein with the low density lipoprotein receptor-related protein (LRP) and heparan sulfate proteoglycans. J. Exp. Med. 1996;184:1699–711.
12. Roselaar S., Daugherty A. Apolipoprotein E-deficient mice have impaired innate immune responses to Listeria monocytogenes in vivo. J. Lipid Res. 1998;39:1740–43
13. de Bont N., Netea M.G., Demacker P.N.M., et al. Apolipoprotein E knock-out mice are highly susceptible to endotoxemia and Klebsiella pneumoniae infection. J. Lipid Res. 1999;40:680–85.
14. Price D.A., Bassendine M.F., Norris S.M., et al. Apolipoprotein epsilon-3 allele is associated with persistent hepatitis C virus infection. Gut. 2006;55:715-718.
15. Theendakara V., Peters-Libeu C.A., Spilman P., et al. Direct transcriptional effects of apolipoprotein E. J. Neurosci. 2016;36:685–700.
16. Phillips M.C. Apolipoprotein E Isoforms and Lipoprotein Metabolism. International Union of Biochemistry and Molecular Biology. 2014;66(9):616–623.
17. Zhong L., Xie Y.Z., Cao T.T., et al. A rapid and cost-effective method for genotyping apolipoprotein E gene polymorphism. Molecular Neurodegeneration. 2016;1(2) doi: 10.1186/s13024-016-0069-4.
18. Rosenberg R.N. The molecular and genetic basis of AD: the end of the beginning. The 2000 Wartenberg lecture. Neurology. 2000;54(11):2045–2054.
19. Mahley R.W., Weisgraber K.H., Huang Y. Apolipoprotein E: Structure determines function, from atherosclerosis to Alzheimer’s disease to AIDS. J. Lipid Res. 2009;50:183-188. doi: 10.1194/jlr. R800069-JLR200.
20. Arbones – Mainar J.M., Johnson L.A., Altenburg M.K., Maeda N. Differential modulation of diet-induced obesity and adipocyte functionality by human apolipoprotein E3 and E4 in mice. Int. J. Obes. (Lond). 2008;32(10):1595–1605. doi: 10.1038/ijo.2008.143.
21. Mahley R.W., Weisgraber K.H., Huang Y. Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer’s disease. Proc. Natl. Acad. Sci. U S A. 2006;103:5644-5651.
22. Finch C.E., Morgan T.E. Systemic inflammation, infection, ApoE alleles, and Alzheimer disease: a position paper. Curr. Alzheimer Res. 2007;4:185-189.
23. Finch .CE. Evolution in health and medicine Sackler colloquium: Evolution of the human lifespan and diseases of aging: roles of infection, inflammation, and nutrition. Proc. Natl. Acad. Sci. U S A. 2010;107(1):1718–1724. doi:10.1073/pnas.0909606106.
24. Zueva I.B., Ulitina A.S., Ghorab D.N., et al. Polimorfizm gena ApoE u patsiyentov s metabolicheskim sindromom i kognitivnymi rasstroystvami [Apo E gene polymorphism in patients with metabolic syndrome and cognitive disorders]. Arterial’naya Gipertenziya [Arterial Hypertension]. 2012;18(5):421-428. (In Russ.)
25. Corder E., Saunders A., Strittmatter W., et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993;261(5123):921–923.
26. Lucotte G., Turpin J.C., Landais P. Apolipoprotein E-epsilon-4 allele doses in late-onset Alzheimer’s disease. Ann. Neurol. 1994;36:681-682, 1994.
27. Goldstein F.C., Ashley A.V., Gearing M., et al. Apolipoprotein E and age at onset of Alzheimer’s disease in African American patients. Neurology. 2001;57:1923-1925.
28. Lannfelt L., Pedersen N.L., Lilius L., et al. Apolipoprotein epsilon-4 allele in Swedish twins and siblings with Alzheimer disease. Alzheimer Dis. Assoc. Disord. 1995;9:166-169.
29. Vinogradova S.V. Rol’ polimorfizma ye2/ye3/ye4 gena apolipoproteina Ye v razvitii ateroskleroza [The role of apolipoprotein E gene polymorphism Е2/EЗ/Е4 in atherosclerosis progression]. Meditsinskaya genetika [Medical genetics]. 2006;5(2):3–10. (In Russ.)
30. Schachter F., Faure-Delanef L., Guenot F., et al. Genetic associations with human longevity at the APOE and ACE loci. Nature Genet. 1994;6:29-32.
31. Knouff C., Hinsdale M.E., Mezdour H., et al. Apo E structure determines VLDL clearance and atherosclerosis risk in mice. J. Clin. Invest. 1999;103(11):1579–1586. doi:10.1172/JCI6172.
32. Garces C., Benavente M., Ortega H., et al. Influence of birth weight on the Apo E genetic determinants of plasma lipid levels in children. Pediatric research. 2002;52(6):873-878. doi: 10.1203/01.PDR.0000037140.57784.8B.
33. Song Y., Stampfer M.J., Liu S. Meta-analysis: apolipoprotein E genotypes and risk for coronary heart disease. Ann. Intern. Med. 2004;141:137–147.
34. Davignon J., Gregg R.E., Sing S.F. Apolipoprotein E polymorphism and atherosclerosis. Arteriosclerosis. 1988;8(1):1–21.
35. Chen D.W., Shi J.K., Li Y., et al. Association between ApoE polymorphism and type 2 diabetes: A meta-analysis of 59 studies. Biomed. Environ. Sci. 2019;32(11):823–838. doi: 10.3967/bes2019.104.
36. Voevoda M.I., Stepanov V.A., Romashchenko A.G., Maksimov V.N. Etnogeneticheskiye osobennosti podverzhennosti aterosklerozu v etnicheskikh gruppakh Sibiri (na primere gena apolipoproteina Ye) [Apolipoprotein E polymorphism in Siberia populations and its association with pathology]. Byulleten’ SO RAMN [Bulletin of the Siberian Branch of the Russian Academy of Medical Sciences]. 2006;26(2):63-72. (In Russ.)
37. Friedman G., Froom P., Sazbon L., Grinblatt I., et al. Apolipoprotein E-epsilon-4 genotype predicts a poor outcome in survivors of traumatic brain injury. Neurology. 1999;52:244-248.
38. Liberman J.N., Stewart W.F., Wesnes K., Troncoso J. Apolipoprotein E epsilon-4 and short-term recovery from predominantly mild brain injury. Neurology. 2002;58:1038-1044.
39. Crawford F., Vanderploeg R., Freeman M., et al. APOE genotype influences acquisition and recall following traumatic brain injury. Neurology. 2002;58:1115–1118.
40. Koponen S., Taiminen T., Kairisto V., et al. APOE-epsilon-4 predicts dementia but not other psychiatric disorders after traumatic brain injury. Neurology. 2004;63:749–750.
41. Deary I.J., Whiteman M.C., Pattie A., et al. Cognitive change and the APOE epsilon-4 allele. Nature. 2002;418(932). doi: https://doi.org/10.1038/418932a.
42. Caselli R.J., Dueck A.C., Osborne D., et al. Longitudinal modeling of age-related memory decline and the APOE epsilon-4 effect. New Eng. J. Med. 2009;361:255-263.
43. Caselli R.J., Reiman E.M., Osborne D., et al. Longitudinal changes in cognition and behavior in asymptomatic carriers of the APOE e4 allele. Neurology. 2004;62:1990-1995.
44. Blesa R., Adroer R., Santacruz P., Ascaso C., et al. High apolipoprotein E epsilon-4 allele frequency in age-related memory decline. Ann. Neurol. 1996;39:548-551.
45. Liao F., Yoon H., Kim J. Apolipoprotein E metabolism and functions in brain and its role in Alzheimer’s disease. Curr. Opin. Lipidol. 2017; 28: 60–67. doi: 10.1097/MOL.0000000000000383.
46. Lanterna L.A., Ruigrok Y., Alexander S., et al. Meta-analysis of APOE genotype and subarachnoid hemorrhage: clinical outcome and delayed ischemia. Neurology. 2007;69:766-775.
47. Li Y.J., Hauser M.A., Scott W.K., et al. Apolipoprotein E controls the risk and age at onset of Parkinson disease. Neurology. 2004;62:2005-2009.
48. Harrington C.R., Roth M., Xuereb J.H., et al. Apolipoprotein E type epsilon-4 allele frequency is increased in patients with schizophrenia. Neurosci. Lett. 1995;202:101-104.
49. Amouyel P., Vidal O., Launay J.M., Laplanche J.L. The apolipoprotein E alleles as major susceptibility factors for Creutzfeldt-Jakob disease. Lancet. 1994;344:1315-1318.
50. de Stefano N., Bartolozzi M.L., Nacmias B., et al. Influence of apolipoprotein E epsilon-4 genotype on brain tissue integrity in relapsing-remitting multiple sclerosis. Arch. Neurol. 2004; 61: 536-540.
51. Chapman J., Korczyn A., Karussis D., et al. The effects of APOE genotype on age at onset and progression of neurodegenerative diseases. Neurology. 2001;57:1482–1485.
52. Kadotani H., Kadotani T., Young T., et al. Association between apolipoprotein E epsilon-4 and sleep-disordered breathing in adults. JAMA. 2001;285:2888-2890.
53. Gozal D., Capdevila O.S., Kheirandish-Gozal L., Crabtree V.M. APOE epsilon-4 allele, cognitive dysfunction, and obstructive sleep apnea in children. Neurology. 2007;69:243-249.
54. Wang J.C., Kwon J.M., Shah P., et al. Effect of APOE genotype and promoter polymorphism on risk of Alzheimer’s disease. Neurology. 2000;55:1644-1649.
55. Grigorieva I.N., Nikitenko T.M., Romanova T.I., et al. Polimorfizm gena apolipoproteina Ye, zhelchnokamennaya bolezn’ i pankreatit [Apolipoprotein E polymorphism, gallstone disease and pancreatitis]. Byulleten’ SO RAMN [Bulletin of the Siberian Branch of the Russian Academy of Medical Sciences]. 2006;26(4):80-86. (In Russ.)
56. Grigor’eva I.N., Notova T.E. Polimorfizm gena apolipoproteina Ye, zhelchnokamennaya bolezn’, sakharnyy diabet 2 tipa i narusheniya lipidnogo obmena [Apolypoprotein E gene polymorphism, gallstone disease, diabetes 2 type and lipid metabolism disorders]. Ateroscleroz [Atherosclerosis]. 2023;19(1):47-56. (In Russ.)
57. Burt T.D., Agan B.K., Marconi V.C., et al. Apolipoprotein (apo) E4 enhances HIV-1 cell entry in vitro, and the APOE epsilon-4/ epsilon-4 genotype accelerates HIV disease progression. Proc. Nat. Acad. Sci. 2008;105:8718-8723.
58. Breslow J.L., Zannis V.I., SanGiacomo T.R., et al. Studies of familial type III hyperlipoproteinemia using as a genetic marker the apoE phenotype E2/2. J. Lipid. Res. 1982;23:1224–1235.
59. Ivanova T.I., Krikunova L.I., Ryabchenko N.I. et al. Sposob opredeleniya riska razvitiya raka tela matki. Patent na izobreteniye nomer RU 2558059 C1 [Method for determining the risk of developing uterine cancer. Patent for invention number RU 2558059 C1]. 2015. (In Russ.)
60. Singh P.P., Singh M., Mastana S.S. APOE distribution in world populations with new data from India and the UK. Ann. Hum. Biol. 2006;33:279–308.
61. Borinskaya S.A., Kal’ina N.R., Sanina E.D. et al. Polymorphism of the apolipoprotein E gene (APOE) in the populations of Russia and neighboring countries. Russ J Genet.2007; 43: 1201–1207.
62. Borovkova N.P., Sheremetyeva V.A., Evsyukov A.N., Spitsyn V.A. Zakonomernosti raspredeleniya alleley apolipoproteina Ye (AROYe) sredi mirovogo narodonaseleniya [Frequency distribution of apolipoprotein E (APOE) alleles in world population]. Vestnik Moskovskogo Universiteta. Seria XXIII. Antropologia [Moscow University Anthropology Bulletin]. 2010;2:21–35. (In Russ.)
63. Mustafina O.E., Mikhailova A.M., Nasibulin T.R., et al. Polymorphism of the apolipoprotein E gene and risk of multiple sclerosis in ethnic Russians. Molecular Biology. 2008; 42(6): 852-858.
64. Gerdes L.U., Klausen I.C., Sihm I., Faergeman O. Apolipoprotein E polymorphism in a Danish population compared to findings in 45 other study populations around the world. Genet. Epidemiol. 1992;9:155–167.
65. Corbo R.M., Scacchi R., Mureddu L., et al. Apolipoprotein E polymorphism in Italy investigated in native plasma by a simple polyacrylamide gel isoelectric focusing technique. Comparison with frequency data of other European populations. Ann. Hum. Genet. 1995;59:197–209.
66. Kowalska A., Wiechmann I., Walter H. Genetic variability of apolipoprotein E in a Polish population. Hum. Biol. 1998;70:1093–1099.
67. Corbo R.M., Scacchi R. Apolipoprotein E (APOE) allele distribution in the world. Is APOE*4 a «thrifty» allele? Ann. Hum. Genet. 1999;63:301–310.
68. Hong S.H., Kang B.Y., Oh J.H., et al. Genetic variation of the APOE-C1-C2 cluster gene in Koreans. Clin. Biochem. 1997;30:215–219.
69. Kamboh M.I. Apolipoprotein E polymorphism and susceptibility to Alzheimer’s disease. Hum. Biol. 1995;67:195–215.
70. Korchagina R.P., Osipova L.P., Vavilova N.A. et al. Polimorfizm genov biotransformatsii ksenobiotikov GSTM1, GSTT1, CYP2D6, veroyatnykh markerov riska onkologicheskikh zabolevaniy, v populyatsiyakh korennykh etnosov i russkikh Severnoy Sibiri [Polymorphism of genes for xenobiotic biotransformation, GSTM1, GSTT1, CYP2D6, candidate markers of cancer risk, in indigenous peoples and Russians in Nothern Siberia]. Vavilovskiy zhurnal genetiki i selektsii [Vavilov Journal of Genetics and Breeding]. 2011;3:448-461. (In Russ.)
71. Tiis R.P., Osipova L.P., Tabikhanova L.E. et al. Geneticheskiy polimorfizm faktorov sistemy svortyvaniya krovi FII i FV v populyatsiyakh korennykh etnosov (tundrovykh i lesnykh nentsev, nganasan), russkikh Severnoy Sibiri i ikh metisov v svyazi s riskom razvitiya trombozov [Genetic polymorphism of coagulation system factors FII and FV in populations of native peoples (Tundra Nenets, Forest Nenets, Nganasans), Russians of the North Siberia and their metis in relation to thrombosis risk]. Meditsinskaya genetika [Medical genetics]. 2015;7:27-31. (In Russ.)
72. Gerdes L.U., Gerdes C., Hansen P.S., et al. The apolipoprotein E polymorphism in Greenland Inuit in its global perspective. Hum. Genet. 1996;98:546–550.
73. Gerdes L.U., Jeune B., Ranberg K.A., et al. Estimation of apolipoprotein E genotype-specific relative mortality risks from the distribution of genotypes in centenarians and middle-aged men: Apolipoprotein E gene is a «frailty gene», not a «longevity gene». Genet. Epidemiol. 2000;19:202–210.
Review
For citations:
Tiis R.P., Tabikhanova L.E., Lichman D.V., Voronina E.N., Osipova L.P., Filipenko M.L. Polymorphism of the APOΕ gene, rs7412 C>T (Arg158Cys) and rs429358 T>C (Cys112Arg), in indigenous populations of Eastern and Southern Siberia. Medical Genetics. 2025;24(3):50-68. (In Russ.) https://doi.org/10.25557/2073-7998.2025.03.50-68
Views:
165
Email this article 