Frecuencias genotípicas y alélicas de apolipoproteina e (APOE) en una muestra de adultos en Bogotá

Genotypic and allelic frequencies of apolipoprotein e (APOE) in a sample of adults in bogotá

Introducción: la apolipoproteína E (APOE) es una glicoproteína implicada en el transporte de moléculas lipídicas. Se han descrito tres alelos del gen APOE: Ɛ2, Ɛ3 y Ɛ4. Varios estudios demuestran asociación de la isoforma APOE4 con Alzheimer de inicio tardío. Objetivos: determinar las frecuencias genotípicas y alélicas del gen APOE en una muestra de adultos en Bogotá. Materiales y métodos: estudio observacional descriptivo de corte transversal. A partir de una muestra de sangre periférica se extrajo ADN genómico y se realizó PCR-Tetraprimer para la determinación de los alelos de APOE. Resultados: se incluyeron 1.254 sujetos, 942 mujeres (75%) y 312 hombres (25%) con edades entre 40 y 100 años. El alelo más frecuente fue el Ɛ3 (85%), seguido por Ɛ4 (11%) y Ɛ2 (2%). De la población que manifestó tener ascendencia cundiboyacense, 567 sujetos (74.6%) presentaban el genotipo Ɛ3/Ɛ3, mientras que 156 (20.4%) el Ɛ3/Ɛ4, 23 (3%) el Ɛ2/Ɛ3, 11 (1.5%) el Ɛ4/Ɛ4, y 4 (0.5%) el Ɛ2/Ɛ4. Los individuos con genotipo Ɛ2/Ɛ2 manifestaron no conocer el dato de ascendencia. Conclusiones: las frecuencias alélicas y genotípicas de APOE varían según el origen étnico, sin embargo es posible la identificación de sujetos con el genotipo menos frecuente (Ɛ2/Ɛ2) al analizar muestras de mayor tamaño. En los reportes previos en el país no se ha descrito el genotipo Ɛ2/Ɛ2, el cual fue identificado en la presente muestra como el de menor proporción.

1. MedlinePlus Connect for EHRs. APOE gene, apolipoprotein E [Internet]. MedlinePlus; 2020 [cited 2019 septiembre 14]; Available from: https://medlineplus.gov/genetics/gene/apoe/.
2. Mahley RW, Weisgraber KH, Huang Y. Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer's disease. Proc Natl Acad Sci. 2006;103(15):5644-51. doi: 10.1073/pnas.0600549103
3. Rall SC Jr, Weisgraber KH, Innerarity TL, Mahley RW Structural basis for receptor binding heterogeneity of Apolipoprotein E from type III hyperlipoproteinemic subjects. Proc Natl Acad Sci U S A. 1982;79(15):4696-700. doi: 10.1073/pnas.79.15.4696
4. Wilson C, Wardell MR, Weisgraber KH, Mahley RW, Agard DA. Three-dimensional structure of the LDL receptor-binding doamin of human apolipoprotein E. Science. 1991;252(5014):1817-22. doi: 10.1126/science.2063194
5. Hixson JE, Vernier DT. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res. 1990;31:545-8.
6. Weisgraber KH, Rall SC, Jr., Mahley RW. Human E apoprotein heterogeneity. Cysteine-arginine interchanges in the amino acid sequence of the apo-E isoforms. J BiolChem. 1981;256 (17):9077-83. doi: 10.1016/s0021-9258(19)52510-8
7. Davignon J, Gregg RE, Sing CF. Apolipoprotein E polymorphism and atherosclerosis. Arteriosclerosis. 1988; (1):1-21. doi: 10.1161/01.atv.8.1.1
8. Huebbe P, Rimbach G. Evolution of human apolipoprotein E (APOE) isoforms: Gene structure, protein function and interaction with dietary factors. Ageing Res Rev. 2017;37:146-61. doi: 10.1016/j.arr.2017.06.002
9. Singh PP, Singh M, Mastana SS. APOE distribution in world populations with new data from India and the UK. Ann Hum Biol. 2006;33(3):279-308. doi: 10.1080/03014460600594513
10. Gerdes LU, Gerdes C., Hansen PS, Klausen IC., Faergeman, O., Dyerberg J. The apolipoprotein E polymorphism in Greenland Inuit in its global perspective. Hum Genet. 1996;98(5):546-50. doi: 10.1007/s004390050257
11. Mastana SS, Calderon R, Pena J, Reddy PH, & Papiha SS. Anthropology of the apolipoprotein E (apo E) gene: Low frequency of apo E4 allele in Basques and in tribal (Baiga) populations of India. Ann Hum Biol. 1998;25(2):137-43. doi: 10.1080/03014469800005512
12. Corbo RM, & Scacchi, R. Apolipoprotein E (APOE) allele distribution in the world. Is APOE* 4 a ‘thrifty’allele? Ann Hum Genet. 1999;63(4):301-10. doi: 10.1046/j.1469-1809.1999.6340301.x
13. Singh P, Singh M, Gerdes U, Mastana SS. Apolipoprotein E polymorphism in India: high APOE* E3 allele frequency in Ramgarhia of Punjab. Anthropol Anz. 2001;59(1):27-34.
14. Singh PP, Singh M, Mastana SS. Genetic variation of apolipoproteins in North Indians. Hum Biol. 2002;74(5):673-82. doi: 10.1353/hub.2002.0057
15. Martínez‐Oliván J, Arias‐Moreno X, Velazquez‐Campoy A, Millet O, Sancho J. LDL receptor/lipoprotein recognition: endosomal weakening of ApoB and ApoE binding to the convex face of the LR5 repeat. FEBS J. 2014;281(6):1534-46. doi: 10.1111/febs.12721
16. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW,Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993;261(5123):921-3. doi: 10.1126/science.8346443
17. Fei M, Jianhua W. Apolipoprotein epsilon4-allele as a significant risk factor for conversion from mild cognitive impairment to Alzheimer’s disease: a meta-analysis of prospective studies. J Mol Neurosci. 2013;50:257-63. doi: 10.1007/s12031-012-9934-y
18. Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA. 1993;90(5):1977-81. doi: 10.1073/pnas.90.5.1977
19. Coon KD, Myers AJ, Craig DW, Webster JA ,Pearson JV, Lince DH et al. A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer's disease. J Clin Psychiatry. 2007;68(4):613-8. doi: 10.4088/jcp.v68n0419
20. Sureshkumar R, Bharath S, Jain S, Prakash O, Purushottam M, Thennarasu K, et al. ApoE4 and late onset depression in Indian population. J Affect Disord. 2012;136(3):244-248. doi: 10.1016/j.jad.2011.12.022
21. Lavretsky H, Ercoli L, Siddarth P, Bookheimer S, Miller K, Small G. Apolipoprotein epsilon4 allele status, depressive symptoms, and cognitive decline in middle-aged and elderly persons without dementia. Am J Geriatr Psychiatry. 2003;11(6):667-673. doi: 10.1176/appi.ajgp.11.6.667
22. Soeira-de-Souza MG, Bio DS, Dias VV, Martins do Prado C, Campos RN, Costa LF, et al. Apolipoprotein E genotype and cognition in bipolar disorder. CNS Neurosci Ther. 2010;16(5):316-321. doi: 10.1111/j.1755-5949.2010.00153.x
23. Bellivier F, Laplanche JL, Schurhoff F, Feingold J, Feline A, Jouvent R, et al. Apolipoprotein E gene polymorphism in early and late onset bipolar patients. Neurosci Lett. 1997;223(1):45-48. doi: 10.1016/s0304-3940(97)00624-1
24. Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, Gaskell Jr PC, et al. Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet. 1994;7(2):180-4. doi: 10.1038/ng0694-180
25. Genin E, Hannequin D, Wallon D, Sleegers K, Hiltunen M, Combarros O, et al. APOE and Alzheimer disease: a major gene with semi-dominant inheritance. Mol Psychiatry. 2011;16(9):903-7. doi: 10.1038/mp.2011.52
26. Rojas W, Parra MV, Campo O, Caro MA, Lopera JG, Arias W et al. Genetic make up and structure of Colombian populations by means of uniparental and biparental DNA markers. Am J Phys Anthropol. 2010;143(1):13-20. doi: 10.1002/ajpa.21270
27. Arango Viana JC VA, Páez AL, Montoya Gómez N, Palacio C, Arbeláez MP, Bedoya Berrío G, García Valencia J. Prevalence of Variants in the Apolipoprotein E (APOE) Gene in a General Population of Adults from an Urban Area of Medellin (Antioquia). Rev Colomb Psiquiatr. 2014;43(2):80-6. doi: 10.1016/j.rcp.2013.11.012
28. Jacquier M, Arango D, Villareal E, Torres O, Serrano ML, Cruts M et al. APOE epsilon4 and Alzheimer's disease: positive association in a Colombian clinical series and review of the Latin-American studies. Arq Neuropsiquiatr. 2001;59(1):11-7. doi: 10.1590/s0004-282x2001000100004
29. Forero DA, Pinzón J, Arboleda GH, Yunis JJ, Alvarez C, Cataño et al. Analysis of common polymorphisms in angiotensin-converting enzyme and apolipoprotein E genes and human longevity in Colombia. Arch Med Res. 2006;37(7):890-4. doi: 10.1016/j.arcmed.2006.04.001
30. Velez-Pardo C, Rojas W, Jimenez-Del-Rio M, Bedoya G. (2014). Distribution of APOE polymorphism in the “Paisa” population from northwest Colombia (Antioquia). Ann Hum Biol 2014;42(2):195-8. doi: 10.3109/03014460.2014.932846
31. Landázuri P, Loango, N., Gallego, M. L., & Restrepo, B. Diferencias de sexo, edad y lípidos plasmáticos asociadas al polimorfismo de la apolipoproteína E en un grupo de escolares de Quindío, Colombia. Biomédica. 2009;29(3):382-91. doi: 10.7705/biomedica.v29i3.10
32. Ruiz M, Arias, I., Rolon, G., Hernández, E., Garavito, P., & Silvera-Redondo, C. A. Análisis del polimorfismo del gen APOE en la población de Barranquilla, Colombia. Biomédica. 2015;36(1):52-58. doi: 10.7705/biomedica.v36i1.2612
33. Jaramillo-Correa JP, Keyeux, G., Ruiz-Garcia, M., Rodas, C., & Bernal, J. Population genetic analysis of the genes APOE, APOB (3′ VNTR) and ACE in some black and Amerindian communities from Colombia. Human Hered. 2001;52(1):14-33. doi: 10.1159/000053351
34. Pedraza OL, Salazar AM, Sierra FA, Montalvo C, Muñoz Y, Díaz JM, et al. Mild cognitive impairment (MCI) and dementia in a sample of adults in the city of Bogotá. Dement Neuropsychol 2017;11(3):262-26. doi: 10.1590/1980-57642016dn11-030008
35. Yang YG KJ, Park SJ, Kim SW, Jeon O, Kim D. Apolipoprotein E genotyping by multiplex tetra-primer amplification refractory mutation system PCR in single reaction tube. J Biotechnol. 2007;131(2):106-10. doi: 10.1016/j.jbiotec.2007.06.001
36. Bertram L, & Tanzi, R. E. Genome-wide association studies in Alzheimer's disease. Human molecular genetics. 2009;18(R2): R137-45. doi: 10.1093/hmg/ddp406
37. Caselli RJ, Dueck, A. C., Osborne, D., Sabbagh, M. N., Connor, D. J., Ahern, G. L., Baxter, L. C., Rapcsak, S. Z., Shi, J., Woodruff, B. K., Locke, D. E. C., Snyder, C. H., Alexander, G. E., Rademakers, R., Reiman, E. M. Longitudinal modeling of age-related memory decline and the APOE epsilon-4 effect. New Eng J Med. 2009;361(3):255-63. doi: 10.1056/NEJMoa0809437
38. Baxter LC CR, Johnson SC, Reiman E, Osborne D. Apolipoprotein E epsilon 4 affects new learning in cognitively normal individuals at risk for Alzheimer’s disease. Neurobiol Aging. 2003;24(7):947-52. doi: 10.1016/s0197-4580(03)00006-x
39. Caselli RJ RE, Osborne D, et al. Longitudinal changes in cognition and behavior in asymptomatic carriers of the APOE e4 allele. Neurology. 2004;62(11): 1990-5. doi: 10.1212/01.wnl.0000129533.26544.bf
40. Caselli RJ RE, Locke DE, et al. Cognitive domain decline in healthy apolipoprotein E epsilon4 homozygotes before the diagnosis of mild cognitive impairment. Arch Neurol. 2007;64(9):1306-1311.
41. Reiman EM, Caselli, R. J., Chen, K., Alexander, G. E., Bandy, D., Frost, J. Declining brain activity in cognitively normal apolipoprotein E epsilon-4 heterozygotes: a foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer's disease. Proc Nat Acad Sci USA. 2001;98(6):3334-9. doi: 10.1073/pnas.061509598
42. Reiman EM, Caselli, R. J., Yun, L. S., Chen, K., Bandy, D., Minoshima, S., Thibodeau, S. N., Osborne, D. Preclinical evidence of Alzheimer's disease in persons homozygous for the epsilon-4 allele for apolipoprotein E. New Eng J Med. 1996;334(12):752-8. doi: 10.1056/NEJM199603213341202
43. Reiman EM, Chen, K., Alexander, G. E., Caselli, R. J., Bandy, D., Osborne, D., Saunders, A. M., Hardy, J. Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia. Proc Nat Acad Sci. 2004;101(1):284-9. doi: 10.1073/pnas.2635903100
44. Marca V AO, Cornejo-Olivas M, Ortega O, Huerta D, Mazzetti P. Genetic polymorphism of apolipoprotein E in a Peruvian population. Rev Peru Med Exp Salud Publica. 2011;28(4):589-94.
45. Molero AE P-RrG, Maestre GE. Modulation by age and gender of risk for Alzheimer's disease and vascular dementia associated with the apolipoprotein E-ε4 allele in Latin Americans: findings from the Maracaibo Aging Study. Neuroscience letters. 2001;307(1):5-8. doi: 10.1016/S0304-3940(01)01911-5
46. Arráiz N, Bermudez V, Prieto C, Sánchez MP, Escalona C, Sanz E, Rondón N, Reyes F, Velasco M. Association between apoliprotein E gene polymorphism and hypercholesterolemic phenotype in Maracaibo, Zulia state, Venezuela. Am J Ther. 2010;17(3):330-6. doi: 10.1097/MJT.0b013e3181c1235d.
47. Paz-y-Miño C CC, López-Cortés A, Munoz MJ, Cumbal N, Castro B, Cabrera A, Sánchez ME. Genetic polymorphisms in apolipoprotein E and glutathione peroxidase 1 genes in the Ecuadorian population affected with Alzheimer's disease. Am J Med Sci. 2010;340(5):373-7. doi: 10.1097/MAJ.0b013e3181e93475
48. Souza DR, De Godoy MR, Hotta J, Tajara EH, Brandao AC, Pinheiro Júnior S, Tognola WA, Dos Santos JE. Association of apolipoprotein E polymorphism in late-onset Alzheimer's disease and vascular dementia in Brazilians. Braz J Med Biol Res. 2003;36(7):919-23. doi: 10.1590/s0100-879x2003000700013
49. De França E, Alves JG, Hutz MH. Apolipoprotein E polymorphism and its association with serum lipid levels in Brazilian children. Human Biol. 2004;76(2):267-75.
50. Fuzikawa AK PS, Taufer M, Moriguchi EH, Lima-Costa MF. Apolipoprotein E polymorphism distribution in an elderly Brazilian population: the Bambuí Health and Aging Study. Braz J Med Biol Res. 2007;40(11):1429-34. doi: 10.1590/s0100-879x2007001100002.
51. Brito DD, Fernandes AP, Gomes KB, Coelho FF, Cruz NG, Sabino AP, Cardoso JE, Figueiredo-Filho PP, Diamante R, Norton CR, Sousa MO. Apolipoprotein A5-1131T> C polymorphism, but not APOE genotypes, increases susceptibility for dyslipidemia in children and adolescents. Molecular Biology Reports. 2011;38(7):4381-8. doi: 10.1007/s11033-010-0565-5
52. Gayà‐Vidal M AG, Carreras‐Torres R, Via M, Esteban E, Villena M, Vasquez R, Dugoujon JM, Moral P. Apolipoprotein E/C1/C4/C2 gene cluster diversity in two native Andean populations: Aymaras and Quechuas. Annals Hum Genet. 2012;76(4):283-95. doi: 10.1111/j.1469-1809.2012.00712.x
53. Quiroga P, Calvo C, Albala C, Urquidi J, Santos JE, Perez H, Klaassen G. Apolipoprotein E polymorphism in elderly Chilean people with Alzheimer’s disease. Neuroepidemiology. 1998;18(1):48-52. doi: 10.1159/000026195
54. Rollan A, Loyola G, Covarrubias C, Giancaspero R, Acevedo K, Nervi F. Apolipoprotein E polymorphism in patients with acute pancreatitis. Pancreas. 1994;9(3):349-53. doi: 10.1097/00006676-199405000-00011
55. Leiva E, Mujica V, Orrego R, Prieto M, Arredondo M. Apolipoprotein E polymorphism in type 2 diabetic patients of Talca, Chile. Diabetes research and clinical practice. 2005;68(3):244-9. doi: 10.1016/j.diabres.2004.09.017
56. Pedraza OL Camacho I, Sierra FA, Rubio-Gómez C, Salazar AM, Montalvo C, Morillo D, Lozano A, Gutiérrez-Castañeda LD, Torres-Tobar L, Piñeros C. Association between ε4 allele, cardio-metabolic and social risk factors in the development of cognitive impairment in elderly adults from Bogota. Sometido a publicación.