Abstract
Large-scale genome-wide studies have revealed the role of several genes and their respective single-nucleotide polymorphisms (SNPs) in the pathophysiology of late-onset Alzheimer’s disease (LOAD). Here, the frequencies of ABCA7 SNPs rs3764650 and rs4147929 and EphA1 SNP rs11771145 were assessed and compared in LOAD patients and healthy subjects. In a case-control study, 110 patients with LOAD (case) and 88 healthy unrelated age- and gender-matched individuals (control), both from Azeri descent, were enrolled. DNA was extracted from blood samples using the salting out method, and the genotyping was performed by RFLP-PCR for rs3764650, rs4147929, and rs11771145 polymorphisms. Electrophoresis was carried out on agarose gel. Sequencing was utilized for confirmation of the results. No differences were found in the frequencies of ABCA7 SNP rs3764650 and EphA1 SNP rs11771145 between healthy subjects and LOAD patients. However, a significant difference was revealed in the frequencies of AA (p = 0.042, OR = 0.150; 95%CI = 0.005–1.410) and GG (p = 0.009, OR = 1.716; 95%CI = 0.918–3.218) genotypes of ABCA7 SNP rs4147929 between the mentioned groups. This study showed that ABCA7 SNP rs4147929 might be a predisposing factor for LOAD. However, such an association was not found between ABCA7 SNP rs3764650 as well as EphA1 SNP rs11771145 and LOAD. These results must be confirmed in other ethnic groups.
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10 December 2019
The original version of this article unfortunately contained a mistake in the Authorgroup section. Author Azra Delpak’s given name was misspelled as “Azar”.
References
Ager A, Sherwani S, Tinsley C, Williams J (2016) Mapping changes to vascular health in Alzheimer’s disease: the role of EPHA1 risk alleles. Alzheimers Dement 12(7):P251. https://doi.org/10.1016/j.jalz.2016.06.450
Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82(4):239–259. https://doi.org/10.1007/bf00308809
Carrasquillo MM, Crook JE, Pedraza O, Thomas CS, Pankratz VS, Allen M, Nguyen T, Malphrus KG, Ma L, Bisceglio GD, Roberts RO, Lucas JA, Smith GE, Ivnik RJ, Machulda MM, Graff-Radford NR, Petersen RC, Younkin SG, Ertekin-Taner N (2015) Late-onset Alzheimer’s risk variants in memory decline, incident mild cognitive impairment, and Alzheimer’s disease. Neurobiol Aging 36(1):60–67. https://doi.org/10.1016/j.neurobiolaging.2014.07.042
Chan SL, Kim WS, Kwok JB, Hill AF, Cappai R, Rye KA, Garner B (2008) ATP-binding cassette transporter A7 regulates processing of amyloid precursor protein in vitro. J Neurochem 106(2):793–804. https://doi.org/10.1111/j.1471-4159.2008.05433.x
Cuyvers E, De Roeck A, Van den Bossche T, Van Cauwenberghe C, Bettens K, Vermeulen S, Mattheijssens M, Peeters K, Engelborghs S, Vandenbulcke M, Vandenberghe R, De Deyn PP, Van Broeckhoven C, Sleegers K (2015) Mutations in ABCA7 in a Belgian cohort of Alzheimer’s disease patients: a targeted resequencing study. Lancet Neurol 14(8):814–822. https://doi.org/10.1016/S1474-4422(15)00133-7
Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, Delacourte A, Galasko D, Gauthier S, Jicha G, Meguro K, O’Brien J, Pasquier F, Robert P, Rossor M, Salloway S, Stern Y, Visser PJ, Scheltens P (2007) Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol 6(8):734–746. https://doi.org/10.1016/s1474-4422(07)70178-3
Gatz M, Reynolds CA, Fratiglioni L, Johansson B, Mortimer JA, Berg S, Fiske A, Pedersen NL (2006) Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry 63(2):168–174. https://doi.org/10.1001/archpsyc.63.2.168
Gerrish A, Russo G, Richards A, Moskvina V, Ivanov D, Harold D, Sims R, Abraham R, Hollingworth P, Chapman J, Hamshere M, Pahwa JS, Dowzell K, Williams A, Jones N, Thomas C, Stretton A, Morgan AR, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Morgan K, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Johnston JA, Holmes C, Mann D, Smith AD, Love S, Kehoe PG, Hardy J, Mead S, Fox N, Rossor M, Collinge J, Maier W, Jessen F, Kolsch H, Heun R, Schurmann B, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frolich L, Hampel H, Hull M, Rujescu D, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Davies G, Harris SE, Starr JM, Deary IJ, Al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Muhleisen TW, Nothen MM, Moebus S, Jockel KH, Klopp N, Wichmann HE, Carrasquillo MM, Pankratz VS, Younkin SG, Jones L, Holmans PA, O’Donovan MC, Owen MJ, Williams J (2012) The role of variation at AbetaPP, PSEN1, PSEN2, and MAPT in late onset Alzheimer’s disease. J Alzheimers Dis 28(2):377–387. https://doi.org/10.3233/jad-2011-110824
Ghatak S, Muthukumaran RB, Nachimuthu SK (2013) A simple method of genomic DNA extraction from human samples for PCR-RFLP analysis. J Biomol Tech 24(4):224–231. https://doi.org/10.7171/jbt.13-2404-001
Gulkovskyi RV, Livshits L, Sivolob A (2015) Association of the EPHA1 gene polymorphism with idiopathic mild intellectual disability. Biopolymers Cell 31(4):272–278. https://doi.org/10.7124/bc.0008EB
Hollingworth P, Harold D, Sims R, Gerrish A, Lambert J-C, Carrasquillo MM, Abraham R, Hamshere ML, Pahwa JS, Moskvina V (2011) Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat Gen 43(5):429–435
Karch CM, Goate AM (2015) Alzheimer’s disease risk genes and mechanisms of disease pathogenesis. Biol Psychiatry 77(1):43–51. https://doi.org/10.1016/j.biopsych.2014.05.006
Karch CM, Jeng AT, Nowotny P, Cady J, Cruchaga C, Goate AM (2012) Expression of novel Alzheimer’s disease risk genes in control and Alzheimer’s disease brains. PloS one 7(11):e50976. https://doi.org/10.1371/journal.pone.0050976
Kim WS, Fitzgerald ML, Kang K, K-i O, Bell SA, Manning JJ, Koehn SL, Lu N, Moore KJ, Freeman MW (2005) Abca7 null mice retain normal macrophage phosphatidylcholine and cholesterol efflux activity despite alterations in adipose mass and serum cholesterol levels. J Biol Chem 280(5):3989–3995. https://doi.org/10.1074/jbc.M412602200
Kim WS, Li H, Ruberu K, Chan S, Elliott DA, Low JK, Cheng D, Karl T, Garner B (2013) Deletion of Abca7 increases cerebral amyloid-β accumulation in the J20 mouse model of Alzheimer’s disease. J Neurosci 33(10):4387–4394. https://doi.org/10.1523/JNEUROSCI.4165-12.2013
Kjeldsen EW, Tybjærg-Hansen A, Nordestgaard BG, Frikke-Schmidt R (2017) ABCA7 and risk of dementia and vascular disease in the Danish population. Ann Clin Transl Neurol 5(1):41–51. https://doi.org/10.1002/acn3.506
Lambert J-C, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, Combarros O, Zelenika D, Bullido MJ, Tavernier B (2009) Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat Genet 41(10):1094–1099. https://doi.org/10.1038/ng.439
Lambert J-C, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, Jun G, DeStefano AL, Bis JC, Beecham GW (2013) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet 45(12):1452–1458. https://doi.org/10.1038/ng.2802
Li X, Long J, He T, Belshaw R, Scott J (2015) Integrated genomic approaches identify major pathways and upstream regulators in late onset Alzheimer’s disease. Sci Rep 5:12393–12393. https://doi.org/10.1038/srep12393
Lin E, Tsai S-J, Kuo P-H, Liu Y-L, Yang AC, Kao C-F (2017) Association and interaction effects of Alzheimer’s disease-associated genes and lifestyle on cognitive aging in older adults in a Taiwanese population. Oncotarget 8(15):24077–24087. https://doi.org/10.18632/oncotarget.15269
Liu G, Li F, Zhang S, Jiang Y, Ma G, Shang H, Liu J, Feng R, Zhang L, Liao M, Zhao B, Li K (2014) Analyzing large-scale samples confirms the association between the ABCA7 rs3764650 polymorphism and Alzheimer’s disease susceptibility. Mol Neurobiol 50(3):757–764. https://doi.org/10.1007/s12035-014-8670-4
Ma FC, Wang HF, Cao XP, Tan CC, Tan L, Yu JT (2018) Meta-analysis of the association between variants in ABCA7 and Alzheimer’s Disease. J Alzheimers Dis 63(4):1261–1267. https://doi.org/10.3233/jad-180107
Moreno-Grau S, Hernandez I, Heilmann-Heimbach S, Ruiz S, Rosende-Roca M, Mauleon A, Vargas L, Rodriguez-Gomez O, Alegret M, Espinosa A, Ortega G, Aguilera N, Abdelnour C, Neuroimaging Initiative AD, Gil S, Maier W, Sotolongo-Grau O, Tarraga L, Ramirez A, Lopez-Arrrieta J, Antunez C, Serrano-Rios M, Boada M, Ruiz A (2018) Genome-wide significant risk factors on chromosome 19 and the APOE locus. Oncotarget 9(37):24590–24600. https://doi.org/10.18632/oncotarget.25083
Naj AC, Jun G, Beecham GW, Wang L-S, Vardarajan BN, Buros J, Gallins PJ, Buxbaum JD, Jarvik GP, Crane PK (2011) Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nature Gen 43(5):436–441. https://doi.org/10.1038/ng.801
Owens HA, Sherwani S, Tinsley C, Alatsatianos M, Dunstan M, Rizkallah P, Knauper V, Ager A, Williams J (2018) The role of epha1 in blood-brain barrier integrity and neuroinflammation in late-onset Alzheimer’s disease. Alzheimers Dement 14(7):P743. https://doi.org/10.1016/j.jalz.2018.06.880
Patterson, C. (2018) "World Alzheimer Report 2018". The state of the art of dementia research: New frontiers. London: Alzheimer’s Dis Int
Ramirez LM, Goukasian N, Porat S, Hwang KS, Eastman JA, Hurtz S, Wang B, Vang N, Sears R, Klein E, Coppola G, Apostolova LG (2016) Common variants in ABCA7 and MS4A6A are associated with cortical and hippocampal atrophy. Neurobiol Aging 39:82–89. https://doi.org/10.1016/j.neurobiolaging.2015.10.037
Roshchupkin GV, Adams HH, van der Lee SJ, Vernooij MW, van Duijn CM, Uitterlinden AG, van der Lugt A, Hofman A, Niessen WJ, Ikram MA (2016) Fine-mapping the effects of Alzheimer’s disease risk loci on brain morphology. Neurobiol Aging 48:204–211. https://doi.org/10.1016/j.neurobiolaging.2016.08.024
Sadigh-Eteghad S, Majdi A, Farhoudi M, Talebi M, Mahmoudi J (2014) Different patterns of brain activation in normal aging and Alzheimer’s disease from cognitional sight: meta analysis using activation likelihood estimation. J Neurol Sci 343(1-2):159–166. https://doi.org/10.1016/j.jns.2014.05.066
Sadigh-Eteghad S, Sabermarouf B, Majdi A, Talebi M, Farhoudi M, Mahmoudi J (2015) Amyloid-beta: a crucial factor in Alzheimer’s disease. Med Princ Pract 24(1):1–10. https://doi.org/10.1159/000369101
Seshadri S, Fitzpatrick AL, Ikram MA, DeStefano AL, Gudnason V, Boada M, Bis JC, Smith AV, Carassquillo MM, Lambert JC, Harold D, Schrijvers EMC, Ramirez-Lorca R, Debette S, Longstreth WT Jr, Janssens ACJW, Pankratz VS, Dartigues JF, Hollingworth P, Aspelund T, Hernandez I, Beiser A, Kuller LH, Koudstaal PJ, Dickson DW, Tzourio C, Abraham R, Antunez C, Du Y, Rotter JI, Aulchenko YS, Harris TB, Petersen RC, Berr C, Owen MJ, Lopez-Arrieta J, Varadarajan BN, Becker JT, Rivadeneira F, Nalls MA, Graff-Radford NR, Campion D, Auerbach S, Rice K, Hofman A, Jonsson PV, Schmidt H, Lathrop M, Mosley TH, Au R, Psaty BM, Uitterlinden AG, Farrer LA, Lumley T, Ruiz A, Williams J, Amouyel P, Younkin SG, Wolf PA, Launer LJ, Lopez OL, van Duijn CM, Breteler MMB, Consortium C, Consortium G, Consortium E (2010) Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA 303(18):1832–1840. https://doi.org/10.1001/jama.2010.574
Shulman JM, Chen K, Keenan BT, Chibnik LB, Fleisher A, Thiyyagura P, Roontiva A, McCabe C, Patsopoulos NA, Corneveaux JJ (2013) Genetic susceptibility for Alzheimer disease neuritic plaque pathology. JAMA Neurol 70(9):1150–1157. https://doi.org/10.1001/jamaneurol.2013.2815
Tan L, Yu J-T, Zhang W, Wu Z-C, Zhang Q, Liu Q-Y, Wang W, Wang H-F, Ma X-Y, Cui W-Z (2013) Association of GWAS-linked loci with late-onset Alzheimer’s disease in a northern Han Chinese population. Alzheimers Dement 9(5):546–553. https://doi.org/10.1016/j.jalz.2012.08.007
Vasquez JB, Fardo DW, Estus S (2013) ABCA7 expression is associated with Alzheimer’s disease polymorphism and disease status. Neurosci Lett 556:58–62. https://doi.org/10.1016/j.neulet.2013.09.058
Wildsmith KR, Holley M, Savage JC, Skerrett R, Landreth GE (2013) Evidence for impaired amyloid β clearance in Alzheimer’s disease. Alzheimers Res Ther 5(4):33. https://doi.org/10.1186/alzrt187
Wilkens S (2015) Structure and mechanism of ABC transporters. F1000Prime Rep 7:14–14. https://doi.org/10.12703/P7-14
World Alzheimer Report (2009) http://www.alz.co.uk/research/files/WorldAlzheimerReport.pdf (accessed Nov 13, 2012).
Yamazaki T, Masuda J, Omori T, Usui R, Akiyama H, Maru Y (2009) EphA1 interacts with integrin-linked kinase and regulates cell morphology and motility. J Cell Sci 122(2):243–255. https://doi.org/10.1242/jcs.036467
Zhao QF, Yu JT, Tan MS, Tan L (2015) ABCA7 in Alzheimer’s Disease. Mol Neurobiol 51(3):1008–1016. https://doi.org/10.1007/s12035-014-8759-9
Acknowledgments
The authors of this study are grateful to the director and staff of the Neurosciences Research Center (NSRC) of Tabriz University of Medical Sciences for the support provided.
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Funding was provided by the Neurosciences Research Center (NSRC) of Tabriz University of Medical Sciences.
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The original version of this article was revised: Author Azra Delpak’s given name was misspelled as “Azar”.
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Talebi, M., Delpak, A., Khalaj-kondori, M. et al. ABCA7 and EphA1 Genes Polymorphisms in Late-Onset Alzheimer’s Disease. J Mol Neurosci 70, 167–173 (2020). https://doi.org/10.1007/s12031-019-01420-x
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DOI: https://doi.org/10.1007/s12031-019-01420-x