Oğuz ÇİLİNGİR, Demet Özbabalık ADAPINAR, Beyhan DURAK ARAS, Ebru Erzurumluoğlu GÖKALP, Serhat ÖZKAN, Serap ARSLAN, Konül HAZİYEVA, Sinem KOCAGİL, Muzaffer BİLGİN, SEVİLHAN ARTAN

Türk Popülasyonunda APOE Polimorfizmleri ve Alzheimer Hastalığı Arasındaki İlişki

Alzheimer Hastalığı (AH), demansın en yaygın nedeni olan, sinaps ve nöronların kaybının yanı sıra hücre dışı amyloid plakların ve hücre içi nörofibriler yapıların patolojik oluşumları ile karakterize, en sık görülen progresif nörodejeneratif bir hastalıktır. Geç başlangıçlı AH’da Apolipoprotein E (APOE) gen polimorfizmleri hücresel seviyelerde önemli bir etkiye sahip olmakla beraber aynı zamanda nöropatolojik koşullarla da ilişkilendirilmiştir. APOE gen polimorfizmlerinin AH' ları üzerinde etkisini saptamak amacıyla yaptığımız çalışmamıza 45-90 yaş arasında olan 629 hasta ve 200 sağlıklı birey dahil edilmiştir. APOE geni izoformları gerçek zamanlı polimeraz zincir reaksiyonu (GZ-PZR) yöntemi ile incelenmiştir. Hasta ve kontrol grupları arasında hem APOE genotip dağılımları (p<0.001) hemde allel frekansları (p<0.001) açısından istatistiksel olarak anlamlı farklar tespit edilmiştir. APOE ε4 allel taşıyıcısı olan bireylerde ε4 alleli taşımayan bireylere göre AH riskinin 5.49 kat fazla olduğu sonucuna ulaşılmıştır (OR= 5.49, %95 CI: 3.86-7.81, p<0.001). MMSE (Mini-Mental Durum Muayenesi) skorunun; ε4 alleli taşıyıcılarında, taşıyıcı olmayanlara göre daha düşük olduğu tespit edilmiştir (p<0.001). Bütün bu verilere dayanarak APOE ?4 allelinin AH’nın gelişim riskini arttırdığı sonucuna varılabilir. Sonuçlarımız APOE genotipinin AH için bir risk faktörü olduğunu doğrulamıştır. APOE'nin AH gelişimine katkısını net olarak saptayabilmek için, coğrafi konumun ve etnik kökenin önemi de dikkate alınarak, daha geniş çaplı moleküler çalışmalara ihtiyaç olduğu bir gerçektir.

Anahtar Kelimeler:

: Alzheimer Hastalığı, APOE, polimorfizm, ε4 allel

Association Between Alzheimer Disease and APOE Gene Polymorphisms in Turkish Population

Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common form of the dementia which is characterized by the accumulation of amyloid plaques at the extracellular compartment and formation of neurofibriller tangles at the intracellular compartment which results in the degeneration of the neuron bodies and synapses. APOE gene polymorphisms in late-onset AD have a significant effect on cellular levels and also have been associated with neuropathological conditions. To determine the effect of APOE gene polymorphisms on Alzheimer's patients, we have included 629 AD patients between 45-90 years and 200 healthy subjects into the study. APOE gene isoforms were determined by real-time PCR method. APOE genotype distributions were significantly different between the patient and control groups (p <0.001). There was a statistically significant difference in allele frequencies between patient and control groups (p <0.001). At ε4 allele carriers there was a 5.49 times higher risk of AD than the subjects that lack the ε4 allele (OR= 5.49, %95 CI: 3.86-7.81, p<0.001). The MMSE (Mini-Mental State Examination) score was lower among APOE ε4-carriers when compared to the non-carriers (p<0.001). On the basis of all these data it can be concluded that the APOE ε4 allele increases the risk of development of AD. Our results confirmed that the APOE genotype is a risk factor for AD. However, considering the importance of the geographic location and ethnicity, it is a fact that larger molecular studies are needed to clearly determine the contribution of the APOE gene to the development of AD.

Keywords:

Alzheimer Diseas, APOE, polymorphism,

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1. Cacabelos R, Martínez R, Fernández-Novoa L, Carril JC, Lombardi V, Carrera I, et al. Genomics of dementia: APOE-and CYP2D6-related pharmacogenetics. International Journal of Alzheimer’s Disease. 2012;2012.
2. Association As. 2013 Alzheimer's disease facts and figures. Alzheimer's & dementia. 2013;9(2):208-45.
3. Yu J-T, Tan L, Hardy J. Apolipoprotein E in Alzheimer's disease: an update. Annual review of neuroscience. 2014;37:79-100.
4. Liu C-C, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nature Reviews Neurology. 2013;9(2):106.
5. Association As. 2012 Alzheimer’s disease facts and figures. Alzheimer's & Dementia. 2012;8(2):131-68.
6. Zhong N, Weisgraber KH. Understanding the association of apolipoprotein E4 with Alzheimer disease: clues from its structure. Journal of Biological Chemistry. 2009;284(10):6027-31.
7. Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris JC, et al. Decreased clearance of CNS β-amyloid in Alzheimer’s disease. Science. 2010;330(6012):1774-.
8. Bales KR, Liu F, Wu S, Lin S, Koger D, DeLong C, et al. Human APOE isoform-dependent effects on brain β-amyloid levels in PDAPP transgenic mice. Journal of Neuroscience. 2009;29(21):6771-9.
9. Castellano JM, Kim J, Stewart FR, Jiang H, DeMattos RB, Patterson BW, et al. Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. Science translational medicine. 2011;3(89):89ra57-89ra57.
10. Youmans KL, Tai LM, Nwabuisi-Heath E, Jungbauer L, Kanekiyo T, Gan M, et al. APOE4-specific changes in Aβ accumulation in a new transgenic model of Alzheimer's Disease. Journal of Biological Chemistry. 2012:jbc. M112. 407957.
11. Christensen DZ, Schneider-Axmann T, Lucassen PJ, Bayer TA, Wirths O. Accumulation of intraneuronal Aβ correlates with ApoE4 genotype. Acta neuropathologica. 2010;119(5):555-66.
12. Hashimoto T, Serrano-Pozo A, Hori Y, Adams KW, Takeda S, Banerji AO, et al. Apolipoprotein E, especially apolipoprotein E4, increases the oligomerization of amyloid β peptide. Journal of Neuroscience. 2012;32(43):15181-92.
13. Koffie RM, Hashimoto T, Tai H-C, Kay KR, Serrano-Pozo A, Joyner D, et al. Apolipoprotein E4 effects in Alzheimer’s disease are mediated by synaptotoxic oligomeric amyloid-β. Brain. 2012;135(7):2155-68.14. Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis. Jama. 1997;278(16):1349-56.
15. Yavlal F, Güngör HA. Demansta Klinik Bulgular. 2016.
16. Kok E, Haikonen S, Luoto T, Huhtala H, Goebeler S, Haapasalo H, et al. Apolipoprotein E–dependent accumulation of Alzheimer disease–related lesions begins in middle age. Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society. 2009;65(6):650-7.
17. Edelberg HK, Wei JY. The biology of Alzheimer's disease. Mechanisms of ageing and development. 1996;91(2):95-114.
18. Alaylıoğlu M, Gezen-Ak D, Dursun E, Bilgiç B, Hanağası H, Ertan T, et al. The association between clusterin and APOE polymorphisms and late-onset Alzheimer disease in a Turkish cohort. Journal of geriatric psychiatry and neurology. 2016;29(4):221-6.
19. KAYA G, GÜNDÜZ E, Acar M, HATİPOĞLU ÖF, Acar B, Ilhan A, et al. Potential genetic biomarkers in the early diagnosisof Alzheimer disease: APOE and BIN1. Turkish journal of medical sciences. 2015;45(5):1058-72.
20. Aslan D, Ercan F, Aybek H, Sahiner T. APOE epsilon4 allele frequency in patients with dementia in different ethnic and geographic groups. Turk J Biochem. 2010;35(3):163-71.
21. Oznur M, Hatipoglu OF, Ayturk Z, Dede S, Akbas K, Aydin D, et al. Association among ABCA7 Gene Polymorphism, rs3764650 and Alzheimer's Disease in the Turkish Population. Clinical and Investigative Medicine (Online). 2015;38(4):E187.
22. Yokes M, Emre M, Harmanci H, Gurvit H, Hanagasi H, Sahin H, et al. The apolipoprotein E (APOE) genotype in a Turkish population with Alzheimer’s disease. Balkan J Med Genet. 2005;8(1-2):57-63.
23. Davidson Y, Gibbons L, Pritchard A, Hardicre J, Wren J, Stopford C, et al. Apolipoprotein E ε4 allele frequency and age at onset of Alzheimer’s disease. Dementia and geriatric cognitive disorders. 2007;23(1):60-6.
24. Kerr DS, Stella F, Radanovic M, Aprahamian I, Bertollucci PHF, Forlenza OV. Apolipoprotein E genotype is not associated with cognitive impairment in older adults with bipolar disorder. Bipolar disorders. 2016;18(1):71-7.
25. Jairani P, Aswathy P, Gopala S, Verghese J, Mathuranath P. Interaction with the MAPT H1H1 genotype increases dementia risk in APOE ε4 carriers in a population of Southern India. Dementia and geriatric cognitive disorders. 2016;42(5-6):255-64.
26. Lanni C, Garbin G, Lisa A, Biundo F, Ranzenigo A, Sinforiani E, et al. Influence of COMT Val158Met polymorphism on Alzheimer's disease and mild cognitive impairment in Italian patients. Journal of Alzheimer's Disease. 2012;32(4):919-26.27. Sando SB, Melquist S, Cannon A, Hutton ML, Sletvold O, Saltvedt I, et al. APOE ε4 lowers age at onset and is a high risk factor for Alzheimer's disease; A case control study from central Norway. BMC neurology. 2008;8(1):9.
28. Raygani AV, Zahrai M, Raygani AV, Doosti M, Javadi E, Rezaei M, et al. Association between apolipoprotein E polymorphism and Alzheimer disease in Tehran, Iran. Neuroscience letters. 2005;375(1):1-6.
29. Chen K-L, Sun Y-M, Zhou Y, Zhao Q-H, Ding D, Guo Q-H. Associations between APOE polymorphisms and seven diseases with cognitive impairment including Alzheimer’s disease, frontotemporal dementia, and dementia with Lewy bodies in southeast China. Psychiatric genetics. 2016;26(3):124.
30. Montufar S, Calero C, Vinueza R, Correa P, Carrera-Gonzalez A, Villegas F, et al. Association between the APOE ε4 Allele and Late-Onset Alzheimer’s Disease in an Ecuadorian Mestizo Population. International Journal of Alzheimer’s Disease. 2017;2017.
31. Bathum L, Christiansen L, Jeune B, Vaupel J, McGue M, Christensen K. Apolipoprotein e genotypes: relationship to cognitive functioning, cognitive decline, and survival in nonagenarians. Journal of the American Geriatrics Society. 2006;54(4):654-8.
32. Quintino-Santos SR, Lima-Costa MF, Uchoa E, Firmo JOdA, Moriguchi EH, Castro-Costa Éd. Homozygosity for the APOE E4 allele is solely associated with lower cognitive performance in Brazilian community-dwelling older adults: the Bambuí Study. Revista Brasileira de Psiquiatria. 2012;34(4):440-5.
33. Small BJ, Rosnick CB, Fratiglioni L, Bäckman L. Apolipoprotein E and cognitive performance: a meta-analysis. Psychology and aging. 2004;19(4):592.34. Christensen H, Batterham PJ, Mackinnon AJ, Jorm AF, Mack HA, Mather KA, et al. The association of APOE genotype and cognitive decline in interaction with risk factors in a 65–69 year old community sample. BMC geriatrics. 2008;8(1):14.
35. Rassas AA, Khiari HM, Fredj SH, Sahnoun S, Batti H, Zakraoui NO, et al. High APOE epsilon 4 allele frequencies associated with Alzheimer disease in a Tunisian population. Neurological Sciences. 2012;33(1):33-7.
36. Ward A, Crean S, Mercaldi CJ, Collins JM, Boyd D, Cook MN, et al. Prevalence of apolipoprotein E4 genotype and homozygotes (APOE e4/4) among patients diagnosed with Alzheimer’s disease: a systematic review and meta-analysis. Neuroepidemiology. 2012;38(1):1-17.