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APOE Promoter Polymorphism-219T/G is an Effect Modifier of the Influence of APOE ε4 on Alzheimer’s Disease Risk in a Multiracial Sample

1
National Research Center for Dementia, Chosun University, Gwangju 61452, Korea
2
Department of Biomedical Science, Chosun University, Gwangju 61452, Korea
3
Department of Life Science, Chosun University, Gwangju 61452, Korea
4
Department of Life Science, Chung-Ang University, Seoul 06974, Korea
5
Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA 02118, USA
6
Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA
7
Department of Biochemistry and Signaling Disorder Research Center, College of Medicine, Chungbuk National University, Cheongju 28644, Korea
8
Department of Premedical Science, Chosun University College of Medicine, Gwangju 61452, Korea
9
Department of Neurology, Chosun University Hospital, Gwangju 61452, Korea
10
Department of Nuclear Medicine, Chosun University Hospital, Gwangju 61452, Korea
11
Department of Neuropsychiatry, Seoul National University Hospital, Seoul 03080, Korea
12
Department of Public Health Science, Graduate School of Public Health, Seoul National University, Seoul 08826, Korea
13
Department of Neurology, Kyungpook National University School of Medicine, Daegu 41944, Korea
14
Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do 13620, Korea
15
Department of Pathology, The Alfred Hospital, Melbourne, Victoria 3004, Australia
16
Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata 951-8585, Japan
17
Department of Neurology, Chonnam National University Medical School, Gwangju 61469, Korea
18
Department of Neurology, Ewha Womans University Mokdong Hospital, Ewha Womans University School of Medicine, Seoul 07985, Korea
19
Chonnam national university Gwangju 2nd geriatric hospital, Gwangju 61748, Korea
20
Department of Bionanotechnology, Gachon University, Seongnam, Gyeonggi-do 13120, Korea
21
Department of Psychiatry, Pusan National University School of Medicine, Busan 50612, Korea
22
Department of Neurology, Donga University College of Medicine, Busan 49315, Korea
23
Department of Neurology, Inha University School of Medicine, Incheon 22212, Korea
24
Bio Imaging and Cell Logistics Research Center, School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Korea
25
Department of Neurology and Sergievsky Center, Columbia University, New York, NY 10032, USA
26
Department of Population & Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH 44106, USA
27
Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33101, USA
28
Department of Neuropsychiatry, Chosun University School of Medicine and Hospital, Gwangju 61453, Korea
29
Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana University School of Medicine, Indianapolis, IN 46202, USA
30
Department of Neurology, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do 13620, Korea
31
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104-4238, USA
32
Departments of Neurology, Ophthalmology, and Epidemiology, Boston University Schools of Medicine and Public Health, Boston, MA 02118, USA
33
Department of Neural Development and Disease, Korea Brain Research Institute, Daegu 41062, Korea
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2019, 8(8), 1236; https://doi.org/10.3390/jcm8081236
Received: 5 July 2019 / Revised: 9 August 2019 / Accepted: 12 August 2019 / Published: 16 August 2019
(This article belongs to the Section Neuroscience)
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PDF [2189 KB, uploaded 16 August 2019]
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Abstract

Variants in the APOE gene region may explain ethnic differences in the association of Alzheimer’s disease (AD) with ε4. Ethnic differences in allele frequencies for three APOE region SNPs (single nucleotide polymorphisms) were identified and tested for association in 19,398 East Asians (EastA), including Koreans and Japanese, 15,836 European ancestry (EuroA) individuals, and 4985 African Americans, and with brain imaging measures of cortical atrophy in sub-samples of Koreans and EuroAs. Among ε4/ε4 individuals, AD risk increased substantially in a dose-dependent manner with the number of APOE promoter SNP rs405509 T alleles in EastAs (TT: OR (odds ratio) = 27.02, p = 8.80 × 10−94; GT: OR = 15.87, p = 2.62 × 10−9) and EuroAs (TT: OR = 18.13, p = 2.69 × 10−108; GT: OR = 12.63, p = 3.44 × 10−64), and rs405509-T homozygotes had a younger onset and more severe cortical atrophy than those with G-allele. Functional experiments using APOE promoter fragments demonstrated that TT lowered APOE expression in human brain and serum. The modifying effect of rs405509 genotype explained much of the ethnic variability in the AD/ε4 association, and increasing APOE expression might lower AD risk among ε4 homozygotes. View Full-Text
Keywords: APOE; promoter polymorphism; Alzheimer’s disease; ethnic variability; brain atrophy; genetic association APOE; promoter polymorphism; Alzheimer’s disease; ethnic variability; brain atrophy; genetic association
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Choi, K.Y.; Lee, J.J.; Gunasekaran, T.I.; Kang, S.; Lee, W.; Jeong, J.; Lim, H.J.; Zhang, X.; Zhu, C.; Won, S.-Y.; Choi, Y.Y.; Seo, E.H.; Lee, S.C.; Gim, J.; Chung, J.Y.; Chong, A.; Byun, M.S.; Seo, S.; Ko, P.-W.; Han, J.-W.; McLean, C.; Farrell, J.; Lunetta, K.L.; Miyashita, A.; Hara, N.; Won, S.; Choi, S.-M.; Ha, J.-M.; Jeong, J.H.; Kuwano, R.; Song, M.K.; An, S.S.A.; Lee, Y.M.; Park, K.W.; Lee, H.-W.; Choi, S.H.; Rhee, S.; Song, W.K.; Lee, J.S.; Mayeux, R.; Haines, J.L.; Pericak-Vance, M.A.; Choo, I.H.; Nho, K.; Kim, K.-W.; Lee, D.Y.; Kim, S.; Kim, B.C.; Kim, H.; Jun, G.R.; Schellenberg, G.D.; Ikeuchi, T.; Farrer, L.A.; Lee, K.H.; Neuroimaging Initative, A.D. APOE Promoter Polymorphism-219T/G is an Effect Modifier of the Influence of APOE ε4 on Alzheimer’s Disease Risk in a Multiracial Sample. J. Clin. Med. 2019, 8, 1236.

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