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J Clin Med. 2019 Aug 16;8(8). pii: E1236. doi: 10.3390/jcm8081236.

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

Author information

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
National Research Center for Dementia, Chosun University, Gwangju 61452, Korea. leekho@chosun.ac.kr.
34
Department of Biomedical Science, Chosun University, Gwangju 61452, Korea. leekho@chosun.ac.kr.
35
Department of Life Science, Chosun University, Gwangju 61452, Korea. leekho@chosun.ac.kr.
36
Department of Neural Development and Disease, Korea Brain Research Institute, Daegu 41062, Korea. leekho@chosun.ac.kr.

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.

KEYWORDS:

APOE; Alzheimer’s disease; brain atrophy; ethnic variability; genetic association; promoter polymorphism

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