Journal of Clinical Medicine (Aug 2019)
<em>APOE</em> Promoter Polymorphism-219T/G is an Effect Modifier of the Influence of <em>APOE</em> ε4 on Alzheimer’s Disease Risk in a Multiracial Sample
- Kyu Yeong Choi,
- Jang Jae Lee,
- Tamil Iniyan Gunasekaran,
- Sarang Kang,
- Wooje Lee,
- Jangho Jeong,
- Ho Jae Lim,
- Xiaoling Zhang,
- Congcong Zhu,
- So-Yoon Won,
- Yu Yong Choi,
- Eun Hyun Seo,
- Seok Cheol Lee,
- Jungsoo Gim,
- Ji Yeon Chung,
- Ari Chong,
- Min Soo Byun,
- Sujin Seo,
- Pan-Woo Ko,
- Ji-Won Han,
- Catriona McLean,
- John Farrell,
- Kathryn L. Lunetta,
- Akinori Miyashita,
- Norikazu Hara,
- Sungho Won,
- Seong-Min Choi,
- Jung-Min Ha,
- Jee Hyang Jeong,
- Ryozo Kuwano,
- Min Kyung Song,
- Seong Soo A. An,
- Young Min Lee,
- Kyung Won Park,
- Ho-Won Lee,
- Seong Hye Choi,
- Sangmyung Rhee,
- Woo Keun Song,
- Jung Sup Lee,
- Richard Mayeux,
- Jonathan L. Haines,
- Margaret A. Pericak-Vance,
- IL Han Choo,
- Kwangsik Nho,
- Ki-Woong Kim,
- Dong Young Lee,
- SangYun Kim,
- Byeong C. Kim,
- Hoowon Kim,
- Gyungah R. Jun,
- Gerard D. Schellenberg,
- Takeshi Ikeuchi,
- Lindsay A. Farrer,
- Kun Ho Lee,
- Alzheimer’s Disease Neuroimaging Initative
Affiliations
- Kyu Yeong Choi
- National Research Center for Dementia, Chosun University, Gwangju 61452, Korea
- Jang Jae Lee
- National Research Center for Dementia, Chosun University, Gwangju 61452, Korea
- Tamil Iniyan Gunasekaran
- National Research Center for Dementia, Chosun University, Gwangju 61452, Korea
- Sarang Kang
- National Research Center for Dementia, Chosun University, Gwangju 61452, Korea
- Wooje Lee
- National Research Center for Dementia, Chosun University, Gwangju 61452, Korea
- Jangho Jeong
- Department of Life Science, Chung-Ang University, Seoul 06974, Korea
- Ho Jae Lim
- National Research Center for Dementia, Chosun University, Gwangju 61452, Korea
- Xiaoling Zhang
- Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA 02118, USA
- Congcong Zhu
- Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA 02118, USA
- So-Yoon Won
- Department of Biochemistry and Signaling Disorder Research Center, College of Medicine, Chungbuk National University, Cheongju 28644, Korea
- Yu Yong Choi
- National Research Center for Dementia, Chosun University, Gwangju 61452, Korea
- Eun Hyun Seo
- National Research Center for Dementia, Chosun University, Gwangju 61452, Korea
- Seok Cheol Lee
- National Research Center for Dementia, Chosun University, Gwangju 61452, Korea
- Jungsoo Gim
- National Research Center for Dementia, Chosun University, Gwangju 61452, Korea
- Ji Yeon Chung
- National Research Center for Dementia, Chosun University, Gwangju 61452, Korea
- Ari Chong
- National Research Center for Dementia, Chosun University, Gwangju 61452, Korea
- Min Soo Byun
- Department of Neuropsychiatry, Seoul National University Hospital, Seoul 03080, Korea
- Sujin Seo
- Department of Public Health Science, Graduate School of Public Health, Seoul National University, Seoul 08826, Korea
- Pan-Woo Ko
- Department of Neurology, Kyungpook National University School of Medicine, Daegu 41944, Korea
- Ji-Won Han
- Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do 13620, Korea
- Catriona McLean
- Department of Pathology, The Alfred Hospital, Melbourne, Victoria 3004, Australia
- John Farrell
- Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA 02118, USA
- Kathryn L. Lunetta
- Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA
- Akinori Miyashita
- Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata 951-8585, Japan
- Norikazu Hara
- Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata 951-8585, Japan
- Sungho Won
- Department of Public Health Science, Graduate School of Public Health, Seoul National University, Seoul 08826, Korea
- Seong-Min Choi
- Department of Neurology, Chonnam National University Medical School, Gwangju 61469, Korea
- Jung-Min Ha
- National Research Center for Dementia, Chosun University, Gwangju 61452, Korea
- Jee Hyang Jeong
- Department of Neurology, Ewha Womans University Mokdong Hospital, Ewha Womans University School of Medicine, Seoul 07985, Korea
- Ryozo Kuwano
- Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata 951-8585, Japan
- Min Kyung Song
- Chonnam national university Gwangju 2nd geriatric hospital, Gwangju 61748, Korea
- Seong Soo A. An
- Department of Bionanotechnology, Gachon University, Seongnam, Gyeonggi-do 13120, Korea
- Young Min Lee
- Department of Psychiatry, Pusan National University School of Medicine, Busan 50612, Korea
- Kyung Won Park
- Department of Neurology, Donga University College of Medicine, Busan 49315, Korea
- Ho-Won Lee
- Department of Neurology, Kyungpook National University School of Medicine, Daegu 41944, Korea
- Seong Hye Choi
- Department of Neurology, Inha University School of Medicine, Incheon 22212, Korea
- Sangmyung Rhee
- Department of Life Science, Chung-Ang University, Seoul 06974, Korea
- Woo Keun Song
- Bio Imaging and Cell Logistics Research Center, School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Korea
- Jung Sup Lee
- National Research Center for Dementia, Chosun University, Gwangju 61452, Korea
- Richard Mayeux
- Department of Neurology and Sergievsky Center, Columbia University, New York, NY 10032, USA
- Jonathan L. Haines
- Department of Population & Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH 44106, USA
- Margaret A. Pericak-Vance
- Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33101, USA
- IL Han Choo
- Department of Neuropsychiatry, Chosun University School of Medicine and Hospital, Gwangju 61453, Korea
- Kwangsik Nho
- Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Ki-Woong Kim
- Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do 13620, Korea
- Dong Young Lee
- Department of Neuropsychiatry, Seoul National University Hospital, Seoul 03080, Korea
- SangYun Kim
- Department of Neurology, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do 13620, Korea
- Byeong C. Kim
- Department of Neurology, Chonnam National University Medical School, Gwangju 61469, Korea
- Hoowon Kim
- National Research Center for Dementia, Chosun University, Gwangju 61452, Korea
- Gyungah R. Jun
- Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA 02118, USA
- Gerard D. Schellenberg
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104-4238, USA
- Takeshi Ikeuchi
- Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata 951-8585, Japan
- Lindsay A. Farrer
- Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA 02118, USA
- Kun Ho Lee
- National Research Center for Dementia, Chosun University, Gwangju 61452, Korea
- Alzheimer’s Disease Neuroimaging Initative
- DOI
- https://doi.org/10.3390/jcm8081236
- Journal volume & issue
-
Vol. 8,
no. 8
p. 1236
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
- <i>APOE</i>
- promoter polymorphism
- Alzheimer’s disease
- ethnic variability
- brain atrophy
- genetic association
