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

TitlePromoter Polymorphism-219T/G is an Effect Modifier of the Influence of ε4 on Alzheimer's Disease Risk in a Multiracial Sample.
Publication TypeJournal Article
Year of Publication2019
AuthorsChoi KYeong, Lee JJae, Gunasekaran TIniyan, Kang S, Lee W, Jeong J, Lim HJae, Zhang X, Zhu C, Won S-Y, Choi YYong, Seo EHyun, Lee SCheol, Gim J, Chung JYeon, Chong A, Byun MSoo, Seo S, Ko P-W, Han J-W, McLean C, Farrell J, Lunetta KL, Miyashita A, Hara N, Won S, Choi S-M, Ha J-M, Jeong JHyang, Kuwano R, Song MKyung, An SSoo A, Lee YMin, Park KWon, Lee H-W, Choi SHye, Rhee S, Song WKeun, Lee JSup, Mayeux R, Haines JL, Pericak-Vance MA, Choo ILHan, Nho K, Kim K-W, Lee DYoung, Kim SY, Kim BC, Kim H, Jun GR, Schellenberg GD, Ikeuchi T, Farrer LA, Lee KHo, Initative A'sDisease Ne
JournalJ Clin Med
Date Published2019 Aug 16

Variants in the gene region may explain ethnic differences in the association of Alzheimer's disease (AD) with ε4. Ethnic differences in allele frequencies for three 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 promoter SNP rs405509 alleles in EastAs : OR (odds ratio) = 27.02, = 8.80 × 10; : OR = 15.87, = 2.62 × 10) and EuroAs (: OR = 18.13, = 2.69 × 10; : OR = 12.63, = 3.44 × 10), and rs405509- homozygotes had a younger onset and more severe cortical atrophy than those with -allele. Functional experiments using promoter fragments demonstrated that lowered 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 expression might lower AD risk among ε4 homozygotes.

Pubmed Link
Alternate JournalJ Clin Med
PubMed ID31426376
PubMed Central IDPMC6723529
Grant ListNRF-2014M3C7A1046041 / / National Research Foundation of Korea /
R01-AG048927; P30-AG13846; U01-AG032984; RF1-AG057519 / AG / NIA NIH HHS / United States
JP18kk0205009 / / Japan Agency for Medical Research and Development /

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