Open AccessRegulation of the Late Onset alzheimer’s Disease Associated HLA-DQA1/DRB1 Expression
Author(s) -
Xiaoyu Zhang,
Meijaun Zou,
Yuwei Wu,
Danli Jiang,
Ting Wu,
Yihan Zhao,
Di Wu,
Jing Cui,
Gang Li
Publication year - 2022
Publication title -
american journal of alzheimer's disease and other dementias
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.653
H-Index - 60
eISSN - 1938-2731
pISSN - 1533-3175
DOI - 10.1177/15333175221085066
Subject(s) - single nucleotide polymorphism , linkage disequilibrium , genome wide association study , human leukocyte antigen , biology , locus (genetics) , expression quantitative trait loci , genetics , allele , genetic association , haplotype , gene , genotype , antigen
(Genome-wide Association Studies) GWAS have identified ∼42 late-onset Alzheimer’s disease (LOAD)-associated loci, each of which contains multiple single nucleotide polymorphisms (SNPs) in linkage disequilibrium (LD) and most of these SNPs are in the non-coding region of human genome. However, how these SNPs regulate risk gene expression remains unknown. In this work, by using a set of novel techniques, we identified 6 functional SNPs (fSNPs) rs9271198, rs9271200, rs9281945, rs9271243, and rs9271247 on the LOAD-associated HLA-DRB1/DQA1 locus and 42 proteins specifically binding to five of these 6 fSNPs. As a proof of evidence, we verified the allele-specific binding of GATA2 and GATA3, ELAVL1 and HNRNPA0, ILF2 and ILF3, NFIB and NFIC, as well as CUX1 to these five fSNPs, respectively. Moreover, we demonstrate that all these nine proteins regulate the expression of both HLA-DQA1 and HLA-DRB1 in human microglial cells. The contribution of HLA class II to the susceptibility of LOAD is discussed.