Information de reference pour ce titreAccession Number: | 00008563-201405150-00018.
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Author: | Raj, Towfique 1, 3, 4; Ryan, Katie J. 1, 3, 4, 5; Replogle, Joseph M. 1, 4; Chibnik, Lori B. 1, 3, 4; Rosenkrantz, Laura 1; Tang, Anna 1; Rothamel, Katie 2; Stranger, Barbara E. 6, 7; Bennett, David A. 8; Evans, Denis A. 9; De Jager, Philip L. 1, 3, 4, 5, +, *; Bradshaw, Elizabeth M. 1, 3, 4, 5, +, *
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Institution: | (1)Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, MA 02115, USA (2)Department of Microbiology and Immunobiology, Division of Immunology and (3)Harvard Medical School, Boston, MA 02115, USA (4)Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA (5)Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA (6)Section of Genetic Medicine, Department of Medicine, and (7)Institute for Genomics and Systems Biology, University of Chicago, Chicago, IL 60637, USA (8)Rush Alzheimer's Disease Center and (9)Rush Institute for Healthy Aging, Rush University Medical Center, Chicago, IL 60612, USA
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Title: | |
Source: | Human Molecular Genetics. 23(10):2729-2736, May 15, 2014.
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Abstract: | : We previously demonstrated that the Alzheimer's disease (AD) associated risk allele, rs3865444C, results in a higher surface density of CD33 on monocytes. Here, we find alternative splicing of exon 2 to be the primary mechanism of the genetically driven differential expression of CD33 protein. We report that the risk allele, rs3865444C, is associated with greater cell surface expression of CD33 in both subjects of European and African-American ancestry and that there is a single haplotype influencing CD33 surface expression. A meta-analysis of the two populations narrowed the number of significant SNPs in high linkage disequilibrium (LD) (r2 > 0.8) with rs3865444 to just five putative causal variants associated with increased protein expression. Using gene expression data from flow-sorted CD14+CD16- monocytes from 398 healthy subjects of three populations, we show that the rs3865444C risk allele is strongly associated with greater expression of CD33 exon 2 (pMETA = 2.36 x 10-60). Western blotting confirms increased protein expression of the full-length CD33 isoform containing exon 2 relative to the rs3865444C allele (P < 0.0001). Of the variants in strong LD with rs3865444, rs12459419, which is located in a putative SRSF2 splice site of exon 2, is the most likely candidate to mediate the altered alternative splicing of CD33's Immunoglobulin V-set domain 2 and ultimately influence AD susceptibility.
(C) Copyright Oxford University Press 2014.
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Language: | English.
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Document Type: | ARTICLES.
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Journal Subset: | Life & Biomedical Sciences.
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ISSN: | 0964-6906
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NLM Journal Code: | brc, 9208958
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DOI Number: | https://dx.doi.org/10.1093/hmg/d...- ouverture dans une nouvelle fenêtre
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