title: Promoter polymorphisms modulating HSPA5 expression may increase susceptibility to Taiwanese Alzheimer's disease.
abstract: Endoplasmic reticulum (ER) chaperone heat shock 70 kDa protein 5 (HSPA5/GRP78) is known to be involved in the metabolism of amyloid precursor protein and neuronal death in Alzheimer's disease (AD) could arise from dysfunction of the ER. Through a case-control study and an expression assay, we investigated the association of HSPA5 -415 G/A (rs391957), -370 C/T (rs17840761) and -180 del/G (rs3216733) polymorphisms with Taiwanese AD. The overall genotype and allele frequency distribution at the completely linked -415 G/A and -180 del/G sites showed significant difference between AD cases and controls (P = 0.020 and 0.009, respectively). A decrease in risk of developing AD was demonstrated for -415 AA/-180 GG genotype [OR = 0.38, 95% confidence interval (CI) = 0.18-0.75, P = 0.007] and -415 A/-180 G allele (OR = 0.69, 95% CI = 0.51-0.91, P = 0.009). The HSPA5 transcriptional activity of the -415 A/-180 G allele was significantly lower than that of the -415 G/-180 del alleles, whereas induction of HSPA5 expression after ER stress was markedly increased in the cells with the -415 A/-180 G allele. Therefore, our preliminary results may suggest a protective role of the HSPA5 -415 A/-180 G allele in Taiwanese AD susceptibility.
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, 10507, Taiwan.
authors.forename: W-C
authors.initials: WC
authors.lastname: Hsu
authors.forename: H-K
authors.initials: HK
authors.lastname: Wang
authors.forename: L-C
authors.initials: LC
authors.lastname: Lee
authors.forename: H-C
authors.initials: HC
authors.lastname: Fung
authors.forename: J-C
authors.initials: JC
authors.lastname: Lin
authors.forename: H-P
authors.initials: HP
authors.lastname: Hsu
authors.forename: Y-R
authors.initials: YR
authors.lastname: Wu
authors.forename: L-S
authors.initials: LS
authors.lastname: Ro
authors.forename: F-J
authors.initials: FJ
authors.lastname: Hu
authors.forename: Y-T
authors.initials: YT
authors.lastname: Chang
authors.forename: G-J
authors.initials: GJ
authors.lastname: Lee-Chen
authors.forename: C-M
authors.initials: CM
authors.lastname: Chen
mesh_terms: D000368:Aged; D000483:Alleles; D000544:Alzheimer Disease / Q000453:epidemiology* / Q000235:genetics*; D004247:DNA / Q000235:genetics; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D015870:Gene Expression / Q000502:physiology; D005787:Gene Frequency; D005838:Genotype; D006360:Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics*; D006801:Humans; D008297:Male; D018832:Molecular Chaperones / Q000096:biosynthesis* / Q000235:genetics*; D016017:Odds Ratio; D011110:Polymorphism, Genetic / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D012307:Risk Factors; D013624:Taiwan / Q000453:epidemiology; D014407:Tumor Cells, Cultured
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D004247:DNA
references.citation: Methods. 2005 Apr;35(4):373-81
references.pmid: 15804610
references.citation: Bioinformatics. 2000 Feb;16(2):182-3
references.pmid: 10842743
references.citation: Am J Hum Genet. 2001 Apr;68(4):978-89
references.pmid: 11254454
references.citation: DNA Cell Biol. 1997 Sep;16(9):1123-31
references.pmid: 9324314
references.citation: Science. 1993 Aug 13;261(5123):921-3
references.pmid: 8346443
references.citation: Trends Biochem Sci. 2001 Aug;26(8):504-10
references.pmid: 11504627
references.citation: Am J Hum Genet. 2004 Apr;74(4):765-9
references.pmid: 14997420
references.citation: J Neural Transm (Vienna). 2006 Oct;113(10):1499-509
references.pmid: 16465461
references.citation: Ann N Y Acad Sci. 2002 Nov;977:327-32
references.pmid: 12480769
references.citation: Neurology. 1984 Jul;34(7):939-44
references.pmid: 6610841
references.citation: Heredity (Edinb). 2001 Jul;87(Pt 1):52-8
references.pmid: 11678987
references.citation: Mutat Res. 2005 Jan 6;569(1-2):29-63
references.pmid: 15603751
references.citation: Mol Cell Biol. 1997 Jan;17(1):54-60
references.pmid: 8972185
references.citation: Biochem Biophys Res Commun. 2005 Nov 4;336(4):1136-43
references.pmid: 16168956
references.citation: Mol Cell Biol. 2001 May;21(9):3220-33
references.pmid: 11287625
references.citation: Neurology. 1997 Oct;49(4):1096-105
references.pmid: 9339696
references.citation: Biochem J. 2007 Mar 15;402(3):581-9
references.pmid: 17132139
references.citation: J Biol Chem. 1998 Oct 2;273(40):25552-5
references.pmid: 9748217
references.citation: J Biol Chem. 2001 Nov 16;276(46):43446-54
references.pmid: 11551913
references.citation: Trends Neurosci. 1997 Apr;20(4):154-9
references.pmid: 9106355
references.citation: Acta Neuropathol. 2005 Aug;110(2):165-72
references.pmid: 15973543
references.citation: J Biol Chem. 1998 Dec 11;273(50):33741-9
references.pmid: 9837962
references.citation: J Biol Chem. 2001 Jan 19;276(3):2108-14
references.pmid: 11031265