Promoter polymorphisms modulating HSPA5 expression may increase susceptibility to Taiwanese Alzheimer's disease.
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.
Hsu
W-C
WC
Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, 10507, Taiwan.
Wang
H-K
HK
Lee
L-C
LC
Fung
H-C
HC
Lin
J-C
JC
Hsu
H-P
HP
Wu
Y-R
YR
Ro
L-S
LS
Hu
F-J
FJ
Chang
Y-T
YT
Lee-Chen
G-J
GJ
Chen
C-M
CM
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
D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D004247:DNA
Methods. 2005 Apr;35(4):373-81
15804610
Bioinformatics. 2000 Feb;16(2):182-3
10842743
Am J Hum Genet. 2001 Apr;68(4):978-89
11254454
DNA Cell Biol. 1997 Sep;16(9):1123-31
9324314
Science. 1993 Aug 13;261(5123):921-3
8346443
Trends Biochem Sci. 2001 Aug;26(8):504-10
11504627
Am J Hum Genet. 2004 Apr;74(4):765-9
14997420
J Neural Transm (Vienna). 2006 Oct;113(10):1499-509
16465461
Ann N Y Acad Sci. 2002 Nov;977:327-32
12480769
Neurology. 1984 Jul;34(7):939-44
6610841
Heredity (Edinb). 2001 Jul;87(Pt 1):52-8
11678987
Mutat Res. 2005 Jan 6;569(1-2):29-63
15603751
Mol Cell Biol. 1997 Jan;17(1):54-60
8972185
Biochem Biophys Res Commun. 2005 Nov 4;336(4):1136-43
16168956
Mol Cell Biol. 2001 May;21(9):3220-33
11287625
Neurology. 1997 Oct;49(4):1096-105
9339696
Biochem J. 2007 Mar 15;402(3):581-9
17132139
J Biol Chem. 1998 Oct 2;273(40):25552-5
9748217
J Biol Chem. 2001 Nov 16;276(46):43446-54
11551913
Trends Neurosci. 1997 Apr;20(4):154-9
9106355
Acta Neuropathol. 2005 Aug;110(2):165-72
15973543
J Biol Chem. 1998 Dec 11;273(50):33741-9
9837962
J Biol Chem. 2001 Jan 19;276(3):2108-14
11031265