Concordant association of insulin degrading enzyme gene (IDE) variants with IDE mRNA, Abeta, and Alzheimer's disease.
BACKGROUND
The insulin-degrading enzyme gene (IDE) is a strong functional and positional candidate for late onset Alzheimer's disease (LOAD).


RESULTS
We examined conserved regions of IDE and its 10 kb flanks in 269 AD cases and 252 controls thereby identifying 17 putative functional polymorphisms. These variants formed eleven haplotypes that were tagged with ten variants. Four of these showed significant association with IDE transcript levels in samples from 194 LOAD cerebella. The strongest, rs6583817, which has not previously been reported, showed unequivocal association (p = 1.5x10(-8), fold-increase = 2.12,); the eleven haplotypes were also significantly associated with transcript levels (global p = 0.003). Using an in vitro dual luciferase reporter assay, we found that rs6583817 increases reporter gene expression in Be(2)-C (p = 0.006) and HepG2 (p = 0.02) cell lines. Furthermore, using data from a recent genome-wide association study of two Croatian isolated populations (n = 1,879), we identified a proxy for rs6583817 that associated significantly with decreased plasma Abeta40 levels (ss = -0.124, p = 0.011) and total measured plasma Abeta levels (b = -0.130, p = 0.009). Finally, rs6583817 was associated with decreased risk of LOAD in 3,891 AD cases and 3,605 controls. (OR = 0.87, p = 0.03), and the eleven IDE haplotypes (global p = 0.02) also showed significant association.


CONCLUSIONS
Thus, a previously unreported variant unequivocally associated with increased IDE expression was also associated with reduced plasma Abeta40 and decreased LOAD susceptibility. Genetic association between LOAD and IDE has been difficult to replicate. Our findings suggest that targeted testing of expression SNPs (eSNPs) strongly associated with altered transcript levels in autopsy brain samples may be a powerful way to identify genetic associations with LOAD that would otherwise be difficult to detect.
Carrasquillo
Minerva M
MM
Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, United States of America.
Belbin
Olivia
O
Zou
Fanggeng
F
Allen
Mariet
M
Ertekin-Taner
Nilufer
N
Ansari
Morad
M
Wilcox
Samantha L
SL
Kashino
Mariah R
MR
Ma
Li
L
Younkin
Linda H
LH
Younkin
Samuel G
SG
Younkin
Curtis S
CS
Dincman
Toros A
TA
Howard
Melissa E
ME
Howell
Chanley C
CC
Stanton
Chloe M
CM
Watson
Christopher M
CM
Crump
Michael
M
Vitart
Veronique
V
Hayward
Caroline
C
Hastie
Nicholas D
ND
Rudan
Igor
I
Campbell
Harry
H
Polasek
Ozren
O
Brown
Kristelle
K
Passmore
Peter
P
Craig
David
D
McGuinness
Bernadette
B
Todd
Stephen
S
Kehoe
Patrick G
PG
Mann
David M
DM
Smith
A David
AD
Beaumont
Helen
H
Warden
Donald
D
Holmes
Clive
C
Heun
Reinhard
R
Kölsch
Heike
H
Kalsheker
Noor
N
Pankratz
V Shane
VS
Dickson
Dennis W
DW
Graff-Radford
Neill R
NR
Petersen
Ronald C
RC
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Alan F
AF
Younkin
Steven G
SG
Morgan
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D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000235:genetics*; D016022:Case-Control Studies; D006801:Humans; D007339:Insulysin / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*
D016229:Amyloid beta-Peptides; D012333:RNA, Messenger; D007339:Insulysin