Contribution of APOE promoter polymorphisms to Alzheimer's disease risk.
OBJECTIVE
To determine whether the effects of APOE promoter polymorphisms on AD are independent of the APOE-epsilon4 allele.


BACKGROUND
Recently, the -491 A-->T and -219 G-->T polymorphisms located in the APOE promoter have been suggested to be risk factors for AD. However, the effects of these polymorphisms have not always been reproduced in case-control studies, possibly because of the strong linkage disequilibrium existing at this locus or the characteristics of the populations studied.


METHODS
Data collection was performed from six independent samples (1,732 patients with AD and 1,926 control subjects) genotyped for APOE exon 4 and the two APOE promoter polymorphisms. The risks associated with the APOE polymorphisms for developing AD were estimated using logistic regression procedures and calculation of odds ratios with 95% CI adjusted by age, sex, and collection center. Independence of the APOE promoter polymorphisms was tested by stratification for APOE-epsilon4 and tertile design was used for age stratification.


RESULTS
The independence of the -491 AA genotype was observed in the whole sample whereas the independence of the -219 TT genotype was observed only in the oldest population.


CONCLUSIONS
The -491 and -219 APOE promoter polymorphisms incur risk for AD in addition to risk associated with the APOE-epsilon4 allele, with age accentuating the effect of the -219 TT genotype. Because these polymorphisms appear to influence apoE levels, these results suggest that APOE expression is an important determinant of AD pathogenesis.
Lambert
J-C
JC
INSERM U508, Institut Pasteur de Lille, Lille, France.
Araria-Goumidi
L
L
Myllykangas
L
L
Ellis
C
C
Wang
J C
JC
Bullido
M J
MJ
Harris
J M
JM
Artiga
M J
MJ
Hernandez
D
D
Kwon
J M
JM
Frigard
B
B
Petersen
R C
RC
Cumming
A M
AM
Pasquier
F
F
Sastre
I
I
Tienari
P J
PJ
Frank
A
A
Sulkava
R
R
Morris
J C
JC
St Clair
D
D
Mann
D M
DM
Wavrant-DeVrièze
F
F
Ezquerra-Trabalon
M
M
Amouyel
P
P
Hardy
J
J
Haltia
M
M
Valdivieso
F
F
Goate
A M
AM
Pérez-Tur
J
J
Lendon
C L
CL
Chartier-Harlin
M-C
MC
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000453:epidemiology* / Q000235:genetics*; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012307:Risk Factors
D053327:Apolipoprotein E4; D001057:Apolipoproteins E