The 4,752 C/T polymorphism in the presenilin 1 gene increases the risk of Alzheimer's disease in apolipoprotein E4 carriers.
OBJECTIVE
We sought to establish an association between sporadic Alzheimer's disease (AD) and presenilin 1 (PSEN1) gene polymorphisms in the Japanese population.


METHODS
A 5 kb fragment containing the putative promoter of the PSEN1 gene for randomly selected control subjects was subcloned into plasmid and sequenced to screen novel polymorphisms in this region. Patients and controls were genotyped for five polymorphic markers in the PSEN1 region. We then constructed haplotypes using the computer program HAPLO and compared the frequencies between cases and controls.


METHODS
A total of 189 AD cases (NINCDS-ADRDA criteria) and 240 controls were studied.


RESULTS
We discovered a novel polymorphism with high heterozygosity on -4,752 of the PSEN1 promoter region. A significant association was observed between the -4,752 C/T polymorphism and late-onset AD. The odds ratio for AD associated with the CC vs non-CC genotype was 1.59 (95% CI = 1.01-2.51), while that of epsilon 4 vs non-epsilon 4 in APOE gene was 4.41 (95% CI = 2.72-7.16). The C allele was associated with a further increase in the risk of AD in APOE epsilon 4 carriers. We found 12 major haplotypes using five polymorphisms. The distribution pattern was significantly different between cases and controls.


CONCLUSIONS
The PSEN1 gene -4,752 C/T polymorphism modifies the risk for AD.
Matsubara-Tsutsui
Miho
M
Department of Geriatric Medicine, Ehime University School of Medicine.
Yamagata
Hidehisa
H
Morishima
Atsuyuki
A
Nakura
Jun
J
Mitsuda
Noriaki
N
Kamino
Kouzin
K
Kondo
Ikuko
I
Miki
Tetsuro
T
D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics*; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000235:genetics*; D004252:DNA Mutational Analysis; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D053764:Presenilin-1; D012307:Risk Factors
D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1