Genetic association of CTNNA3 with late-onset Alzheimer's disease in females.
Alzheimer's disease (AD), the most common form of dementia in the elderly, was found to exhibit a trend toward a higher risk in females than in males through epidemiological studies. Therefore, we hypothesized that gender-related genetic risks could exist. To reveal the ones for late-onset AD (LOAD), we extended our previous genetic work on chromosome 10q (genomic region, 60-107 Mb), and single nucleotide polymorphism (SNP)-based genetic association analyses were performed on the same chromosomal region, where the existence of genetic risk factors for plasma Abeta42 elevation in LOAD was implied on a linkage analysis. Two-step screening of 1140 SNPs was carried out using a total of 1408 subjects with the APOE-epsilon3*3 genotype: we first genotyped an exploratory sample set (LOAD, 363; control, 337), and then genotyped some associated SNPs in a validation sample set (LOAD, 336; control, 372). Seven SNPs, spanning about 38 kb, in intron 9 of CTNNA3 were found to show multiple-hit association with LOAD in females, and exhibited more significant association on Mantel-Haenszel test (allelic P-values(MH-F) = 0.000005945-0.0007658). Multiple logistic regression analysis of a total of 2762 subjects (LOAD, 1313; controls, 1449) demonstrated that one of the seven SNPs directly interacted with the female gender, but not with the male gender. Furthermore, we found that this SNP exhibited no interaction with the APOE-epsilon4 allele. Our data suggest that CTNNA3 may affect LOAD through a female-specific mechanism independent of the APOE-epsilon4 allele.
Miyashita
Akinori
A
Center for Bioresources, Brain Research Institute, Niigata University, Niigata, Japan.
Arai
Hiroyuki
H
Asada
Takashi
T
Imagawa
Masaki
M
Matsubara
Etsuro
E
Shoji
Mikio
M
Higuchi
Susumu
S
Urakami
Katsuya
K
Kakita
Akiyoshi
A
Takahashi
Hitoshi
H
Toyabe
Shinichi
S
Akazawa
Kohei
K
Kanazawa
Ichiro
I
Ihara
Yasuo
Y
Kuwano
Ryozo
R
D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000544:Alzheimer Disease / Q000097:blood / Q000209:etiology / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000097:blood; D053327:Apolipoprotein E4 / Q000235:genetics; D016022:Case-Control Studies; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D005260:Female; D006801:Humans; D015810:Linkage Disequilibrium; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000097:blood; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012737:Sex Factors; D051178:alpha Catenin / Q000235:genetics*
D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; C441963:CTNNA3 protein, human; D010446:Peptide Fragments; D051178:alpha Catenin; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)