Interaction of CTSD and A2M polymorphisms in the risk for Alzheimer's disease.
The proteins cathepsin D, encoded by CTSD gene, and alpha2-macroglobulin, encoded by A2M gene, are involved in the biochemical pathway leading to deposition of beta-amyloid. In these proteins two amino acid polymorphisms (CTSD-Ala/Val C-->T and A2M-Ile/Val A-->G) have been associated with an increased risk for Alzheimer's disease (AD), but conflicting results have been reported. We studied the association and the mutual interactions of the CTSD-C/T and A2M-A/G polymorphisms with sporadic AD in 100 patients with late-onset AD and 136 healthy elderly subjects as controls. The CTSD-T allele and the CTSD-C/T genotype are significantly more frequent in AD than in controls. The odds ratio (OR) for CTSD-T subjects is 1.93 [95% confidence interval (CI)=1.01-3.72], and 2.07 (95% CI=1.01-4.21) after adjustment for age, sex and APOE epsilon4+ status, while no significant association was found for the A2M-A/G polymorphism. The coexistence of the CTSD-T with the A2M-G allele synergistically increased the OR for AD to 2.69 (95% CI=1.13-6.34) [2.82 (95% CI=1.12-7.17) after adjustment], and to 3.29 (95% CI=1.33-8.16) if estimated for the allelic combination. Our data suggest that the CTSD-T allele of the CTSD-C/T polymorphism is associated with an increased relative risk for late-onset AD and, more interestingly, the combination of CTSD-T with the A2M-G allele seems to increase this risk.
Mariani
Elena
E
Institute of Gerontology and Geriatrics, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy.
Seripa
Davide
D
Ingegni
Tiziana
T
Nocentini
Giuseppe
G
Mangialasche
Francesca
F
Ercolani
Sara
S
Cherubini
Antonio
A
Metastasio
Antonio
A
Pilotto
Alberto
A
Senin
Umberto
U
Mecocci
Patrizia
P
D000368:Aged; D000369:Aged, 80 and over; D000409:Alanine / Q000235:genetics; D000544:Alzheimer Disease / Q000235:genetics*; D002402:Cathepsin D / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D007532:Isoleucine / Q000235:genetics; D008297:Male; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D012306:Risk; D014633:Valine / Q000235:genetics; D000511:alpha-Macroglobulins / Q000235:genetics*
D000511:alpha-Macroglobulins; D007532:Isoleucine; D002402:Cathepsin D; D014633:Valine; D000409:Alanine