title: Interaction of CTSD and A2M polymorphisms in the risk for Alzheimer's disease.
abstract: 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.
authors.affiliation: Institute of Gerontology and Geriatrics, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Mariani
authors.forename: Davide
authors.initials: D
authors.lastname: Seripa
authors.forename: Tiziana
authors.initials: T
authors.lastname: Ingegni
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Nocentini
authors.forename: Francesca
authors.initials: F
authors.lastname: Mangialasche
authors.forename: Sara
authors.initials: S
authors.lastname: Ercolani
authors.forename: Antonio
authors.initials: A
authors.lastname: Cherubini
authors.forename: Antonio
authors.initials: A
authors.lastname: Metastasio
authors.forename: Alberto
authors.initials: A
authors.lastname: Pilotto
authors.forename: Umberto
authors.initials: U
authors.lastname: Senin
authors.forename: Patrizia
authors.initials: P
authors.lastname: Mecocci
mesh_terms: 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*
chemical_list: D000511:alpha-Macroglobulins; D007532:Isoleucine; D002402:Cathepsin D; D014633:Valine; D000409:Alanine