The SIRT2 polymorphism rs10410544 and risk of Alzheimer's disease in two Caucasian case-control cohorts.
BACKGROUND
Human sirtuins are a current hotspot for research in neurodegenerative disorders, including Alzheimer's disease (AD). This study investigated whether genetic variants in two members of the sirtuin family, SIRT2 and SIRT3, affected AD susceptibility.


METHODS
A genetic case-control study was performed, comprising 534 probable AD cases and 638 nondemented control subjects from the north of Italy and Canton Ticino, Switzerland (discovery population). The study was focused on SIRT2 rs10410544, SIRT3 rs4980329, and SIRT3 rs536715 single nucleotide polymorphisms (SNPs). These SNPs were genotyped by real-time polymerase chain reaction allelic discrimination assay or restriction fragment length polymorphism. The SNPs rs7412 and rs429358, mapping within the apolipoprotein E (APOE) gene, were genotyped by real-time polymerase chain reaction allelic discrimination assay too. In a replication population comprising 756 AD cases and 847 nondemented control subjects, SIRT2 rs10410544, APOE rs7412, and APOE rs429358 were genotyped as mentioned previously.


RESULTS
In the discovery population, we observed an association between SIRT2 rs10410544 T allele and AD (adjusted odds ratio [OR] = 1.23, 95% confidence interval [CI]: 1.02-1.50, P = .02, after correction for sex, age, and APOE ε4 genotype). The association between AD and SIRT2 rs10410544 T allele was only present in APOE ε4 noncarriers (adjusted OR = 1.29, 95% CI: 1.03-1.61, P = .03). The replication study did not confirm this evidence. However, the combined analysis on the two cohorts detected the association (adjusted OR = 1.17, 95% CI: 1.02-1.35, P = .02), and only APOE ε4 noncarriers were at risk (adjusted OR = 1.2, 95% CI: 1.02-1.43, P = .03).


CONCLUSIONS
The SIRT2 rs10410544 T allele deserves further investigation as a novel minor genetic risk factor for AD in the APOE ε4-negative Caucasian population.
Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Milan, Italy; Golgi Cenci Foundation, Abbiategrasso, Italy.
Letizia
L
Polito
Patrick G
PG
Kehoe
Annalisa
A
Davin
Luisa
L
Benussi
Roberta
R
Ghidoni
Giuliano
G
Binetti
Pierluigi
P
Quadri
Ugo
U
Lucca
Mauro
M
Tettamanti
Francesca
F
Clerici
Silvia
S
Bagnoli
Daniela
D
Galimberti
Benedetta
B
Nacmias
Sandro
S
Sorbi
Antonio
A
Guaita
Elio
E
Scarpini
Claudio
C
Mariani
Gianluigi
G
Forloni
Diego
D
Albani
D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics*; D053327:Apolipoprotein E4 / Q000235:genetics; D001057:Apolipoproteins E / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D060888:Real-Time Polymerase Chain Reaction; D015203:Reproducibility of Results; D012306:Risk; D056565:Sirtuin 2 / Q000235:genetics*; D056566:Sirtuin 3 / Q000235:genetics; D013557:Switzerland; D044465:White People / Q000235:genetics
D053327:Apolipoprotein E4; D001057:Apolipoproteins E; C474199:SIRT2 protein, human; C466093:SIRT3 protein, human; D056565:Sirtuin 2; D056566:Sirtuin 3