Effect of the functional toll-like receptor 4 Asp299Gly polymorphism on susceptibility to late-onset Alzheimer's disease.
Experimental data have shown an upregulated expression of toll-like receptors, particularly toll-like receptor 4 (TLR4), in neurodegeneration. The Asp299Gly polymorphism of the TLR4 gene has been associated with an attenuated receptor signalling and a blunted inflammatory response. In the present study, we sought to determine whether this common genetic variant could influence susceptibility to late-onset Alzheimer's disease (LOAD) in an Italian population sample. A cohort of 277 LOAD patients and 300 cognitively healthy controls were genotyped for the TLR4 Asp299Gly polymorphism using restriction isotyping. The frequency of the minor 299Gly allele was significantly higher in the controls than in the LOAD cases (7.2% versus 3.1%, respectively, P=0.003). Additionally, the frequency of the variant genotypes (Asp/Gly and Gly/Gly) was 13.0% in the controls and 5.4% in LOAD patients (P=0.002). After adjustment for age, gender, and the APOE varepsilon4 carrier status, the odds ratio for the development of LOAD associated with the Asp/Gly and Gly/Gly versus Asp/Asp genotype was 0.37 (95% CI: 0.20-0.69, P=0.002). Our data further support a role for innate immunity in neurodegeneration and give the first evidence that the TLR4 Asp299Gly variant may be protective toward the development of LOAD.
Minoretti
Piercarlo
P
Interdepartmental Center for Research in Molecular Medicine (CIRMC), University of Pavia, Viale Taramelli 24, I-27100 Pavia, Italy.
Gazzaruso
Carmine
C
Vito
Clara Di
CD
Emanuele
Enzo
E
Bianchi
Marika
M
Coen
Enrico
E
Reino
Marta
M
Geroldi
Diego
D
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008297:Male; D009154:Mutation; D010641:Phenotype; D011110:Polymorphism, Genetic; D015995:Prevalence; D018570:Risk Assessment / Q000379:methods*; D012307:Risk Factors; D013223:Statistics as Topic; D051197:Toll-Like Receptor 4 / Q000235:genetics*
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4