Abstract
BackgroundToll-like receptor 2 (TLR2) represents a reasonable functional and positional candidate gene for Alzheimer's disease (AD) as it is located under the linkage region of AD on chromosome 4q, and functionally is involved in the microglia-mediated inflammatory response and amyloid-β clearance. The -196 to -174 del polymorphism affects the TLR2 gene and alters its promoter activity.MethodsWe recruited 800 unrelated Northern Han Chinese individuals comprising 400 late-onset AD (LOAD) patients and 400 healthy controls matched for gender and age. The -196 to -174 del polymorphism in the TLR2 gene was genotyped using the polymerase chain reaction (PCR) method.ResultsThere were significant differences in genotype (P = 0.026) and allele (P = 0.009) frequencies of the -196 to -174 del polymorphism between LOAD patients and controls. The del allele was associated with an increased risk of LOAD (OR = 1.31, 95% CI = 1.07-1.60, Power = 84.9%). When these data were stratified by apolipoprotein E (ApoE) ε4 status, the observed association was confined to ApoE ε4 non-carriers. Logistic regression analysis suggested an association of LOAD with the polymorphism in a recessive model (OR = 1.64, 95% CI = 1.13-2.39, Bonferroni corrected P = 0.03).ConclusionsOur data suggest that the -196 to -174 del/del genotype of TLR2 may increase risk of LOAD in a Northern Han Chinese population.
Highlights
Toll-like receptor 2 (TLR2) represents a reasonable functional and positional candidate gene for Alzheimer’s disease (AD) as it is located under the linkage region of AD on chromosome 4q [1], and is functionally involved in the microglia-mediated inflammatory response and amyloid b (Ab) clearance [2,3,4,5,6]
In order to rule out confounding in our crude association analyses, we reevaluated the polymorphism effect under 3 different models using logistic regression adjusting for age and apolipoprotein E (ApoE) ε4 status (Table 2)
The -196 to -174 del polymorphism was still found to increase the risk of late-onset AD (LOAD) via a recessive model (OR = 1.64, 95% confidence intervals (CI) = 1.132.39, P = 0.01, Bonferroni corrected P = 0.03)
Summary
Toll-like receptor 2 (TLR2) represents a reasonable functional and positional candidate gene for Alzheimer’s disease (AD) as it is located under the linkage region of AD on chromosome 4q, and functionally is involved in the microglia-mediated inflammatory response and amyloid-b clearance. Genetic studies on the TLR2 gene have identified a number of polymorphisms which have been shown to affect host defense, disease progression and be linked to differential disease susceptibilities [7]. A 22-bp nucleotide deletion at position -196 to -174 of the untranslated 5’-region in TLR2 gene is associated with reduced transcriptional activity compared to the wild type allele in luciferase reporter assays [10]. This polymorphism has already been shown to be associated with an increased risk of noncardiac gastric cancer, susceptibility to cervical cancer, hepatitis C viral loads and susceptibility to hepatocellular carcinoma [11,12,13]. In light of the important role that TLR2 plays with respect to the immune response in the pathogenesis of AD [2,3,4,5,6], we hypothesized that the -196 to -174
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