Sequence Variants of Toll Like Receptor 4 and Late-Onset Alzheimer's Disease

Yen-Ching Chen,Ping-Keung Yip,Yu Sun,Yi-Ling Huang,Li-Li Wen,Yi-Min Chu,Ta-Fu Chen,Colin Combs

doi:10.1371/journal.pone.0050771

Abstract

BackgroundToll like receptor 4 (TLR4) has been related to inflammation and beta-amyloid deposition in Alzheimer's disease (AD) brain. No study has explored the association between haplotype-tagging single nucleotide polymorphisms (htSNPs) of TLR4 and AD risk previously and ApoE e4 status alone showed low sensitivity in identifying late-onset AD (LOAD) patients.MethodsA total of 269 LOAD patients were recruited from three hospitals in northern Taiwan (2007–2010). Controls (n = 449) were recruited from elderly health checkup and volunteers of the hospital during the same period of time. Five common (frequency≥5%) TLR4 htSNPs were selected to assess the association between TLR4 polymorphisms and the risk of LOAD in the Chinese ethnic population.ResultsHomozygosity of TLR4 rs1927907 was significantly associated with an increased risk of LOAD [TT vs. CC: adjusted odds ratio (AOR) = 2.45, 95% confidence interval (CI) = 1.30–4.64]. After stratification, the association increased further in ApoE e4 non-carriers (AOR = 3.07) and in hypertensive patients (AOR = 3.60). Haplotype GACGG was associated with a decreased risk of LOAD (1 vs. 0 copies: AOR = 0.59, 95% CI = 0.36–0.96; 2 vs. 0 copies: AOR = 0.31, 95% CI = 0.14–0.67) in ApoE e4 non-carriers. ApoE e4 status significantly modified this association (p interaction = 0.01). These associations remained significant after correction for multiple tests.ConclusionsSequence variants of TLR4 were associated with an increased risk of LOAD, especially in ApoE e4 non-carriers and in hypertensive patients. The combination of TLR4 rs1927907 and ApoE e4 significantly increased the screening sensitivity in identifying LOAD patients from 0.4 to 0.7.

Highlights

Alzheimer’s Disease (AD) is the most common cause of dementia, and is characterized by accumulation of extracellular senile plaques, intracellular neurofibrillary tangles, and degenerating neurons [1]
The minor allele frequency (MAFs) of the five single nucleotide polymorphism (SNP) among controls ranged from 11% to 41%, which were similar to the MAFs of Han Chinese in Beijing (CHB) genotype data from the International HapMap Project (7% to 36%, Table 2)
Participants carrying two copies of variant SNP3 had a significantly increased risk of late-onset Alzheimer’s disease (AD) (LOAD) [TT vs. CC: adjusted odds ratios (OR) (AOR) = 2.45, 95% confidence interval (CI) = 1.30–4.64, p = 0.004 Table 3]

Summary

Introduction

Alzheimer’s Disease (AD) is the most common cause of dementia, and is characterized by accumulation of extracellular senile plaques (composed by amyloid-b peptide, Ab), intracellular neurofibrillary tangles (containing hyperphosphorylated tau protein), and degenerating neurons [1]. Beta amyloid (Ab) load has been related to AD pathogenesis via its role in triggering the innate immune response. Toll like receptors (TLRs) recognize various pathogens infection and damaged host cells, which lead to the subsequent inflammation responses [5]. An animal study showed that the Ab load was greater in mutant TLR4 AD mice than that of wild-type mice [11]. These reflect that TLR4 may be an important susceptibility gene to AD via its role in innate immunity. Toll like receptor 4 (TLR4) has been related to inflammation and beta-amyloid deposition in Alzheimer’s disease (AD) brain. No study has explored the association between haplotype-tagging single nucleotide polymorphisms (htSNPs) of TLR4 and AD risk previously and ApoE e4 status alone showed low sensitivity in identifying late-onset AD (LOAD) patients

Objectives

Methods

Results

Conclusion