Dataset Information

Sequence variants of toll like receptor 4 and late-onset Alzheimer's disease.

ABSTRACT:

Background

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.

Methods

A 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.

Results

Homozygosity 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.

Conclusions

Sequence 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.

SUBMITTER: Chen YC

PROVIDER: S-EPMC3525588 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Publications

Sequence variants of toll like receptor 4 and late-onset Alzheimer's disease.

Chen Yen-Ching YC Yip Ping-Keung PK Huang Yi-Ling YL Sun Yu Y Wen Li-Li LL Chu Yi-Min YM Chen Ta-Fu TF

PloS one 20121218 12

<h4>Background</h4>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.<h4>Methods</h4>A total of 269 LOAD patients were recruited from three hospitals in northern Taiwan (2007-2010). Controls (n = 4 ...[more]

PMID: 23272070

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Project description:Base excision repair (BER) defects and concomitant oxidative DNA damage accumulation play a role in the etiology and progression of late-onset Alzheimer's disease (LOAD). However, it is not known whether genetic variant(s) of specific BER genes contribute to reduced BER activity in LOAD patients and whether they are associated with risk, development and/or progression of LOAD. Therefore, we performed targeted next generation sequencing for three BER genes, uracil glycosylase (UNG), endonuclease VIII-like DNA glycosylase 1 (NEIL1) and polymerase β (POLβ) including promoter, exonic and intronic regions in peripheral blood samples and postmortem brain tissues (temporal cortex, TC and cerebellum, CE) from LOAD patients, high-pathology control and cognitively normal age-matched controls. In addition, the known LOAD risk factor, APOE was included in this study to test whether any BER gene variants associate with APOE variants, particularly APOE ε4. We show that UNG carry five significant variants (rs1610925, rs2268406, rs80001089, rs1018782 and rs1018783) in blood samples of Turkish LOAD patients compared to age-matched controls and one of them (UNG rs80001089) is also significant in TC from Brazilian LOAD patients (p<0.05). The significant variants present only in CE and TC from LOAD are UNG rs2569987 and POLβ rs1012381950, respectively. There is also significant epistatic relationship (p = 0.0410) between UNG rs80001089 and NEIL1 rs7182283 in TC from LOAD subjects. Our results suggest that significant BER gene variants may be associated with the risk of LOAD in non-APOE ε4 carriers. On the other hand, there are no significant UNG, NEIL1 and POLβ variants that could affect their protein level and function, suggesting that there may be other factors such as post-transcriptional or-translational modifications responsible for the reduced activities and protein levels of these genes in LOAD pathogenesis. Further studies with increased sample size are needed to confirm the relationship between BER variants and LOAD risk.

Dataset Information

Sequence variants of toll like receptor 4 and late-onset Alzheimer's disease.

Background

Methods

Results

Conclusions

Publications

Sequence variants of toll like receptor 4 and late-onset Alzheimer's disease.

Similar Datasets

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