Dataset Information

Association of rs2062323 in the TREM1 gene with Alzheimer's disease and cerebrospinal fluid-soluble TREM2.

ABSTRACT:

Introduction and aims

Genetic variations play a significant role in determining an individual's AD susceptibility. Research on the connection between AD and TREM1 gene polymorphisms (SNPs) remained lacking. We sought to examine the associations between TREM1 SNPs and AD.

Methods

Based on the 1000 Genomes Project data, linkage disequilibrium (LD) analyses were utilized to screen for candidate SNPs in the TREM1 gene. AD cases (1081) and healthy control subjects (870) were collected and genotyped, and the associations between candidate SNPs and AD risk were analyzed. We explored the associations between target SNP and AD biomarkers. Moreover, 842 individuals from ADNI were selected to verify these results. Linear mixed models were used to estimate associations between the target SNP and longitudinal cognitive changes.

Results

The rs2062323 was identified to be associated with AD risk in the Han population, and rs2062323T carriers had a lower AD risk (co-dominant model: OR, 0.67, 95% CI, 0.51-0.88, p = 0.0037; additive model: OR, 0.82, 95% CI, 0.72-0.94, p = 0.0032). Cerebrospinal fluid (CSF) sTREM2 levels were significantly increased in middle-aged rs2062323T carriers (additive model: β = 0.18, p = 0.0348). We also found significantly elevated levels of CSF sTREM2 in the ADNI. The rate of cognitive decline slowed down in rs2062323T carriers.

Conclusions

This study is the first to identify significant associations between TREM1 rs2062323 and AD risk. The rs2062323T may be involved in AD by regulating the expression of TREM1, TREML1, TREM2, and sTREM2. The TREM family is expected to be a potential therapeutic target for AD.

SUBMITTER: Wang ZT

PROVIDER: S-EPMC10173721 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Publications

Association of rs2062323 in the TREM1 gene with Alzheimer's disease and cerebrospinal fluid-soluble TREM2.

Wang Zuo-Teng ZT Fu Yan Y Chen Shi-Dong SD Huang Yu-Yuan YY Ma Ya-Hui YH Wang Yan-Jiang YJ Tan Lan L Yu Jin-Tai JT

CNS neuroscience & therapeutics 20230223 6

<h4>Introduction and aims</h4>Genetic variations play a significant role in determining an individual's AD susceptibility. Research on the connection between AD and TREM1 gene polymorphisms (SNPs) remained lacking. We sought to examine the associations between TREM1 SNPs and AD.<h4>Methods</h4>Based on the 1000 Genomes Project data, linkage disequilibrium (LD) analyses were utilized to screen for candidate SNPs in the TREM1 gene. AD cases (1081) and healthy control subjects (870) were collected ...[more]

PMID: 36815315

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Project description:BACKGROUND:Reliable biomarkers of frontotemporal dementia (FTD) are currently lacking. FTD may be associated with chronic immune dysfunction, microglial activation and raised inflammatory markers, particularly in progranulin (GRN) mutation carriers. Levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2) are elevated in Alzheimer's disease (AD), but they have not been fully explored in FTD. METHODS:We investigated whether cerebrospinal fluid (CSF) sTREM2 levels differ between FTD and controls, across different clinical and genetic subtypes of FTD, or between individuals with FTD due to AD versus non-AD pathology (based on CSF neurodegenerative biomarkers). We also assessed relationships between CSF sTREM2 and other CSF biomarkers (total tau [T-tau], tau phosphorylated at position threonine-181 [P-tau] and ?-amyloid 1-42 [A?42]) and age and disease duration. Biomarker levels were measured using immunoassays in 17 healthy controls and 64 patients with FTD (behavioural variant FTD, n?=?20; primary progressive aphasia, n?=?44). Ten of 64 had familial FTD, with mutations in GRN (n?=?3), MAPT (n?=?4), or C9orf72 (n?=?3). Fifteen of 64 had neurodegenerative biomarkers consistent with AD pathology (11 of whom had logopenic variant PPA). Levels were compared using multivariable linear regressions. RESULTS:CSF sTREM2 levels did not differ between FTD and controls or between clinical subgroups. However, GRN mutation carriers had higher levels than controls (mean ([SD]?=?9.7 [2.9] vs. 6.8 [1.6] ng/ml; P?= 0.028) and MAPT (3.9 [1.5] ng/ml; P?=?0.003] or C9orf72 [4.6 [1.8] ng/ml; P?=?0.006) mutation carriers. Individuals with AD-like CSF had higher sTREM2 levels than those with non-AD-like CSF (9.0 [3.6] vs. 6.9 [3.0] ng/ml; P?=?0.029). CSF sTREM2 levels were associated with T-tau levels in control and FTD groups and also with P-tau in those with FTD and AD-like CSF. CSF sTREM2 levels were influenced by both age and disease duration in FTD. CONCLUSIONS:Although CSF sTREM2 levels are not raised in FTD overall or in a particular clinical subtype of FTD, levels are raised in familial FTD associated with GRN mutations and in FTD syndromes due to AD pathology. Because CSF sTREM2 levels correlate with a marker of neuronal injury (T-tau), sTREM2 should be explored as a biomarker of disease intensity in future longitudinal studies of FTD.

Dataset Information

Association of rs2062323 in the TREM1 gene with Alzheimer's disease and cerebrospinal fluid-soluble TREM2.

Introduction and aims

Methods

Results

Conclusions

Publications

Association of rs2062323 in the TREM1 gene with Alzheimer's disease and cerebrospinal fluid-soluble TREM2.

Similar Datasets

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