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DNA methylation changes at TREM2 intron 1 and TREM2 mRNA expression in patients with Alzheimer's disease
Yuki Ozaki1, Yuta Yoshino1, Kiyohiro Yamazaki1
1Department of Neuropsychiatry, Molecules and Function, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan.
Objectives:
Recent genome-wide association studies revealed that Triggering receptor expressed on myeloid cells 2 (TREM2) was associated with Alzheimer's disease (AD) and other neurodegenerative diseases. We previously reported that TREM2 mRNA is highly expressed in leukocytes of AD patients compared to those in healthy controls. However, the mechanism of TREM2 expression change is still not known. In this study, we examined the involvement of the DNA methylation status of TREM2 in its high gene expression.
Materials And Methods:
Fifty AD subjects and age- and sex-matched control subjects were recruited (25 males, 25 females; 79.9 ± 5.27 and 79.4 ± 3.92 years old, respectively). TREM2 mRNA expression and the percentage of DNA methylation at four CpG sites in intron 1 of TREM2 were studied using their peripheral leukocytes.
Results:
We confirmed that TREM2 mRNA expression in leukocytes was significantly higher in AD patients than in controls (p = 0.007). The percentage methylation at three CpG sites in TREM2 intron 1 was significantly lower in AD subjects than in control: CpG1, 9.4 ± 3.2 vs 11.9 ± 4.0 (p = 0.001); CpG2, 15.4 ± 4.9 vs 19.1 ± 4.8 (p = 0.001); CpG3, 20.8 ± 5.5 vs 25.5 ± 5.4 (p < 0.001); and the average percentage methylation of all CpG sites: 13.5 ± 3.7 vs 16.1 ± 3.8 (p = 0.002), respectively. In addition, there were significant negative correlations between TREM2 mRNA expression and the percentage DNA methylation of each of CpG sites (CpG1, r = -0.416, p < 0.001; CpG2, r = -0.510, p < 0.001; CpG3, r = -0.504, p < 0.001; CpG4, r = -0.356, p < 0.001).
Conclusions:
Lower DNA methylation at TREM2 intron 1 caused higher TREM2 mRNA expression in the leukocytes of AD subjects versus controls and may be a biomarker for AD.
Insights
Lower DNA methylation in Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) intron 1 is linked to higher TREM2 mRNA expression in Alzheimer's disease (AD) patients. This epigenetic change may serve as a potential biomarker for AD.
Area of Science:
- Neuroscience
- Genetics
- Immunology
Background:
- Genome-wide association studies link TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) to Alzheimer's disease (AD).
- Previous research indicated elevated TREM2 mRNA in leukocytes of AD patients compared to controls.
- The precise mechanism driving altered TREM2 expression in AD remains unclear.
Purpose of the Study:
- To investigate the role of DNA methylation status of TREM2 in its elevated gene expression in Alzheimer's disease.
- To explore the potential of TREM2 DNA methylation as a biomarker for AD.
Main Methods:
- Peripheral leukocytes were collected from 50 AD subjects and 50 age- and sex-matched controls.
- TREM2 mRNA expression levels were quantified.
- DNA methylation percentages at four CpG sites within TREM2 intron 1 were analyzed.
Main Results:
- TREM2 mRNA expression was significantly higher in AD patients' leukocytes (p=0.007).
- AD subjects showed significantly lower DNA methylation at three CpG sites in TREM2 intron 1 compared to controls (p<0.001).
- Significant negative correlations were observed between TREM2 mRNA expression and DNA methylation levels at all four CpG sites (r=-0.356 to -0.510, p<0.001).
Conclusions:
- Reduced DNA methylation at TREM2 intron 1 is associated with increased TREM2 mRNA expression in the leukocytes of AD patients.
- This epigenetic alteration in TREM2 may represent a novel biomarker for Alzheimer's disease.