Key result
Dilated cardiomyopathy is linked to decreased leukocyte FKBP5 methylation levels.
Why the study?
The regulatory mechanisms by leukocyte FKBP5 DNA methylation in patients with dilated cardiomyopathy remain unclear.
Case-Control (n=74)
Specific CpG hypomethylation of leukocyte FKBP5 is associated with dilated cardiomyopathy and may contribute to its pathogenesis through immune cell-mediated cardiac remodeling.
Answers are grounded in this paper and cite their sources.
Should not change clinical management of dilated cardiomyopathy; hypothesis-generating for FKBP5 methylation as immune biomarker or target.
Background Blood‐based DNA methylation patterns are linked to types of diseases. FKBP prolyl isomerase 5 (FKBP5), a protein cochaperone, is known to be associated with the inflammatory response, but the regulatory mechanisms by leukocyte FKBP5 DNA methylation in patients with dilated cardiomyopathy (DCM) remain unclear. Methods and Results The present study enrolled patients with DCM (n=31) and age‐matched and sex‐matched control participants (n=43). We assessed FKBP5 CpG (cytosine‐phosphate‐guanine) methylation of CpG islands at the 5′ side as well as putative promoter regions by methylation‐specific quantitative polymerase chain reaction using leukocyte DNA isolated from the peripheral blood. FKBP5 CpG methylation levels at the CpG island of the gene body and the promoter regions were significantly decreased in patients with DCM. Leukocyte FKBP5 and IL‐1β (interleukin 1β) mRNA expression levels were significantly higher in patients with DCM than in controls. The protein expressions of DNMT1 (DNA methyltransferase 1) and DNMT3A (DNA methyltransferase 3A) in leukocytes were significantly reduced in patients with DCM. In vitro methylation assay revealed that FKBP5 promoter activity was inhibited at the methylated conditions in response to immune stimulation, suggesting that the decreased FKBP5 CpG methylation was functionally associated with elevation of FKBP5 mRNA expressions. Histological analysis using a mouse model with pressure overload showed that FKBP5‐expressing cells were substantially infiltrated in the myocardial interstitium in the failing hearts, indicating a possible role of FKBP5 expressions of immune cells in the cardiac remodeling. Conclusions Our findings demonstrate a link between specific CpG hypomethylation of leukocyte FKBP5 and DCM. Blood‐based epigenetic modification in FKBP5 may be a novel molecular mechanism that contributes to the pathogenesis of DCM.
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A 2021 study conducted a case-control in Dilated Cardiomyopathy (n=74). Dilated cardiomyopathy vs. Age- and sex-matched controls was evaluated on FKBP5 CpG methylation levels at the CpG island of the gene body and the promoter regions. Leukocyte FKBP5 CpG methylation levels were significantly decreased in patients with dilated cardiomyopathy compared to age- and sex-matched controls.
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