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Correlation Analysis of CTSB Promoter Polymorphism and Function in Patients with Dilated Cardiomyopathy
Yu Zhou1, Shuang Gao2, Liangcai Ding3
1Department of Cardiology, Affiliated Hospital of Jining Medical University, Jining, China.
Insights
Rare genetic variants in the Cathepsin B (CTSB) gene promoter are associated with dilated cardiomyopathy (DCM). These CTSB variants increase gene transcription, suggesting a role in DCM development and offering potential diagnostic markers.
Area of Science:
- Genetics
- Molecular Biology
- Cardiology
Background:
- Dilated cardiomyopathy (DCM) pathogenesis involves genetic and environmental factors.
- The precise molecular role of Cathepsin B (CTSB) in DCM remains unclear.
- Investigating genetic variations in CTSB may elucidate its contribution to DCM.
Purpose of the Study:
- To investigate the association between rare CTSB gene variants and the occurrence of DCM.
- To understand the functional impact of identified CTSB variants on gene expression and transcription factor binding.
Main Methods:
- A case-control study involving 142 DCM patients and 252 healthy controls.
- Polymerase chain reaction amplification for CTSB variant identification.
- Dual-luciferase reporter assay and electrophoretic mobility shift assay (EMSA) for functional analysis of CTSB variants and transcription factor (TF) interactions.
Main Results:
- Two single-nucleotide polymorphisms (SNPs) in the CTSB promoter were identified: g.4803T>C (rs1293312) and g.4954T>A (rs942670850).
- The g.4803T>C SNP was more prevalent in DCM patients.
- Both identified SNPs significantly enhanced CTSB promoter transcriptional activity and altered TF binding, as confirmed by EMSA.
Conclusions:
- Rare genetic variants g.4803T>C (rs1293312) and g.4954T>A (rs942670850) within the CTSB promoter are identified as rare risk factors for DCM development.
- These CTSB variants influence gene transcription, potentially contributing to DCM pathogenesis.
Abstract:
Dilated cardiomyopathy (DCM) is caused by a combination of genetic susceptibility and environmental factors. Cathepsin B affects the pathogenesis of DCM; however, its molecular mechanism is still unclear. In this study, we examined the association of rare CTSB variants with the occurrence of DCM. This case-control study involved 394 participants: 142 patients with DCM and 252 healthy controls. DNA was extracted from the peripheral leukocytes of all participants, and CTSB variants were analyzed and identified using polymerase chain reaction amplification. Functional analysis was performed using the dual-luciferase reporter assay, and the ability of genetic CTSB variants to bind to transcription factors (TFs) was analyzed and validated using the electrophoretic mobility shift assay (EMSA). Two single-nucleotide polymorphisms (SNPs) were identified in the study population. One SNP, g.4803 T > C (rs1293312), was more common in patients with DCM. A second SNP, g.4954 T > A (rs942670850), was identified in two patients with DCM. Both SNPs significantly enhanced the transcriptional activity of CTSB promoters. An analysis using the TRANSFAC database revealed that these SNPs affect TF binding, which was confirmed using the EMSA. Our results demonstrate that within the CTSB promoter, the genetic variants g.4803T>C (rs1293312) and g.4954 T > A (rs942670850) are rare risk factors for DCM development.
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