Functional mutation in the promoter region of thrombomodulin gene in relation to carotid atherosclerosis
1Department of Internal Medicine, College of Medicine, National Cheng Kung University, 138 Sheng Li Road, 70428, Tainan, Taiwan, ROC.
Insights
The thrombomodulin G-33A promoter mutation reduces gene activity. This genetic factor is linked to carotid atherosclerosis in younger individuals, suggesting a potential risk for vascular disease.
Area of Science:
- Cardiovascular Genetics
- Molecular Biology
- Vascular Medicine
Background:
- Thrombomodulin is a key endothelial anticoagulant protein.
- A G-33A promoter mutation in the thrombomodulin gene has been linked to coronary artery disease.
- The role of this mutation in ischemic stroke and carotid atherosclerosis requires further investigation.
Purpose of the Study:
- To investigate the thrombomodulin G-33A promoter mutation as a risk factor for ischemic stroke and carotid atherosclerosis.
- To evaluate the functional significance of the G-33A mutation on thrombomodulin gene expression.
Main Methods:
- Case-control study involving 333 ischemic stroke patients and 257 controls.
- Carotid atherosclerosis assessed by Duplex scanning.
- Thrombomodulin G-33A mutation detected by single-strand conformation polymorphism.
- Functional analysis using luciferase reporter gene assays.
Main Results:
- No significant difference in G-33A mutation frequency between stroke patients and controls.
- Similar mutation frequency in participants with and without carotid atherosclerosis overall.
- In subjects ≤60 years, G-33A mutation was more frequent in those with carotid atherosclerosis (OR=2.38, P=0.027).
- Diabetes and G-33A mutation were independent risk factors for carotid atherosclerosis in younger subjects.
- Luciferase assays showed a 36% decrease in transcriptional activity for the G-33A mutation.
Conclusions:
- The thrombomodulin G-33A mutation significantly reduces thrombomodulin promoter activity.
- This mutation is associated with carotid atherosclerosis in younger individuals.
- The G-33A mutation may represent a specific genetic risk factor for vascular disease in certain populations.
Abstract:
Thrombomodulin is an important endothelial anticoagulant protein that decreases thrombin activity and activates protein C. Our recent study has shown that the G-33A promoter mutation of thrombomodulin gene is associated with coronary artery disease. This study was conducted to determine whether the G-33A mutation in the promoter region of thrombomodulin gene is a genetic risk factor for ischemic stroke or carotid atherosclerosis. The functional significance of this mutation was also evaluated. We recruited 333 patients (mean age 64 years, 59% male) with ischemic stroke and 257 age- and sex-matched controls. In all study participants, carotid atherosclerosis was assessed by Duplex scanning, and thrombomodulin G-33A promoter mutation was detected by single-strand conformation polymorphism. Luciferase reporter gene assay was used to assess the influence of this mutation on thrombomodulin promoter activity. There was no significant difference in the thrombomodulin G-33A mutation frequency (GA+AA genotypes) between the stroke and the control groups (18.3 vs. 24. 1%, P=0.105). The G-33A mutation frequency was also similar between the study participants with and without carotid atherosclerosis (22.2 vs. 19.8%, P=0.550). When only younger subjects (age
