Functional mutation in the promoter region of thrombomodulin gene in relation to carotid atherosclerosis

Yi Heng Li, Chih Hung Chen, Poh Shiow Yeh, Huey Juan Lin, Bi Ing Chang, Jia Chung Lin, How Ran Guo, Hua Lin Wu, Guey Yueh Shi, Ming Liang Lai, Jyh Hong Chen

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35 Citations (Scopus)

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 ≤60 years) were included in the analysis, however, we found the mutation occurred more frequently in participants with carotid atherosclerosis (33.3 vs. 17.3%, odds ratio [OR] = 2.38, 95% confidence interval [CI] = 1.16-4.90, P = 0.027). Multiple logistic regression analyses showed that only diabetes mellitus (OR = 3.11, 95% CI = 1.33-7.30, P = 0.009) and G-33A mutation (OR = 2.46, 95% CI = 1.14-5.29, P = 0.021) were associated independently with carotid atherosclerosis in younger subjects. As assessed by luciferase reporter gene assays, the contructs bearing the G-33A mutation showed a significant decrease (36 ± 12%) in transcriptional activity in comparison with the wild type constructs. Our findings suggest that G-33A mutation reduces the thrombomodulin promoter activity and is associated with carotid atherosclerosis in younger subjects.

Original languageEnglish
Pages (from-to)713-719
Number of pages7
JournalAtherosclerosis
Volume154
Issue number3
DOIs
Publication statusPublished - 2001 Feb 15

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All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

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