Research On The Relationship Between The Protein C And Thrombomodulin Gene Polymorphisms And Ischemic Stroke

Objective:Protein C （PC） is a well-characterized anticoagulant enzyme. However, the association between PC and ischemic stroke （IS） remains controversial. The aim of the present study was to investigate whether any genetic variant in the human protein C gene （PROC） was associated with susceptibility to IS in the Chinese Han population.Methods:All exons and the5’-and3’-untranslated regions of PROC were initially sequenced to identify informative variants. Potential abnormal variants were analyzed in a population of788IS patients and1200healthy controls. The analysis was stratified by stroke etiology, and the results were replicated in262IS patients and288healthy controls. Finally, functional studies were performed to evaluate the effects of the variant.Results:A3-nucleotide duplication/deletion variant （c.574₅76del） was identified and found to be significantly associated with IS （OR=2.56;95%CI:1.45-4.52, p=0.001）. Stratification by stroke etiology after adjustment for IS risk factors showed that this association persisted in the lacunar and cardioembolic subtypes （p<0.001and p=0.008, respectively） but not in the atherothrombotic and undetermined subtypes （p=0.070and p=0.998, respectively）. The functional studies showed a significant difference in the anticoagulant activity of PC in c.574₅76del carriers and non-carriers （p<0.001）.Conclusion:Our results suggested that the novel PROC c.574₅76del variant is a possible genetic determinant of an increased risk of IS and diminished anticoagulant activity of PC. Objective:Ischemic stroke （IS） is the leading cause of long-term adult disability and the second leading cause of death in China, and recently this disease rate is rising. Thrombomodulin （TM） is the important part of protein C pathway, the changes of structure and function can destroy the balance between the coagulation and anticoagulation system. The relationship between TM and artery thrombosis remains controversial c.-151G>T variant is located in the promotor area of THBD gene, which is the coding gene of TM. c.-151G>T variant was found to associated with the development of venous thrombosis, so the aim of our study was to investigate whether the c.-151G>T variant was associated with susceptibility to IS in the Chinese Han population.Methods:A case-control study was introduced. The c.-151G>T variant was analyzed in the discovery group （667IS patients and872healthy controls） and replication group （277IS patients and381healthy controls）. The analysis was stratified by stroke etiology, according to the different causes all patients were divided into two subgroups: atherothrombotic subtype and lacunar subtype. PCR-RFLP method was used to analyzed the polymorphism of c.-151G>T and statistical analysis was performed to evaluate the correlation between c.-151G>T variant and IS.Results:c.-151G>T variant had some correlations with IS. In all samples, the heterozygous genotype for this variant conferred an approximately2.05-fold increased risk of IS, but it had no significant difference because p=0.105. Stratification by stroke etiology after adjustment for IS risk factors showed that c.-151G>T was significantly associated with IS in the atherothrombotic subtype （OR=2.43;95%CI:1.03-4.58; p=0.043） but not in the lacunar subtype （OR=0.26;95%CI:0.03-2.21; p=0.220）.Conclusion:Our results suggested that c.-151G>T variant is a possible genetic determinant of an increased risk of atherothrombotic IS.