A Predominant Mutation in Regulatory Region of SERPINC1 Gene and Venous Thrombosis

Background

Antithrombin (AT) is a critical physiological anticoagulant in haemostasis. SERPINC1, the gene encoding antithrombin, is 13.5kb in length and located on chromosome 1q23-25. Mutations in the SERPINC1 gene may cause antithrombin deficiency and are supposed to confer a high risk for venous thrombosis. However, most mutations reported so far are located in the coding or splicing region of this gene. Therefore, we investigate SERPINC1 gene to identify possible regulatory variants that would increase susceptibility of thrombosis in Chinese people.

Methods and Results

The potential promoter and 5'-untranslated region of SERPINC1 was screened by direct DNA sequencing in 100 individuals diagnosed with unprovoked venous thrombosis. Further genotyping was performed by Restriction Fragment Length Polymorphism (RFLP) analysis in case-control populations (1750 vs 1900). By DNA sequencing, we identified a c.-11.G>A transition, located 11bp upstream from the transcription initiation codon. Next case-control study showed that this mutation was present in ten individuals of thrombosis group and two of control group. All the mutation carriers we identified were heterozygotes. Therefore, individuals carrying the mutant A allele conferred a 5.42-fold increased risk for venous thrombosis (p<0.05) .

Conclusion

The c.-11G>A mutation of SERPINC1 gene is a risk factor for venous thrombosis in the Chinese population. It's the first time that a predominant mutation in the regulatory region of SERPINC1 gene reported to be associated with venous thrombosis in a large population.