Evaluation of Protein C Gene Polymorphism in Patients with Diagnosis of Pulmonary embolism in Turkish Population

Abstract

Objective: Pulmonary embolism is usually a complication of deep vein thrombosis (DVT) and develops as a result of obstruction of pulmonary artery and/or branches with pieces that ruptured from the DVT of the leg. Pulmonary embolism and DVT is also referred as venous thrombo-embolism (VTE), because two events often remain together. In the studies, it was found that protein C (PROC) deficiency is a risk factor for pulmonary embolism. In this study, we aimed to evaluate the association between pulmonary embolism and PROC gene -1654C>T polymorphism in Turkish population. Methods: The DNAs of 114 pulmonary embolism cases and 120 healthy controls have been analyzed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) to evaluate the relation between PROC gene -1654C>T polymorphism and pulmonary embolism in our study. Statistical analyses were performed by using chisquare and analysis of variance tests. Results: The proportion of individuals with CT genotype carrying polymorphic T allele as heterozygous form was 38.7% in the control group and 21.9% in the pulmonary embolism cases (p=0.047). When demographic and clinical characteristics of cases compared with PROC gene -1654C>T polymorphism, it was observed that the changes in chest CT ratios could be associated with -1654C>T polymorphism (p=0.017). Conclusion: As a result, individuals with CT genotypes carrying the polymorphic T allele as heterozygous form have a lower risk of developing pulmonary embolism.

Keywords

• PROC,VTE,pulmonary embolism,polymorphism

Kaynakça

1. 1. Periard D, Haesler E, Ducrey N, et al. Venous thromboembolic disease in adolescents. Rev Med Suisse 2006;2(51):318-22.
2. 2. Cohen AT, Agnelli G, Anderson FA, et al. VTE Impact Assessment Group in Europe (VITAE). Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality. Thromb Haemost 2007;98(4):756- 64.
3. 3. Deitelzweig S, Jaff MR. Medical management of venous thromboembolic disease. Tech Vasc Interv Radiol 2004;7(2):63-7.
4. 4. Silverstein MD, Heit JA, Mohr DN, et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998;158:585-93.
5. 5. Righini M, Paris S, Le Gal G, et al. Clinical relevance of distal deep vein thrombosis. Rewiew of literature data. Thromb Haemost 2006;95(1):56- 64.
6. 6. Rosendaal FR, Doggen CJ, Zivelin A, et al. Geographic distribution of the 20210 G to A prothrombin variant. Thromb Haemost 1998;79:706-8.
7. 7. De Stefano V, Martinelli I, Mannucci PM, et al. The risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and the G20210A prothrombin mutation. N Engl J Med 1999;341:801-6.
8. 8. Lu Y, Zhao Y, Liu G, et al. Factor V gene G1691A mutation, prothrombin gene G20210A mutation, and MTHFR gene C677T mutation are not risk factors for pulmonary thromboembolism in Chinese population. Thromb Res 2002;106:7-12.

9. 9. Zhu C, Jiang T, Miao Y, et al. The SNPs (- 1654C/T, -1641A/ G and -1476A/T) of protein C promoter are associated with susceptibility to pulmonary thromboembolism in a Chinese population. J Thorac Dis 2014;6(7):943-48.
10. 10. Sugahara Y, Miura O, Hirosawa S, et al. Compound heterozygous protein C deficiency caused by two mutations, Arg-178 to Gln and Cys- 331 to Arg, leading to impaired secretion of mutant protein C. Thromb Haemost 1994;72:814-18.
11. 11. Naito M, Mimuro J, Endo H, et al. Defectives or ting to secretory vesicles in trans-Golgi network is partly responsible for protein C deficiency: molecular mechanisms of impaired secretion of abnormal protein C R169W, R352W, and G376D. Circ Res 2003;92:865-72.
12. 12. Yang LH, Wang MS, Zheng FX, et al. Different impact of two mutations of a novel compound heterozygous protein C deficiency with late onset thrombosis. Genet Mol Res 2014;13(2):2969-77.
13. 13. Esmon CT. The regulation of natural anticoagulant pathways. Science 1987;235:1348-52.
14. 14. Miletich J, Sherman L, Broze G. Absence of thrombosis in subjects with heterozygous protein C deficiency. N Engl J Med 1987;317:991-96.
15. 15. Griffin JH. Control of coagulation reactions. In: Beutler E, Lichtman MA Eds. Williams Hematology, 6th ed. McGraw-Hill 2000;1435-49.
16. 16. Foster DC, Yoshitake S, Davie EW. The nucleotide sequence of the gene for human protein C. Proc Natl Acad Sci USA 1985;82:4673- 77.
17. 17. Spek CA, Poort SR, Bertina RM, et al. Determination of the allelic and haplotype frequencies of three polymorphisms in the promoter region of the human protein C gene. Blood Coagul Fibrinolysis 1994;5:309-11.
18. 18. Spek CA, Koster T, Rosendaal FR, et al. Genotypic variation in the promoter region of the protein C gene is associated with plasma protein C levels and thrombotic risk. Arterioscler Thromb Vasc Biol 1995;15:214-18.
19. 19. Aiach M, Nicaud V, Alhenc-Gelas M, et al. Complex association of protein C gene promoter polymorphism with circulating protein C levels and thrombotic risk. Arterioscler Thromb Vasc Biol 1999;19:1573-76.
20. 20. Tapson VF. Acute Pulmonary Embolism. N Engl J Med 2008;358:1037-52. 21. Griffin JH, Fernandez JA, Gale AJ, et al. Activated protein C. J Thromb Haemost 2007;5(Suppl.1):73–80.
21. 22. Hoshi S, Hijikata M, Togashi Y, et al. Protein C Deficiency in a Family with Thromboembolism and Identified Gene Mutations. Intern Med 2007;46(13):997-1003.
22. 23. Tsay W, Lee YM, Lee SC, et al. Characterization of human protein C gene promoter: insights from natural human mutants. DNA Cell Biol 1996;15:907-19.
23. 24. Zhang YJ, Miao YF, Cheng KB, et al. Protein C polymorphism and susceptibility to PTE in China. Blood Coagul Fibrinolysis 2012;23(8):693-99.
24. 25. Pomp Doggen CJ, Vos HL, Reitsma PH, et al. Polymorphisms in the protein C gene as risk factor for venous thrombosis. Thromb Haemost 2009;101(1):62-7.