Abstract
Coagulation factor XI (FXI) is essential for normal function of the intrinsic pathway of blood coagulation. A nucleotide variant (rs3756008) in the promoter region of the FXI gene was recently reported for association with venous thromboembolism. This study aimed to examine promoter activity of the rs3756008 or other variants linked with it. Luciferase assay was analyzed with minigenes including haplotypes (AA with frequency of 0.62 and TG with frequency of 0.38) of 2 completely linked nucleotide variants (rs3756008 and rs3756009) in 5′-upstream region of the FXI gene. While their expression did not differ in hepatic cell (P > 0.05), the major haplotype (AA) made a significantly more expression (P < 0.05) than the minor haplotype (TG) in human embryonic kidney 293 cells. Further luciferase analysis with additional haplotypes (artificial; TA, AG) revealed that the large expression was caused by the major allele of rs3756008 (P < 0.05), but not by that of rs3756009 (P > 0.05). We suggested that the minor allele of rs3756008 in the promoter of FXI gene could reduce its expression in kidney.
Similar content being viewed by others
References
Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J (2008) Harrison’s principles of internal medicine. In: Konkle BA (ed) Bleeding and thromobosis, 17th edn. McGrau-Hill, New York, pp 363–369
Meijers JC, Tekelenburg WL, Bouma BN, Bertina RM, Rosendaal FR (2000) High levels of coagulation factor XI as a risk factor for venous thrombosis. N Engl J Med 342:696–701
Tarumi T, Kravtsov DV, Zhao M, Williams SM, Gailani D (2002) Cloning and characterization of the human factor XI gene promoter: transcription factor hepatocyte nuclear factor 4alpha (HNF-4alpha) is required for hepatocyte-specific expression of factor XI. J Biol Chem 277:18510–18516
Sabater-Lleal M, Martinez-Perez A, Buil A, Folkersen L, Souto JC, Bruzelius M, Borrell M, Odeberg J, Silveira A, Eriksson P, Almasy L, Hamsten A, Soria JM (2012) A genome-wide association study identifies KNG1 as a genetic determinant of plasma factor XI level and activated partial thromboplastin time. Arterioscler Thromb Vasc Biol 32:2008–2016
Zhang H, Lowenberg EC, Crosby JR, MacLeod AR, Zhao C, Gao D, Black C, Revenko AS, Meijers JC, Stroes ES, Levi M, Monia BP (2010) Inhibition of the intrinsic coagulation pathway factor XI by antisense oligonucleotides: a novel antithrombotic strategy with lowered bleeding risk. Blood 116:4684–4692
Austin H, De Staercke C, Lally C, Bezemer ID, Rosendaal FR, Hooper WC (2011) New gene variants associated with venous thrombosis: a replication study in White and Black Americans. J Thromb Haemost 9:489–495
Germain M, Saut N, Greliche N, Dina C, Lambert JC, Perret C, Cohen W, Oudot-Mellakh T, Antoni G, Alessi MC, Zelenika D, Cambien F, Tiret L, Bertrand M, Dupuy AM, Letenneur L, Lathrop M, Emmerich J, Amouyel P, Treqouet DA, Morange PE (2011) Genetics of venous thrombosis: insights from a new genome wide association study. PLoS ONE 6:e25581
Martincic D, Kravtsov V, Gailani D (1999) Factor XI messenger RNA in human platelets. Blood 94:3397–3404
Cheng Q, Kantz J, Poffenberger G, Powers AC, Gailani D (2008) Factor XI protein in human pancreas and kidney. Thromb Haemost 100:158–160
Poli D, Zanazzi M, Antonucci E, Marcucci R, Rosati A, Bertoni E, Salvadori M, Liotta AA, Abbate R, Prisco D, Gensini GF (2005) High rate of recurrence in renal transplant recipients after a first episode of venous thromboembolism. Transplantation 80:789–793
Wattanakit K, Cushman M (2009) Chronic kidney disease and venous thromboembolism: epidemiology and mechanisms. Curr Opin Pulm Med 15:408–412
Wattanakit K, Cushman M, Stehman-Breen C, Heckbert SR, Folsom AR (2008) Chronic kidney disease increases risk for venous thromboembolism. J Am Soc Nephrol 19:135–140
Rabelink TJ, Zwaginga JJ, Koomans HA, Sixma JJ (1994) Thrombosis and hemostasis in renal disease. Kidney Int 46:287–296
He R, Chen D, He S (2012) Factor XI: hemostasis, thrombosis, and antithrombosis. Thromb Res 129:541–550
Di Cera E (2007) Thrombin as procoagulant and anticoagulant. J Thromb Haemost 5:196–202
Rugeri L, Quelin F, Chatard B, De Mazancourt P, Negrier C, Dargaud Y (2010) Thrombin generation in patients with factor XI deficiency and clinical bleeding risk. Haemophilia 16:771–777
Tsai HM (2006) ADAMTS13 and microvascular thrombosis. Expert Rev Cardiovasc Ther 4:813–825
Anderson PJ, Gailani D, Feys HB, Gao W, Majerus EM, Vanhoorelbeke K, Sadler JE (2007) Factor XI/ADAMTS13 complexes are quantitatively insignificant in human plasma. Haematologica 92:1419–1422
Mikhailidis DP, Fonseca VA, Barradas MA, Jeremy JY, Dandona P (1987) Platelet activation following intravenous injection of a conventional heparin: absence of effect with a low molecular weight heparinoid (Org 10172). Br J Clin Pharmacol 24:415–424
Meltzer ME, Lisman T, de Groot PG, Meijers JC, Ie Cessie S, Doggen CJ, Rosendaal FR (2010) Venous thrombosis risk associated with plasma hypofibrinolysis is explained by elevated plasma levels of TAFI and PAI-1. Blood 116:113–121
Hrafnkelsdottir T, Ottosson P, Gudnason T, Samuelsson O, Jern S (2004) Impaired endothelial release of tissue-type plasmogen activator in patients with chronic kidney disease and hypertension. Hypertension 44:300–304
Brodsky JB, Burgess GE III (1975) Pulmonary embolism with factor XI deficiency. JAMA 1156:234–237
Bolton-Maggs PH, Peretz H, Butler R, Mountford R, Keeney S, Zacharski L, Zivelin A, Seligsohn U (2004) A common ancestral mutation (C128X) occurring in 11 non-Jewish families from the UK with factor XI deficiency. J Thromb Haemost 2:1–7
von dem Borne PA, Bajzar L, Meijers JC, Nesheim ME, Bouma BN (1997) Thrombin-mediated activation of factor XI results in a thrombin-activatable fibrinolysis inhibitor-dependent inhibition of fibrinolysis. J Clin Invest 99:2323–2327
Tuszynski G, Bevacqua S, Schmaier A, Colman R, Walsh P (1982) Factor XI antigen and activity in human platelets. Blood 59:1148–1156
Pedicord DL, Seiffert D, Blat Y (2007) Feedback activation of factor XI by thrombin does not occur in plasma. Proc Natl Acad Sci USA 104:12860–12885
Bicer M, Yanar M, Tuydes O (2009) Spontaneous deep vein thrombosis in hemophilia A: a case reports. Cases J 2:6390
Pruthi RK, Heit JA, Green MM, Emiliusen LM, Nichols WL, Wilke JL, Gastineau DA (2000) Venous thromboembolism after hip fracture surgery in a patient with haemophilia B and factor V Arg506Gln (factor V Leiden). Haemophilia 6:631–634
Casserly LF, Reddy SM, Dember LM (2000) Venous thromboembolism in end-stage renal disease. Am J Kidney Dis 36:405–411
Kamphuisen PW, Rosendaal FR, Eikenboom JC, Bos R, Bertina RM (2000) Factor V antigen levels and venous thrombosis: risk profile, interaction with factor V leiden, and relation with factor VIII antigen levels. Arterioscler Thromb Vasc Biol 20:1382–1386
Boehlen F, Hohlfeld P, Extermann P et al (2000) Platelet count at term pregnancy: a reappraisal of the threshold. Obvstet Gynecol 95:29–33
Hellgren M, Blomback M (1981) Studies on blood coagulation and fibrinolysis in pregnancy, during delivery and in the puerperium. I. Normal condition. Gynecol Obstet Invest 12:141–154
Salvagno GL, Lippi G, Franchini M, Targher G, Montagnana M, Franchi M, Guidi GC (2007) The cost-benefit ratio of screening pregnant women for thrombophilia. Blood Transfus 5:189–203
Acknowledgments
This study was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science, and Technology (Grant No. 2012002096).
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Kong, M., Kim, Y. & Lee, C. Functional investigation of a venous thromboembolism GWAS signal in a promoter region of coagulation factor XI gene. Mol Biol Rep 41, 2015–2019 (2014). https://doi.org/10.1007/s11033-014-3049-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11033-014-3049-1