Detection of New Polymorphic Markers in the Factor V Gene: Association with Factor V Levels in Plasma

Summary

Three novel polymorphisms were found in the repeated region of the large exon 13 of factor V gene, one giving rise to a codon dimorphism (Serl240) and two causing aminoacid substitutions (Hisl299Arg, Leul257Ile). An increasing frequency of the Argl299 (R2 allele) correlated with a decreasing mean plasma factor V activity in the groups of subjects under study, which included 26 unrelated subjects with partial factor V deficiency. Family studies supported the co-inheritance both of low factor V activity and of R2 allele. The reduction of factor V activity associated with the R2 allele was not clinically symptomatic even in the homozygous condition and was characterized by a parallel reduction of antigen in plasma, in which abnormal molecules were not detected. Data suggest that the R2 allele represents a marker in linkage with an unknown defect rather than a functional polymorphism.

These studies provide the first evidence of a genetic component in determining factor V levels in plasma and of a genetic linkage between the factor V gene and factor V deficiency. They also define specific haplotypes which are associated with factor V deficiency or with APC resistance (Arg506Gln) and are valuable fools for the study of factor V defects.

• References

• 1 Nesheim ME, Katzmann JA, Tracy PB, Mann KG. Factor V. Meth Enzy-mol 1981; 80: 249-274
• 2 Wilson DB, Salem HH, Mruk JS, Majerus PW. Biosynthesis of coagulation factor V by a human hepatocellular carcinoma cell line. J Clin Invest 1984; 73: 654-661
• 3 Mazzorana M, Cornillou B, Baffet G, Hubert N, Eloy R, Guguen-Guilluo-zo C. Biosynthesis of factor V by normal adult rat hepatocytes. Thromb Res 1989; 54: 655-675
• 4 Gewirtz AM, Keefer M, Doshi K, Annamalai AE, Chiu HC, Colman RW. Biology of human megakaryocyte factor V. Blood 1986; 67: 1639-1648
• 5 Gewirtz AM, Shapiro C, Shen YM, Boyd R, Colman RW. Cellular and molecular regulation of factor V expression in human megakaryocytes. J Cell Physiol 1992; 153: 277-287
• 6 Tracy PB, Eide LL, Bowie EJW, Mann KG. Radioimmunoassay of factor V in human plasma and platelets. Blood 1982; 60: 59-63
• 7 Esmon CT. The subunit structure of thrombin-activated factor V. J Biol Chem 1979; 254: 964-973
• 8 Monkovic DD, Tracy PB. Activation of human factor V by factor Xa and thrombin. Biochemistry 1990; 29: 1118-1128
• 9 Mann KG, Nesheim ME, Hibbard LS, Tracy PB. The role of factor V in the assembly of the prothrombinase complex. Ann NY Acad Sci 1985; 370: 8
• 10 Clouse LH, Comp PC. The regulation of haemostasis: the protein C system. N Eng J Med 1986; 314: 1298-1304
• 11 Esmon CT. Protein C: biochemistry, physiology, and clinical implications. Blood 1983; 62: 1155-1158
• 12 Walker FJ, Fay PJ. Regulation of blood coagulation by the protein C system. Faseb J 1992; 6: 2561-2567
• 13 Vehar GA, Keyt B, Eaton D, Rodriguez H, O’Brien DP, Rotblat F, Oppermann H, Keck R, Wood WI, Harkins RN, Tuddenham EGD, Lawn RM, Capon DJ. Structure of human factor VIII. Nature 1984; 312: 337-342
• 14 Toole JJ, Knopf JL, Wozney JM, Sultzman LA, Buecker JL, Pittman DD, Kaufman RJ, Brown E, Shoemaker C, Orr EC, Amphlett GW, Foster B, Coe ML, Knutson GJ, Fass DN, Hewick RM. Molecular cloning of a cDNA encoding human antihaemophilic factor. Nature 1984; 312: 342-347
• 15 Chuch WR, Jemigan RL, Toole J, Hewick RM, Knopf J, Knutson GJ, Nesheim ME, Mann KG, Fass DN. Coagulation factors V and VIII and ceruloplasmin constitute a family of structurally related proteins. Proc Natl Acad Sci USA 1984; 81: 6934-6937
• 16 Gitschier J, Wood WI, Goralka TM, Wion KL, Chen EY, Eaton DH, Vehar GA, Capon DJ, Lawon RM. Characterization of the human factor VIII gene. Nature 1984; 312: 326-330
• 17 Jenny RJ, Pittman DD, Toole JJ, Kriz RW, Aldape RA, Hewick RM, Kaufman RJ, Mann KG. Complete cDNA and derived amino acid sequence of human factor V. Proc Natl Acad Sci USA 1987; 84: 4846-4850
• 18 Cripe LD, Moore KD, Kane WH. Structure of the gene for human coagulation factor V. Biochemistry 1992; 31: 3777-3785
• 19 Wang H, Riddell DC, Guinto ER, MacGillivray RT, Hamerton JL. Localization of the gene encoding human factor V to chromosome lq21-25.. Genomics 1988; 2: 324-328
• 20 Shen NLL, Fan ST, Pyati J, Graff R, La Polla RJ, Edgington TS. 1993 The serine protease cofactor factor V is synthesized by lymphocytes. The Journal of Immunology 1988; 150: 2992-3001
• 21 Bayston TA, Ireland H, Olds RJ, Thein SL, Lane DA. A polymorphism in the human coagulation factor V gene. Hum Mol Genet 1994; 3: 2085
• 22 Faioni EM, Franchi F, Asti D, Sacchi E, Bemardi F, Mannucci PM. Resistance to activated protein C in nine thrombophilic families: interference in a protein S functional assay. Thromb Haemost 1993; 70: 1067-1071
• 23 Dahlbäck B. Physiological anticoagulation. Resistance to activated protein C and venous thromboembolism. J Clin Invest 1994; 94: 923-927
• 24 Zöller B, Svensson PJ, He X, Dahlbäck B. Identification of the same factor V gene mutation in 47 out of 50 thrombosis-prone families with inherited resistance to activated protein C. J Clin Invest 1994; 94: 2521-2524
• 25 Beauchamp NJ, Daly ME, Hampto KK, Cooper PC, Preston E, Peake IR. High prevalence of a mutation in the factor V gene within the UK population: relationship to activated protein C resistance and familial thrombosis. Br J Haematol 1994; 88: 219-222
• 26 Svensson PJ, Dahlbäck B. Resistance to activated protein C as a basis for venous thrombosis. New Engl J Med 1994; 330: 517-521
• 27 Bertina RM, Koeleman BPC, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van der Velden PA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-67
• 28 Greengard JS, Sun X, Xu X, Fernandez JA, Griffin JH, Evatt B. Activated protein C resistance caused by Arg506Gln mutation in factor Va. Lancet 1994; 343: 1362-1363
• 29 Majerus PW. Bad blood by mutation. Nature 1994; 369: 14-15
• 30 Dahlbäck B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: Prediction of a cofactor to activated protein C. Proc Natl Acad Sci USA 1993; 90: 1004-1008
• 31 Griffin JH, Evatt B, Wideman C, Fernandez JA. Anticoagulant protein C pathway defective in a majority of thrombophilic patients. Blood 1993; 82: 1989-1993
• 32 Koster T, Rosendaal FR, de Ronde F, Briet E, Vandenbroucke JP, Bertina RM. Venous trombosis due to a poor response to activated Protein C: Leiden thrombophilia study. Lancet 1993; 342: 1503-1506
• 33 Owen PA. 1947 Parahemophilia, hemorragic diathesis due to the absence of a previously unknown clotting factor. Lancet 1993; 1: 446
• 34 Kingsley CS. Familial factor V deficiency: the pattern of heredity. J Med 1954; 23: 323
• 35 Owen CA. Parahemophilia. Arch Intern Med 1955; 95: 194
• 36 Seeler RA. Parahemophilia factor V deficiency. Med Clin North Am 1972; 56: 119
• 37 Miletich JP, Majerus DW, Majerus PW. Patient with congenital factor V deficiency have decreased factor Xa binding sites on their platelets. J Clin Invest 1978; 62: 824-831
• 38 Borchgrevink CF, Owren PA. The hemostatic effect of normal platelets in hemophilia and factor V deficiency. Acta Med Scand 1961; 170: 375-383
• 39 Tracy PB, Giles AR, Mann KG, Eide LL, Hoogendoom H, Rivard GE. Factor V (Quebec): a bleeding diathesis associated with a qualitative platelet Factor V deficiency. J Clin Invest 1984; 74: 1221-1228
• 40 Hayward CPM, Rivard GE, Moore JC, Kelton JG. Identification of an autosomal dominant bleeding disorder with a combined deficiency of platelet factor V. Thromb Haemost 1995; 73: 1190 (Abstr)
• 41 Humphries SE, Cook M, Dubowitz M, Stirling Y, Meade TW. 1987 Role of the genetic variation at the fibrinogen locus in determination of plasma fibrinogen concentrations. Lancet 1995; i: 1452-1455
• 42 Green F, Kelleher C, Wilkes H, Temple A, Meade T, Humphries S. A common genetic polymorphism associated with lower coagulation FVII levels in healthy individuals. Arterioscler Thromb 1991; 11: 540-546
• 43 Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 1970; 227: 680-685
• 44 Miller MA, Palascak JE, Thompson MR, Martello OJ. A modified SDS agarose gel method for determining factor VIII von Willebrand factor multimers using commercially available reagents. Thromb Res 1985; 39: 777-780
• 45 Sacchi E, Pinotti M, Marchetti G, Merati G, Tagliabue L, Mannucci PM, Bemardi F. Protein S mRNA in patients with Protein S deficiency. Thromb Haemost 1995; 73: 746-749
• 46 Monckton DG, Neumann R, Guram T, Fretwell N, Tamaki K, MacLeod A, Jeffreys AJ. Minisatellite mutation rate variation associated with a flanking DNA sequence polymorphism. Nature Genet 1994; 8: 162-170
• 47 Greengard JS, Alhenc-Gelas M, Gandrille S, Emmerich J, Aiach M, Griffin JH. Pseudo-homozygous activated protein C resistance due to coinheritance of heterozygous factor V-R506Q and type I factor V deficiency associated with thrombosis. Thromb Haemost 1995; 73: 1361 (Abstr)