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DOI: 10.1055/s-0037-1613822
The G20210A Prothrombin Polymorphism Is not Associated with Increased Thromboembolic Risk in a Large Protein C Deficient Kindred
Supported in part by the Public Health Service National Heart, Lung and Blood Institute, Grant No. P01 HL46703 “Surface dependent reactions in thrombosis and thrombolysis”. The analysis in this study was partially supported by Grant No. HD17463 from NIH/NICHD.Publication History
Received
08 February 1999
Accepted after revision
08 September 1999
Publication Date:
14 December 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/200003/lookinside/thumbnails/10-1055s-0037-1613822-1.jpg)
Summary
Likelihood analysis was used to test the effect of the G20210A prothrombin mutation and the His107Pro protein C mutation (resulting from a C insertion) on thrombosis status and prothrombin level in a large kindred of French Canadian descent with type I protein C deficiency. Genotypes were available on 279 pedigree members or their spouses. Of this total, 36 pedigree members were heterozygous for the G20210A variant and one pedigree member was homozygous for G20210A, while 64 were heterozygous for the His107Pro protein C mutation. The factor V Leiden mutation (Arg506Gln) was observed in only one of 181 tested family members. Objectively verified thrombosis was present in 26 of the 279 pedigree members. Thrombosis was suspected in an additional 19 pedigree members. The transmission disequilibrium test of Spielman, 1996, as extended to pedigrees, was used to test for excess transmission of G20210A or His107Pro to thrombosis cases, with transmission of 0.5 specifying no effect. Although the His107Pro mutation was over transmitted (0.837 ± 0.075 p <0.001) to thrombosis cases in this pedigree, the G20210A variant was not (0.491 ± 0.130 NS).
Measured genotype analysis was used to examine a total of 184 individuals for the relationship between prothrombin level and both the G20210A variant and thrombosis. The G20210A variant increased prothrombin level from 97 ± 2% to 124 ± 4% (p <0.0001), but thrombosis status was not associated with any additional increase in prothrombin level. Thus, in a large thrombophilic, protein C deficient kindred, with the G20210A variant present in a proportion (13%) far higher than the general Caucasian population (∼2%), neither the presence of the variant nor the plasma concentration of prothrombin were associated with increased risk for thrombosis. These findings contrast with those of others who have established the G20210A variant as a thrombophilic risk factor; and emphasize the complex nature of the multigenic pathogenesis of thrombophilia.
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References
- 1 Lane DA, Mannucci PM, Bauer KA, Bertina RM, Bochkov NP, Boulyjenkov V, Chandy M, Dahlback B, Ginter EK, Miletich JP, Rosendaal FR, Seligsohn U. Inherited Thrombophilia: Part 1. Thromb Haemost 1996; 76: 651-2.
- 2 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: 64-7.
- 3 Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3’-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88: 3698.
- 4 Seligsohn U, Berger AAbend, Rubin L, Attias D, Zivelin A, Rapaport SI. Homozygous protein C deficiency manifested by massive venous thrombosis in the newborn. N Engl J Med 1984; 310: 559.
- 5 Mahasandana C, Suvatte V, Chuansumrit AS, Marlar RA, Manco-Johnson MJ, Jacobson LJ, Hathaway WE. Homozygous protein S deficiency in an infant with purpura fulmination. J Pediatr 1990; 117: 750.
- 6 Kyrle PA, Mannhalter C, Beguin S, Stumpflen A, Hirsschl M, Weltermann A, Stain M, Brenner B, Speiser W, Pabinger I, Lechner K, Eichinger S. Clinical studies and thrombin generation in patients homozygous or heterozygous for the G20210A mutation in the prothrombin gene. Arterioscler Thromb Vasc Biol 1998; 18: 1287.
- 7 Rosendahl FR, Koster T, Vandenbroucke JP. et al. High Risk of thrombosis in individuals homozygous for factor V Leidin (activated protein C resistance). Blood 1995; 85: 1504-8.
- 8 Bovill EG, Bauer KA, Dickerman JD, Callas P, West B. The clinical spectrum of heterozygous protein C deficiency in a large New England kindred. Blood 1989; 73: 712.
- 9 Seligsohn U, Zivelin A. Thrombophilia as a multigenic disorder. Thromb Haemost 1997; 78: 297.
- 10 Koeleman BPC, Reitsma PH, Allaart CF, Bertina RM. Activated protein C resistance as an additional risk factor for thrombosis in protein C-deficient families. Blood 1995; 84: 1031.
- 11 Zoller B, Berntsdotter A, de Grutos PG, Dahlback B. Resistance to activated protein C as an additional genetic risk factor in hereditary deficiency of protein S. Blood 1995; 85: 3518.
- 12 Van Boven HH, Reitsma PH, Rosendahl FR, Bayston TA, Chowdhury V, Bauer KA, Scharrer I, Conard J, Lane DA. Factor V Leiden (FV R506Q) in families with inherited antithrombin deficiency. Thromb Haemost 1996; 75: 417.
- 13 Zoller B, Svensson PJ, Dahlback B, Hillarp A. The A20210 allele of the prothrombin gene is frequently associated with the factor V Arg 506 to Gln mutation but not with protein S deficiency in thrombophilic families (letter). Blood 1998; 91: 2210.
- 14 Conard J, Mabileau-Brouzes C, Horellou MH, Elalamy I, Samama MMI. Multigenic thrombophilia: genetic anomaly of factor II and mutation of factor V Leiden. Study in a French family. Presse Medicale 1997; 26: 951.
- 15 Ehrenforth S, Ludwig G, Klinke S, Krause M, Scharrer I, Nowak-Gottl U. The prothrombin 20210 A allele is frequently coinherited in young carriers of the factor V Arg 506 to Gln mutation with venous thrombophilia (letter). Blood 1998; 91: 2209.
- 16 Makris M, Preston FE, Beauchamp NJ, Cooper PC, Daly ME, Hampton KK, Bayliss P, Peake IR, Miller GJ. Co-inheritance of the 20210A allele of the prothrombin gene increases the risk of thrombosis in subjects with familial thrombophilia. Thromb Haemost 1997; 78: 1426.
- 17 Tomczak JA, Ando RA, Sobel HG, Bovill EG, Long GL. Genetic analysis of a large kindred exhibiting type I protein C deficiency and associated thrombosis. Thromb Res 1994; 74: 243.
- 18 Hasstedt SJ, Bovill EG, Callas PW, Long GL. An unknown genetic defect increases venous thrombosis risk, through interaction with protein C deficiency. Am J Hum Genet 1998; 63: 569.
- 19 Teitel JM, Bauer KA, Lau HK, Rosenberg RD. Studies of the prothrombin activation pathway utilizing radioimmunoassays for the F2/F1.2 fragment and thrombin-antithrombin complex. Blood 1982; 59: 1086.
- 20 Elston RC, Stewart J. A general model for the genetic analysis of pedigree data. Hum Hered 1971; 21: 523.
- 21 Hasstedt SJPAP. Pedigree Analysis Package, rev 5. Department of Human Genetics, University of Utah, Salt Lake City, UT. 1998
- 22 Gill PE, Murra MASaunders, Wright MH. A fortran package for nonlinear programming. Tech rep SOL 86-2. Department of Operations Research, Stanford University. Stanford, California: 1986
- 23 Spielman RD, Ewens WJ. The TDT and other Family-based tests for linkage disequilibrium and association. Am J Hum Genet 1996; 59: 983.
- 24 Spielman RS, McGinnis RE, Ewens WJ. Transmission test for linkage disequilibrium: The insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 1993; 52: 506-16.
- 25 Hasstedt SJ. The transmission/disequilibrium test by computing likelihoods on pedigrees. In press, Genet Epidemiol; 1999
- 26 Boerwinkle E, Chakraborty R, Sing CF. The use of measured genotype information in the analysis of quantitative phenotypes in man. I. Models and analytical methods. Ann Hum Genet 1986; 50: 181.
- 27 Miletich J, Sherman L, Broze G. Absence of thrombosis in subjects with heterozygous protein C deficiency. N Engl J Med 1987; 317: 991.
- 28 Cumming AM, Keeney S, Salden A, Bhavnani M, Shwe KH, Hay CR. The prothrombin gene G20210A variant: prevalence in a U.K. anticoagulant clinic population. Br J Haematol 1997; 98: 353.
- 29 Lensen RPM, Rosendaal FR, Koster T, Allaart CF, deRonde H, Vandenbroucke JP, Reitsma PH, Bertina RM. Apparent different thrombotic tendency in patients with factor V Leiden and protein C deficiency due to selection of patients. Blood 1996; 88: 4205.
- 30 Scott BT, Bovill EG, Valliere JE, Leppert MF, Hasstedt SJ, Varvil TS, Callas PW, Long GL. Genetic linkage analysis for cosegregating candidate genes associated with thrombosis in a large protein C deficient kindred. Blood (abstract) 1998; 92: 758.
- 31 Ress DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet 1995; 346: 1133-4.
- 32 Miletich JP, Prescott SM, White R, Majerus PW, Bovill EG. Inherited predisposition to thrombosis (Review) Cell. 1993; 72: 477.