Skip to main content
PMC home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1998 Aug;63(2):569–576. doi: 10.1086/301947

An unknown genetic defect increases venous thrombosis risk, through interaction with protein C deficiency.

S J Hasstedt 1, E G Bovill 1, P W Callas 1, G L Long 1
PMCID: PMC1377289  PMID: 9683579

Abstract

We used two-locus segregation analysis to test whether an unknown genetic defect interacts with protein C deficiency to increase susceptibility to venous thromboembolic disease in a single large pedigree. Sixty-seven pedigree members carry a His107Pro mutation in the protein C gene, which reduces protein C levels to a mean of 46% of normal. Twenty-one carriers of the mutation and five other pedigree members had verified thromboembolic disease. We inferred the presence in this pedigree of a thrombosis-susceptibility gene interacting with protein C deficiency, by rejecting the hypothesis that the cases of thromboembolic disease resulted from protein C deficiency alone and by not rejecting Mendelian transmission of the interacting gene. When coinherited with protein C deficiency, the interacting gene conferred a probability of a thrombotic episode of approximately 79% for men and approximately 99% for women, before age 60 years.

Full Text

The Full Text of this article is available as a PDF (377.0 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anderson F. A., Jr, Wheeler H. B., Goldberg R. J., Hosmer D. W., Patwardhan N. A., Jovanovic B., Forcier A., Dalen J. E. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med. 1991 May;151(5):933–938. [PubMed] [Google Scholar]
  2. Beauchamp N. J., Daly M. E., Cooper P. C., Makris M., Preston F. E., Peake I. R. Molecular basis of protein S deficiency in three families also showing independent inheritance of factor V leiden. Blood. 1996 Sep 1;88(5):1700–1707. [PubMed] [Google Scholar]
  3. Beckmann R. J., Schmidt R. J., Santerre R. F., Plutzky J., Crabtree G. R., Long G. L. The structure and evolution of a 461 amino acid human protein C precursor and its messenger RNA, based upon the DNA sequence of cloned human liver cDNAs. Nucleic Acids Res. 1985 Jul 25;13(14):5233–5247. doi: 10.1093/nar/13.14.5233. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Berruyer M., Francina A., Ffrench P., Negrier C., Boneu B., Dechavanne M. Increased thrombosis incidence in a family with an inherited protein S deficiency and a high oxygen affinity hemoglobin variant. Am J Hematol. 1994 Jul;46(3):214–217. doi: 10.1002/ajh.2830460310. [DOI] [PubMed] [Google Scholar]
  5. Bovill E. G., Bauer K. A., Dickerman J. D., Callas P., West B. The clinical spectrum of heterozygous protein C deficiency in a large New England kindred. Blood. 1989 Feb 15;73(3):712–717. [PubMed] [Google Scholar]
  6. Boyle C. R., Elston R. C. Multifactorial genetic models for quantitative traits in humans. Biometrics. 1979 Mar;35(1):55–68. [PubMed] [Google Scholar]
  7. Branson H. E., Katz J., Marble R., Griffin J. H. Inherited protein C deficiency and coumarin-responsive chronic relapsing purpura fulminans in a newborn infant. Lancet. 1983 Nov 19;2(8360):1165–1168. doi: 10.1016/s0140-6736(83)91216-3. [DOI] [PubMed] [Google Scholar]
  8. Brenner B., Zivelin A., Lanir N., Greengard J. S., Griffin J. H., Seligsohn U. Venous thromboembolism associated with double heterozygosity for R506Q mutation of factor V and for T298M mutation of protein C in a large family of a previously described homozygous protein C-deficient newborn with massive thrombosis. Blood. 1996 Aug 1;88(3):877–880. [PubMed] [Google Scholar]
  9. Broekmans A. W., Veltkamp J. J., Bertina R. M. Congenital protein C deficiency and venous thromboembolism. A study of three Dutch families. N Engl J Med. 1983 Aug 11;309(6):340–344. doi: 10.1056/NEJM198308113090604. [DOI] [PubMed] [Google Scholar]
  10. Dahlbäck B., Carlsson M., Svensson P. J. 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 U S A. 1993 Feb 1;90(3):1004–1008. doi: 10.1073/pnas.90.3.1004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dahlbäck B. Inherited resistance to activated protein C, a major cause of venous thrombosis, is due to a mutation in the factor V gene. Haemostasis. 1994 Mar-Apr;24(2):139–151. doi: 10.1159/000217094. [DOI] [PubMed] [Google Scholar]
  12. Elston R. C., Stewart J. A general model for the genetic analysis of pedigree data. Hum Hered. 1971;21(6):523–542. doi: 10.1159/000152448. [DOI] [PubMed] [Google Scholar]
  13. Esmon C. T. Molecular events that control the protein C anticoagulant pathway. Thromb Haemost. 1993 Jul 1;70(1):29–35. [PubMed] [Google Scholar]
  14. Estellés A., Garcia-Plaza I., Dasí A., Aznar J., Duart M., Sanz G., Pérez-Requejo J. L., España F., Jimenez C., Abeledo G. Severe inherited "homozygous" protein C deficiency in a newborn infant. Thromb Haemost. 1984 Aug 31;52(1):53–56. [PubMed] [Google Scholar]
  15. Florell S. R., Rodgers G. M. Inherited thrombotic disorders: an update. Am J Hematol. 1997 Jan;54(1):53–60. doi: 10.1002/(sici)1096-8652(199701)54:1<53::aid-ajh8>3.0.co;2-3. [DOI] [PubMed] [Google Scholar]
  16. Foster D. C., Yoshitake S., Davie E. W. The nucleotide sequence of the gene for human protein C. Proc Natl Acad Sci U S A. 1985 Jul;82(14):4673–4677. doi: 10.1073/pnas.82.14.4673. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Gandrille S., Greengard J. S., Alhenc-Gelas M., Juhan-Vague I., Abgrall J. F., Jude B., Griffin J. H., Aiach M. Incidence of activated protein C resistance caused by the ARG 506 GLN mutation in factor V in 113 unrelated symptomatic protein C-deficient patients. The French Network on the behalf of INSERM. Blood. 1995 Jul 1;86(1):219–224. [PubMed] [Google Scholar]
  18. Gandrille S., Priollet P., Capron L., Roncato M., Fiessinger J. N., Aiach M. Association of inherited dysfibrinogenaemia and protein C deficiency in two unrelated families. Br J Haematol. 1988 Mar;68(3):329–337. doi: 10.1111/j.1365-2141.1988.tb04210.x. [DOI] [PubMed] [Google Scholar]
  19. Gladson C. L., Scharrer I., Hach V., Beck K. H., Griffin J. H. The frequency of type I heterozygous protein S and protein C deficiency in 141 unrelated young patients with venous thrombosis. Thromb Haemost. 1988 Feb 25;59(1):18–22. [PubMed] [Google Scholar]
  20. Griffin J. H., Evatt B., Zimmerman T. S., Kleiss A. J., Wideman C. Deficiency of protein C in congenital thrombotic disease. J Clin Invest. 1981 Nov;68(5):1370–1373. doi: 10.1172/JCI110385. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Hasstedt S. J. Variance components/major locus likelihood approximation for quantitative, polychotomous, and multivariate data. Genet Epidemiol. 1993;10(3):145–158. doi: 10.1002/gepi.1370100302. [DOI] [PubMed] [Google Scholar]
  22. Horellou M. H., Conard J., Bertina R. M., Samama M. Congenital protein C deficiency and thrombotic disease in nine French families. Br Med J (Clin Res Ed) 1984 Nov 10;289(6454):1285–1287. doi: 10.1136/bmj.289.6454.1285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kato A., Miura O., Sumi Y., Aoki N. Assignment of the human protein C gene (PROC) to chromosome region 2q14----q21 by in situ hybridization. Cytogenet Cell Genet. 1988;47(1-2):46–47. doi: 10.1159/000132503. [DOI] [PubMed] [Google Scholar]
  24. Koeleman B. P., Reitsma P. H., Allaart C. F., Bertina R. M. Activated protein C resistance as an additional risk factor for thrombosis in protein C-deficient families. Blood. 1994 Aug 15;84(4):1031–1035. [PubMed] [Google Scholar]
  25. Koeleman B. P., van Rumpt D., Hamulyák K., Reitsma P. H., Bertina R. M. Factor V Leiden: an additional risk factor for thrombosis in protein S deficient families? Thromb Haemost. 1995 Aug;74(2):580–583. [PubMed] [Google Scholar]
  26. Koster T., Rosendaal F. R., Briët E., van der Meer F. J., Colly L. P., Trienekens P. H., Poort S. R., Reitsma P. H., Vandenbroucke J. P. Protein C deficiency in a controlled series of unselected outpatients: an infrequent but clear risk factor for venous thrombosis (Leiden Thrombophilia Study) Blood. 1995 May 15;85(10):2756–2761. [PubMed] [Google Scholar]
  27. Lalouel J. M., Rao D. C., Morton N. E., Elston R. C. A unified model for complex segregation analysis. Am J Hum Genet. 1983 Sep;35(5):816–826. [PMC free article] [PubMed] [Google Scholar]
  28. Lane D. A., Bayston T., Olds R. J., Fitches A. C., Cooper D. N., Millar D. S., Jochmans K., Perry D. J., Okajima K., Thein S. L. Antithrombin mutation database: 2nd (1997) update. For the Plasma Coagulation Inhibitors Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost. 1997 Jan;77(1):197–211. [PubMed] [Google Scholar]
  29. Marciniak E., Wilson H. D., Marlar R. A. Neonatal purpura fulminans: a genetic disorder related to the absence of protein C in blood. Blood. 1985 Jan;65(1):15–20. [PubMed] [Google Scholar]
  30. Marlar R. A., Montgomery R. R., Broekmans A. W. Report on the diagnosis and treatment of homozygous protein C deficiency. Report of the Working Party on Homozygous Protein C Deficiency of the ICTH-Subcommittee on Protein C and Protein S. Thromb Haemost. 1989 Jun 30;61(3):529–531. [PubMed] [Google Scholar]
  31. McColl M., Tait R. C., Walker I. D., Perry D. J., McCall F., Conkie J. A. Low thrombosis rate seen in blood donors and their relatives with inherited deficiencies of antithrombin and protein C: correlation with type of defect, family history, and absence of the factor V Leiden mutation. Blood Coagul Fibrinolysis. 1996 Oct;7(7):689–694. doi: 10.1097/00001721-199610000-00005. [DOI] [PubMed] [Google Scholar]
  32. Miletich J. P., Prescott S. M., White R., Majerus P. W., Bovill E. G. Inherited predisposition to thrombosis. Cell. 1993 Feb 26;72(4):477–480. doi: 10.1016/0092-8674(93)90063-v. [DOI] [PubMed] [Google Scholar]
  33. Miletich J., Sherman L., Broze G., Jr Absence of thrombosis in subjects with heterozygous protein C deficiency. N Engl J Med. 1987 Oct 15;317(16):991–996. doi: 10.1056/NEJM198710153171604. [DOI] [PubMed] [Google Scholar]
  34. Morton N. E., MacLean C. J. Analysis of family resemblance. 3. Complex segregation of quantitative traits. Am J Hum Genet. 1974 Jul;26(4):489–503. [PMC free article] [PubMed] [Google Scholar]
  35. Pabinger I., Schneider B. Thrombotic risk in hereditary antithrombin III, protein C, or protein S deficiency. A cooperative, retrospective study. Gesellschaft fur Thrombose- und Hamostaseforschung (GTH) Study Group on Natural Inhibitors. Arterioscler Thromb Vasc Biol. 1996 Jun;16(6):742–748. doi: 10.1161/01.atv.16.6.742. [DOI] [PubMed] [Google Scholar]
  36. Plutzky J., Hoskins J. A., Long G. L., Crabtree G. R. Evolution and organization of the human protein C gene. Proc Natl Acad Sci U S A. 1986 Feb;83(3):546–550. doi: 10.1073/pnas.83.3.546. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Poort S. R., Rosendaal F. R., Reitsma P. H., Bertina R. M. 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 Nov 15;88(10):3698–3703. [PubMed] [Google Scholar]
  38. Reitsma P. H. Protein C deficiency: summary of the 1995 database update. Nucleic Acids Res. 1996 Jan 1;24(1):157–159. doi: 10.1093/nar/24.1.157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Risch N., Ghosh S., Todd J. A. Statistical evaluation of multiple-locus linkage data in experimental species and its relevance to human studies: application to nonobese diabetic (NOD) mouse and human insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet. 1993 Sep;53(3):702–714. [PMC free article] [PubMed] [Google Scholar]
  40. Seligsohn U., Berger A., Abend M., Rubin L., Attias D., Zivelin A., Rapaport S. I. Homozygous protein C deficiency manifested by massive venous thrombosis in the newborn. N Engl J Med. 1984 Mar 1;310(9):559–562. doi: 10.1056/NEJM198403013100904. [DOI] [PubMed] [Google Scholar]
  41. Seligsohn U., Zivelin A. Thrombophilia as a multigenic disorder. Thromb Haemost. 1997 Jul;78(1):297–301. [PubMed] [Google Scholar]
  42. Simmonds R. E., Ireland H., Kunz G., Lane D. A. Identification of 19 protein S gene mutations in patients with phenotypic protein S deficiency and thrombosis. Protein S Study Group. Blood. 1996 Dec 1;88(11):4195–4204. [PubMed] [Google Scholar]
  43. Tait R. C., Walker I. D., Reitsma P. H., Islam S. I., McCall F., Poort S. R., Conkie J. A., Bertina R. M. Prevalence of protein C deficiency in the healthy population. Thromb Haemost. 1995 Jan;73(1):87–93. [PubMed] [Google Scholar]
  44. Tomczak J. A., Ando R. A., Sobel H. G., Bovill E. G., Long G. L. Genetic analysis of a large kindred exhibiting type I protein C deficiency and associated thrombosis. Thromb Res. 1994 May 1;74(3):243–254. doi: 10.1016/0049-3848(94)90112-0. [DOI] [PubMed] [Google Scholar]
  45. Trauscht-Van Horn J. J., Capeless E. L., Easterling T. R., Bovill E. G. Pregnancy loss and thrombosis with protein C deficiency. Am J Obstet Gynecol. 1992 Oct;167(4 Pt 1):968–972. doi: 10.1016/s0002-9378(12)80021-4. [DOI] [PubMed] [Google Scholar]
  46. Zöller B., Berntsdotter A., García de Frutos P., Dahlbäck B. Resistance to activated protein C as an additional genetic risk factor in hereditary deficiency of protein S. Blood. 1995 Jun 15;85(12):3518–3523. [PubMed] [Google Scholar]
  47. Zöller B., He X., Dahlbäck B. Homozygous APC-resistance combined with inherited type I protein S deficiency in a young boy with severe thrombotic disease. Thromb Haemost. 1995 May;73(5):743–745. [PubMed] [Google Scholar]
  48. Züger M., Biasiutti F. D., Furlan M., Mannhalter C., Lämmle B. Plasminogen deficiency: an additional risk factor for thrombosis in a family with factor V R506Q mutation? Thromb Haemost. 1996 Sep;76(3):475–476. [PubMed] [Google Scholar]
  49. van Boven H. H., Reitsma P. H., Rosendaal F. R., Bayston T. A., Chowdhury V., Bauer K. A., Scharrer I., Conard J., Lane D. A. Factor V Leiden (FV R506Q) in families with inherited antithrombin deficiency. Thromb Haemost. 1996 Mar;75(3):417–421. [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES