This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Souto, J. C. Articles by Fontcuberta, J. Search for Related Content PubMed PubMed Citation Articles by Souto, J. C. Articles by Fontcuberta, J. Related Collections Clinical genetics Fibrinolysis Epidemiology Coagulation and fibronolysis

(Circulation. 2000;101:1546.)
© 2000 American Heart Association, Inc.

Clinical Investigation and Reports

Genetic Determinants of Hemostasis Phenotypes in Spanish Families

Juan Carlos Souto, MD; Laura Almasy, PhD; Montserrat Borrell, PhD; Merce Garí, BSc; Elisabet Martínez, BSc; José Mateo, MD; William H. Stone, PhD; John Blangero, PhD; Jordi Fontcuberta, MD, PhD

From the Unit of Thrombosis and Hemostasis, Department of Hematology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain (J.C.S., M.B., M.G., E.M., J.M., J.F.); the Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, Tex (L.A., J.B.); and the Department of Biology, Trinity University, San Antonio, Tex (W.H.S.).

Correspondence to Dr John Blangero, Department of Genetics, Southwest Foundation for Biomedical Research, PO Box 760549, San Antonio, TX 78245-0549. E-mail john{at}darwin.sfbr.org

Background—Recent studies have described genetic mutations that affect the risk of thrombosis as a result of abnormal levels of such hemostatic parameters as protein C, protein S, and the activated protein C resistance ratio. Although these mutations suggest that genes play a part in determining variability in some hemostasis-related phenotypes, the relative importance of genetic influences on these traits has not been evaluated.

Methods and Results—The relative contributions of genetic and environmental influences to a panel of hemostasis-related phenotypes were assessed in a sample of 397 individuals in 21 extended pedigrees. The effects of measured covariates (sex, age, smoking, and exogenous sex hormones), genes, and environmental variables shared by members of a household were quantified for 27 hemostasis-related measures. All of these phenotypes showed significant genetic contributions, with the majority of heritabilities ranging between 22% and 55% of the residual phenotypic variance after correction for covariate effects. Activated protein C resistance ratio, activated partial thromboplastin time, and Factor XII showed the strongest heritabilities, with 71.3%, 83.0%, and 67.3%, respectively, of the residual phenotypic variation attributable to genetic effects.

Conclusions—These results clearly demonstrate the importance of genetic factors in determining variation in hemostasis-related phenotypes that are components of the coagulation and fibrinolysis pathways and that have been implicated in risk for thrombosis. The presence of such strong genetic effects suggests that it will be possible to localize previously unknown genes that influence quantitative variation in these hemostasis-related phenotypes that may contribute to risk for thrombosis.

Key Words: genetics • coagulation • fibrinolysis • epidemiology • thrombosis