Genetic heterogeneity in hereditary thrombophilia.
Venous thromboembolism is a multifactorial disease that depends on variable combinations of acquired and genetic risk factors. The genetic risk factors include loss-of-function mutations in the genes that encode proteins with clot-restraining function, and gain-of-function mutations in procoagulant factors. The loss-of-function mutations are heterogeneous and comprise any mutation that impairs gene function. On the whole, these mutations are rare, with fewer than 1/200--500 individuals affected. This low prevalence in the population is probably caused by the loss of mutant alleles from the gene pool through critically ill homozygous subjects. The gain-of-function mutations in procoagulant proteins differ from the loss-of-function mutations in at least three important respects: these are more homogeneous (factor V Leiden and PT 20210), homozygous individuals are relatively mildly affected, and these are relatively prevalent (3--15%) in Caucasian populations.
Laboratory for Experimental Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands. p.h.reitsma@amc.uva.nl
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D020413:3' Untranslated Regions / Q000235:genetics; D020016:Activated Protein C Resistance / Q000235:genetics; D000991:Antithrombins / Q000172:deficiency / Q000235:genetics; D001779:Blood Coagulation Factors / Q000235:genetics; D005165:Factor V / Q000235:genetics; D005176:Factor XIII / Q000235:genetics; D005177:Factor XIII Deficiency / Q000235:genetics; D005787:Gene Frequency; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation; D020125:Mutation, Missense; D015995:Prevalence; D011486:Protein C / Q000235:genetics; D020151:Protein C Deficiency / Q000235:genetics; D017293:Protein S / Q000235:genetics; D018455:Protein S Deficiency / Q000235:genetics; D011516:Prothrombin / Q000235:genetics; D018180:Thrombomodulin / Q000172:deficiency; D019851:Thrombophilia / Q000145:classification / Q000453:epidemiology / Q000235:genetics*; D044465:White People / Q000235:genetics
D020413:3' Untranslated Regions; D000991:Antithrombins; D001779:Blood Coagulation Factors; D011486:Protein C; D017293:Protein S; D018180:Thrombomodulin; C095381:factor V Leiden; D005165:Factor V; D011516:Prothrombin; D005176:Factor XIII