Familial segregation of venous thromboembolism

Abstract

Summary. Background: Venous thromboembolism (VTE) is postulated as a complex disease, but the heritability and mode of inheritance are uncertain. Objective: To determine if VTE (i) segregates in families; (ii) is attributable to inheritance, shared environment, or both; and (iii) the possible mode of inheritance. Patients and methods: In a family-based study of relatives from 751 probands (60% female) with objectively diagnosed VTE (without cancer), we performed complex segregation analyses corrected for mode of ascertainment, considering agespecific, non-gender-and gender-specific liability classes under Mendelian and non-Mendelian assumptions. We tested 12 models categorized into four model sets: (i) sporadic (assumes no genetic effect); (ii) Mendelian inheritance of a major gene (including dominant, additive, recessive or codominant classes); (iii) mixed model (Mendelian inheritance including the same four classes plus the effect of polygenes); and (iv) nonMendelian. Results: Among the 16 650 relatives, 753 (48% female) were affected with VTE, of whom 62% were first-degree relatives. The sporadic model was rejected in both non-genderand gender-specific liability class analyses. Among the remaining gender-specific models, the unrestricted (non-Mendelian) inheritance model was favored with an estimated heritability of 0.52. Among the Mendelian models, the dominant mixed model was preferred, with an estimated heritability and major disease allele frequency of 0.62 and 0.25, respectively, suggesting an effect of several minor genes. Conclusion: A multifactorial non-Mendelian inheritance model was favored as the cause for VTE, while a model postulating a purely environmental cause was rejected. VTE is probably a result of multigenic action as well as environmental exposures.

The Epidemiology of Venous Thromboembolism in the Community

“…41,42 Inherited reductions in plasma natural anticoagulants (eg, antithrombin, protein C, or protein S) have long been recognized as uncommon but potent risk factors for venous thromboembolism. 43 More recent discoveries of impaired downregulation of the procoagulant system (eg, activated protein C [APC] resistance, Factor V Leiden), increased plasma concentrations of procoagulant factors (eg, factors I [fibrinogen], II [prothrombin], VIII, IX, and XI) and increased basal procoagulant activity, impaired fibrinolysis, and increased basal innate immunity activity and reactivity have added new paradigms to the list of inherited or acquired disorders predisposing to thrombosis (thrombophilia).…”

Novel genetic predictors of venous thromboembolism risk in African Americans

“…4,5 Twin and family studies among populations of EA suggest that genetic factors explain up to 60% of VTE heritability. 8,9 Genome-wide association studies (GWASs) in populations of EA have confirmed the 2 well-established risk variants, factor V Leiden (rs6025) and prothrombin G20210A (rs1799963), and have identified several singlenucleotide polymorphisms (SNPs) in the ABO blood group gene (ABO) as susceptibility loci. [10][11][12] However, these variants are found in higher frequencies among individuals of EA compared with AAs, particularly rs6025 and rs1799963 which are nearly absent in AAs.…”

Genetic Variations Associated With Recurrent Venous Thrombosis

“…The heritability of venous thrombosis is high at 50% to 60%. [8][9][10] Previously, we showed that a positive family history of venous thrombosis increases the risk of venous thrombosis even when a genetic risk factor has been identified, suggesting the presence of additional unidentified genetic risk factors. 11 Genome-wide association studies have identified common genetic variants with a modest effect on risk.…”