Heritability of Inter-Related Clotting Factors.

The identification of genes affecting plasma concentrations of biological traits remains difficult, as the loci affecting such traits (termed quantitative trait loci) tend to explain only a fraction of the phenotypic variation. Evidence on inter-relation (i.e. clustering) of coagulation factors in the literature (Van Hylckama Vlieg 2003) suggests the existence of quantitative trait loci, which influence plasma concentrations of several quantitative traits (i.e.have a pleiotropic effect) outside the genes coding for these factors. The aim of the present study was to identify clusters of pro- and anticoagulant factors within a large protein C deficient kindred using principal components analysis. In addition, we wanted to determine how much of the variance within these clusters could be attributed to the genetic variation within a single large pedigree. Levels of the following analytes were measured in family members: prothrombin, factor V, VII, VIII, IX, X, fibrinogen, von Willebrand factor, antithrombin, protein C and protein S. Subjects with the 3363C protein C mutation, a personal history of thrombosis or those using oral anticoagulants, and women pregnant at the time of the blood draw were excluded from the analyses. To identify clusters of haemostatic factors, the principal component method with orthogonal varimax rotation was performed using SPSS. We used a factor loading of >0.40 as a marginal value to include coagulation factors in a cluster. Heritability, the proportion of the phenotypic variance attributed to polygenes, and common household effect, the proportion of the variance attributed to environmental factors shared within a household, were estimated for each principal component score with an eigenvalue (the variance attributable to a particular principal component) greater than or equal to 1 using the variance component method in SOLAR (Almasy & Blangero 1998). The distribution of each score was assumed to be multivariate normal with a variance-covariance matrix following the formula: covariance (one person to another person)=h²K + c²H + e²I, with K derived from the kinship matrix, H from the household matrix and I from the identity matrix. The additive genetic and household components of variance were estimated using maximum likelihood analysis. A total of 87 family members met the inclusion criteria. The principal components analysis identified 3 components which explained 60% of the variance: component 1 included all vitamin K dependent factors (prothrombin, factor VII, factor IX and factor X, protein C and protein S), component 2 consisted of factor V, factor IX, fibrinogen and antithrombin, which all can interact directly with thrombin, and component 3 consisted of factor VIII and its carrier protein von Willebrand factor. The heritability estimates for these 3 components were, respectively, 96% (p=0.002), 87% (p<0.001) and 12% (p=0.33). These findings appear to provide evidence for the existence of genes that regulate the levels of distinct groups of proteins in the coagulation system, thus leading to clustering of levels suggestive of a pleiotropic effect.