Delineating the Hemostaseome as an aid to individualize the analysis of the hereditary basis of thrombotic and bleeding disorders

Abstract

Next-generation sequencing and genome-wide association studies represent powerful tools to identify genetic variants that confer disease risk within populations. On their own, however, they cannot provide insight into how these variants contribute to individual risk for diseases that exhibit complex inheritance, or alternatively confer health in a given individual. Even in the case of well-characterized variants that confer a significant disease risk, more healthy individuals carry the variant, with no apparent ill effect, than those who manifest disease. Access to low-cost genome sequence data promises to provide an unprecedentedly detailed view of the nature of the hereditary component of complex diseases, but requires the large-scale comparison of sequence data from individuals with and without disease to deliver a clinical calibration. The provision of informatics support remains problematic as there are currently no means to interpret the data generated. Here, we initiate this process, a prerequisite for such a study, by narrowing the focus from an entire genome to that of a single biological system. To this end, we examine the `Hemostaseome,' and more specifically focus on DNA sequence changes pertaining to those human genes known to impact upon hemostasis and thrombosis that can be analyzed coordinately, and on an individual basis, to interrogate how specific combinations of variants act to confer disease predisposition. As a first step, we delineate known members of the Hemostaseome and explore the nature of the genetic variants that may cause disease in individuals whose hemostatic balance has become shifted toward either a prothrombotic or anticoagulant phenotype.

Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease

“…The risk of venous thromboembolism is known to be increased in patients who carry more than one genetic variant disrupting the 100+ genes of the ‘hemostaseome’ (Fechtel et al 2011). Thus, 19 % of symptomatic individuals harbouring a protein C ( PROC ) gene mutation were also found to be heterozygous for factor V Leiden ( F5 Arg534Gln; Koeleman et al 1994), a functional polymorphism which occurs at a frequency of 2–5 % in European populations.…”

“…This means that the vast majority of individuals bearing these variants do not suffer from thrombotic disease. It is nevertheless reasonable to suppose that patients with recurrent venous thrombosis will tend to have a greater number of prothrombotic variants than those who have experienced a single thrombotic event, with those individuals who never experienced thrombosis harbouring even fewer prothrombotic variants (Fechtel et al 2011). Since the number of genes known to influence haemostasis is large and the number of variants with potential impact larger still, we may expect that a substantial number of different variant combinations will be capable of conferring an increased risk.…”

“…Since the number of genes known to influence haemostasis is large and the number of variants with potential impact larger still, we may expect that a substantial number of different variant combinations will be capable of conferring an increased risk. This genetic risk will accompany each prothrombotic challenge (such as pregnancy, long haul air travel, contraceptive pill usage and immobilization after surgery), with the greatest risk of venous thrombosis accruing to those possessing the largest number of prothrombotic variants in their genomes (Fechtel et al 2011). Our task is to come to understand how specific DNA sequence changes in the large number of genes known to play a role in haemostasis and thrombosis act either synergistically or antagonistically so as to confer disease predisposition upon the individual, thereby influencing the clinical penetrance, by shifting their haemostatic balance towards either a prothrombotic or anticoagulant phenotype (Franchini and Mannucci 2009; Westrick and Ginsburg 2009; Fechtel et al 2011).…”

Guidance for the evaluation and treatment of hereditary and acquired thrombophilia

“…We will not address other conditions, such as abnormal levels of other coagulation proteins (e.g., elevated factor VIII levels) elevated homocysteine, or abnormalities of fibrinolytic proteins. Over time it is likely that more defects will be identified [ 6 ]. This guidance statement also does not address hereditary factors not assessed in the laboratory, such as gender, height, leg length, and body mass index; which also affect thrombosis risk [ 7 – 10 ].…”

Haemostaseome-associated SNPs: has the thrombotic phenotype a greater influence than ethnicity?

“…Single nucleotide polymorphisms (SNPs) account for more than 80 % of human genetic variability, including the predisposition to disease. Our study focused on 384 SNPs from 164 genes or DNA regions selected for their implication in the so-called "haemostaseome" (3).…”