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What is currently known about the genetics of venous thromboembolism at the dawn of next generation sequencing technologies

Abstract : The genetic contribution to the risk of venous thromboembolism (VTE) has been established since 1960s with the observation of an association of antithrombin deficiency and ABO blood type with clinical risk (Egeberg, 1965; Jick et al, 1969). Since then, improved molecular technology has expanded the scientific community's ability to better identify and characterize the loci and their functional impact on VTE risk. In this review, we provide an overview of what is currently known about the genetics of VTE,. and summarize in a table (Table 1) the main genetic associations that have been robustly validated so far, either experimentally or using epidemiological data from several independent studies. Genes with well characterized functions and with identified causal coding variations As could be expected from population genomics, genetic variants with strong impact on VTE risk are uncommon and are often private mutations (i.e present in less than 0.1% of the population). There are dozens of loss-of-function variants in anticoagulant genes coding for the three natural coagulation inhibitors: antithrombin (SERPINC1 gene), protein C (PROC) and protein S (PROS1) (Egeberg, 1965; Griffin et al, 1981; Schwarz et al, 1984). The risk of developping the disease in carriers of such mutations is ~10 fold increased. Interestingly, two of these genes (PROS1 and SERPINC1) have been found to harbour less uncommon polymorphisms that also modulate the susceptibility to VTE. As far PROS1 is concerned, a meta-analysis of 4 French case-control studies for VTE demonstrated that the rs121918472, also referred to as the Protein S Heerlen mutation, a non synonymous Serine to Proline (Ser501Pro) substitution of frequency <1% in the general population which was previously considered has a benigh polymorphism, was associated with ~4 6 fold increased risk of VTE (Suchon et al, 2017). The rs121918474 (Lys196Glu) is another PROS1 coding mutation associated with increased risk of VTE (OR ~5) by lowering protein S anticoagulant activity but this mutation is specific to the Japanese population, approximately 1/12 000 individuals being homozygous for the 196Glu allele (Liu et al, 2013; Kimura et al, 2006). Specifically, Banno et al (Banno et al, 2015) generated PS-Lys196Glu knock-in mice and analyzed phenotypes comparing homozygous vs heterozygous PS-deficient mice. Using 2 animal models, they showed that the murine PS-Lys196Glu mutation reduces its APC anticoagulant cofactor activity in plasma and that PS-Lys196Glu mice and heterozygous PS deficiency are more vulnerable to VTE than wild-type mice, proving pathogenic causality for the Lys196Glu mutation. In a recent meta-analysis of 12 case-control studies for VTE conducted on behalf of the INVENT consortium (Germain et al, 2015) and
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https://hal-amu.archives-ouvertes.fr/hal-01753821
Contributor : Marie-Christine Alessi <>
Submitted on : Thursday, March 29, 2018 - 5:05:21 PM
Last modification on : Tuesday, October 20, 2020 - 10:26:49 AM

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David-Alexandre Trégouët, Pierre-Emmanuel Morange. What is currently known about the genetics of venous thromboembolism at the dawn of next generation sequencing technologies. British Journal of Haematology, Wiley, 2018, 180 (3), pp.335 - 345. ⟨10.1111/bjh.15004⟩. ⟨hal-01753821⟩

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