Abstract
BackgroundDeep vein thrombosis (DVT) genetic predisposition is partially known.ObjectivesThis study aimed at assessing the functional impact of nine ADAMTS13 single nucleotide variants (SNVs) previously reported to be associated as a group with DVT in a burden test and the individual association of selected variants with DVT risk in two replication studies.MethodsWild-type and mutant recombinant ADAMTS13 were transiently expressed in HEK293 cells. Antigen and activity of recombinant ADAMTS13 were measured by ELISA and FRETS-VWF73 assays, respectively. The replication studies were performed in an Italian case-control study (Milan study; 298/298 patients/controls) using a next-generation sequencing approach and in a Dutch case-control study (MEGA study; 4306/4887 patients/controls) by TaqMan assays.ResultsIn vitro results showed reduced ADAMTS13 activity for three SNVs (p.Val154Ile [15%; 95% confidence interval [CI] 14–16], p.Asp187His [19%; 95%[CI] 17–21], p.Arg421Cys [24%; 95%[CI] 22–26]) similar to reduced plasma ADAMTS13 levels of patients carriers for these SNVs. Therefore these three SNVs were interrogated for risk association. The first replication study identified 3 heterozygous carriers (2 cases, 1 control) of p.Arg421Cys (odds ratio [OR] 2, 95%[CI] 0.18–22.25). The second replication study identified 2 heterozygous carriers (1 case, 1 control) of p.Asp187His ([OR] 1.14, 95%[CI] 0.07–18.15) and 10 heterozygous carriers (4 cases, 6 controls) of p.Arg421Cys ([OR] 0.76, 95%[CI] 0.21–2.68).ConclusionsThree SNVs (p.Val154Ile, p.Asp187His and p.Arg421Cys) showed reduced ex vivo and in vitro ADAMTS13 levels. However, the low frequency of these variants makes it difficult to confirm their association with DVT.
Highlights
Deep vein thrombosis (DVT) is a common, life-threatening thrombotic disease caused by both environmental [1] and genetic risk factors [2,3,4,5,6].Previously, we used a tailored next-generation sequencing (NGS; SOLiD4 platform, Applied Biosystem, Foster, USA) approach [7] to sequence the coding region of 186 haemostatic and pro-inflammatory genes to evaluate the contribution of rare and low-frequency coding variants to DVT risk, in 94 Italian patients affected with idiopathic DVT and 98 frequency-matched controls [8]
In vitro results showed reduced ADAMTS13 activity for three single nucleotide variants (SNVs) (p.Val154Ile [15%; 95% confidence interval [confidence intervals (CI)] 14–16], p.Asp187His [19%; 95%[CI] 17–21], p.Arg421Cys [24%; 95%[CI] 22–26]) similar to reduced plasma ADAMTS13 levels of patients carriers for these SNVs. These three SNVs were interrogated for risk association
The low frequency of these variants makes it difficult to confirm their association with DVT
Summary
Deep vein thrombosis (DVT) is a common, life-threatening thrombotic disease caused by both environmental [1] and genetic risk factors [2,3,4,5,6].Previously, we used a tailored next-generation sequencing (NGS; SOLiD4 platform, Applied Biosystem, Foster, USA) approach [7] to sequence the coding region of 186 haemostatic and pro-inflammatory genes to evaluate the contribution of rare and low-frequency coding variants to DVT risk, in 94 Italian patients affected with idiopathic DVT and 98 frequency-matched controls [8]. Deep vein thrombosis (DVT) is a common, life-threatening thrombotic disease caused by both environmental [1] and genetic risk factors [2,3,4,5,6]. Rare and low-frequency coding variants of ADAMTS13 (minor allele frequency [MAF]
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