Next‐generation sequencing study finds an excess of rare, coding single‐nucleotide variants of ADAMTS13 in patients with deep vein thrombosis

Summary Background The considerable genetic predisposition to deep vein thrombosis (DVT) is only partially accounted for by known genetic risk variants. Rare single‐nucleotide variants (SNVs) of the coding areas of hemostatic genes may explain part of this missing heritability. The ADAMTS13 and VWF...

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Bibliographic Details
Published in:Journal of thrombosis and haemostasis 2013-07, Vol.11 (7), p.1228-1239
Main Authors: Lotta, L. A., Tuana, G., Yu, J., Martinelli, I., Wang, M., Yu, F., Passamonti, S. M., Pappalardo, E., Valsecchi, C., Scherer, S. E., Hale, W., Muzny, D. M., Randi, G., Rosendaal, F. R., Gibbs, R. A., Peyvandi, F.
Format: Article
Language:English
Subjects:
ADAM Proteins - blood
ADAM Proteins - genetics
ADAMTS13 Protein
ADAMTS‐13
Adult
Case-Control Studies
deep vein thrombosis
exome
Female
Gene Frequency
Genetic Predisposition to Disease
High-Throughput Nucleotide Sequencing
Humans
Italy - epidemiology
Linear Models
Logistic Models
Male
Middle Aged
Odds Ratio
Phenotype
Polymorphism, Single Nucleotide
Predictive Value of Tests
Prevalence
Risk Factors
venous thromboembolism
Venous Thrombosis - blood
Venous Thrombosis - enzymology
Venous Thrombosis - epidemiology
Venous Thrombosis - genetics
von Willebrand Factor - genetics
VWF
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Summary:Summary Background The considerable genetic predisposition to deep vein thrombosis (DVT) is only partially accounted for by known genetic risk variants. Rare single‐nucleotide variants (SNVs) of the coding areas of hemostatic genes may explain part of this missing heritability. The ADAMTS13 and VWF genes encode two interconnected proteins with fundamental hemostatic functions, the disruption of which may result in thrombosis. Objectives To study the distribution and burden of rare coding SNVs of ADAMTS13 and VWF found by sequencing in cases and controls of DVT. Patients/Methods The protein‐coding areas of 186 hemostatic/proinflammatory genes were sequenced by next‐generation technology in 94 thrombophilia‐negative patients with DVT and 98 controls. Gene‐specific information on ADAMTS13 and VWF was used to study the association between DVT and rare coding SNVs of the two genes. Results More than 70 billion base pairs of raw sequence data were produced to sequence the 700‐kb target area with a median redundancy of × 45 in 192 individuals. Most of the 4366 SNVs identified were rare and non‐synonymous, indicating pathogenetic potential. Rare (frequency of
ISSN:1538-7933
1538-7836
1538-7836
DOI:10.1111/jth.12291