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

Authors

  • L. A. Lotta,

    Corresponding author
    1. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
    • Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, Università degli Studi di Milano and Fondazione Luigi Villa, Milan, Italy
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  • G. Tuana,

    1. Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, Università degli Studi di Milano and Fondazione Luigi Villa, Milan, Italy
    2. Hematology 1 CTMO, Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, Milan, Italy
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  • J. Yu,

    1. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
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  • I. Martinelli,

    1. Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, Università degli Studi di Milano and Fondazione Luigi Villa, Milan, Italy
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  • M. Wang,

    1. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
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  • F. Yu,

    1. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
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  • S. M. Passamonti,

    1. Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, Università degli Studi di Milano and Fondazione Luigi Villa, Milan, Italy
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  • E. Pappalardo,

    1. Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, Università degli Studi di Milano and Fondazione Luigi Villa, Milan, Italy
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  • C. Valsecchi,

    1. Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, Università degli Studi di Milano and Fondazione Luigi Villa, Milan, Italy
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  • S. E. Scherer,

    1. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
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  • W. Hale IV,

    1. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
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  • D. M. Muzny,

    1. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
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  • G. Randi,

    1. Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
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  • F. R. Rosendaal,

    1. Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, Università degli Studi di Milano and Fondazione Luigi Villa, Milan, Italy
    2. Departments of Clinical Epidemiology, Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands
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  • R. A. Gibbs,

    1. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
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    • These authors contributed equally to this work.
  • F. Peyvandi

    1. Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, Università degli Studi di Milano and Fondazione Luigi Villa, Milan, Italy
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    • These authors contributed equally to this work.

  • Manuscript handled by: M. Greaves.
  • Final decision: M. Greaves, 30 April 2013.

Correspondence: Luca A. Lotta, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, Università degli Studi di Milano and Fondazione Luigi Villa, Via Pace 9, 20122 Milan, Italy.

Tel.: +39 02 5503 5414; fax: +39 02 54 100 125.

E-mail: luca.lotta@unimi.it

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 < 1%) and low-frequency (< 5%) coding SNVs of ADAMTS13 were associated with DVT (prevalence 17% vs. 4%; odds ratio [OR] 4.8 and 95% confidence interval [CI] 1.6–15.0 for rare coding; prevalence 36% vs. 23%, OR 1.9 and 95% CI 1.0–3.5 for low-frequency coding). Patients with rare coding SNVs of ADAMTS13 had lower plasma levels of ADAMTS-13 activity than patients without them. SNVs of VWF were not associated with DVT.

Conclusions

We found an excess of rare coding SNVs of the ADAMTS13 gene in patients with DVT.

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