title: Next-generation sequencing study finds an excess of rare, coding single-nucleotide variants of ADAMTS13 in patients with deep vein thrombosis.
abstract: 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.
  
  
  OBJECTIVE
  To study the distribution and burden of rare coding SNVs of ADAMTS13 and VWF found by sequencing in cases and controls of DVT.
  
  
  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.
authors: 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, Milan, Italy. luca.lotta@unimi.it
authors: L A
authors: LA
authors: Lotta
authors: G
authors: G
authors: Tuana
authors: J
authors: J
authors: Yu
authors: I
authors: I
authors: Martinelli
authors: M
authors: M
authors: Wang
authors: F
authors: F
authors: Yu
authors: S M
authors: SM
authors: Passamonti
authors: E
authors: E
authors: Pappalardo
authors: C
authors: C
authors: Valsecchi
authors: S E
authors: SE
authors: Scherer
authors: W
authors: W
authors: Hale
authors: D M
authors: DM
authors: Muzny
authors: G
authors: G
authors: Randi
authors: F R
authors: FR
authors: Rosendaal
authors: R A
authors: RA
authors: Gibbs
authors: F
authors: F
authors: Peyvandi
mesh_terms: D051722:ADAM Proteins / Q000097:blood / Q000235:genetics*; D000071120:ADAMTS13 Protein; D000328:Adult; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007558:Italy / Q000453:epidemiology; D016014:Linear Models; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D015995:Prevalence; D012307:Risk Factors; D020246:Venous Thrombosis / Q000097:blood / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics*; D014841:von Willebrand Factor / Q000235:genetics
chemical_list: D014841:von Willebrand Factor; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human
keywords: ADAMTS-13; VWF; deep vein thrombosis; exome; venous thromboembolism