title: Rare Variants in the ADAMTS13 Von Willebrand Factor-Binding Domain Contribute to Pediatric Stroke.
abstract: BACKGROUND
  Recently, we reported a gene network of ADAMTS (A Disintegrin-like and Metalloprotease with Thrombospondin motifs) genes as central component of the genetic risk contributing to pediatric stroke. ADAMTS13 is a prime example for such a key component as it cleaves von Willebrand factor multimers, reduces platelet adhesion and aggregation, and downregulates thrombus formation and inflammation.
  
  
  RESULTS
  We characterized the genetic architecture of ADAMTS13 through targeted next-generation sequencing of 48 affected children and their unaffected siblings and identified in total 241 variants (single nucleotide polymorphisms or insertions/deletions) in the ADAMTS13 gene. From these, based on significance in the sibship disequilibrium test (P<0.05) or protein-altering properties, we selected 21 common variants covering the complete ADAMTS13 gene for genotyping in 270 trios and subsequent association analyses. Transmission disequilibrium testing was performed for affection status and ADAMTS13 activity levels using PLINK and FBAT, respectively. Ten single nucleotide polymorphisms were significantly associated with pediatric stroke (P<0.05 to P<0.001), 2 of which (rs2285489 and rs28793911) were also significantly associated with ADAMTS13 levels (P=0.0004 and P=0.0092). The resulting protective haplotype H1.1. (T:U 95.5: 144.4; P=0.0016) is associated with increased ADAMTS13 levels (age-adjusted P=0.0108). Haplotype association using a sliding window approach assigns this association to the ADAMTS13 von Willebrand factor-binding domain (P=1.2×10(-4)).
  
  
  CONCLUSIONS
  Our data provide a link between the genetic architecture of ADAMTS13, ADAMTS13 levels, and stroke susceptibility. Altogether, these studies render ADAMTS13 an attractive candidate for functional studies and may contribute to personalized diagnosis and treatment options in future.
authors.affiliation: From the Institute of Human Genetics, Genetic Epidemiology, University of Münster, Münster, Germany (M.S., F.R., A.W., A.B., A.A., C.S.); and Institute of Clinical Chemistry, Thrombosis & Hemostasis Treatment Center, University Hospital Schleswig-Holstein, Kiel, Germany (U.N.-G.). mstoll@uni-muenster.de.
authors.forename: Monika
authors.initials: M
authors.lastname: Stoll
authors.affiliation: From the Institute of Human Genetics, Genetic Epidemiology, University of Münster, Münster, Germany (M.S., F.R., A.W., A.B., A.A., C.S.); and Institute of Clinical Chemistry, Thrombosis & Hemostasis Treatment Center, University Hospital Schleswig-Holstein, Kiel, Germany (U.N.-G.).
authors.forename: Frank
authors.initials: F
authors.lastname: Rühle
authors.affiliation: From the Institute of Human Genetics, Genetic Epidemiology, University of Münster, Münster, Germany (M.S., F.R., A.W., A.B., A.A., C.S.); and Institute of Clinical Chemistry, Thrombosis & Hemostasis Treatment Center, University Hospital Schleswig-Holstein, Kiel, Germany (U.N.-G.).
authors.forename: Anika
authors.initials: A
authors.lastname: Witten
authors.affiliation: From the Institute of Human Genetics, Genetic Epidemiology, University of Münster, Münster, Germany (M.S., F.R., A.W., A.B., A.A., C.S.); and Institute of Clinical Chemistry, Thrombosis & Hemostasis Treatment Center, University Hospital Schleswig-Holstein, Kiel, Germany (U.N.-G.).
authors.forename: Andrei
authors.initials: A
authors.lastname: Barysenka
authors.affiliation: From the Institute of Human Genetics, Genetic Epidemiology, University of Münster, Münster, Germany (M.S., F.R., A.W., A.B., A.A., C.S.); and Institute of Clinical Chemistry, Thrombosis & Hemostasis Treatment Center, University Hospital Schleswig-Holstein, Kiel, Germany (U.N.-G.).
authors.forename: Astrid
authors.initials: A
authors.lastname: Arning
authors.affiliation: From the Institute of Human Genetics, Genetic Epidemiology, University of Münster, Münster, Germany (M.S., F.R., A.W., A.B., A.A., C.S.); and Institute of Clinical Chemistry, Thrombosis & Hemostasis Treatment Center, University Hospital Schleswig-Holstein, Kiel, Germany (U.N.-G.).
authors.forename: Christina
authors.initials: C
authors.lastname: Strauss
authors.affiliation: From the Institute of Human Genetics, Genetic Epidemiology, University of Münster, Münster, Germany (M.S., F.R., A.W., A.B., A.A., C.S.); and Institute of Clinical Chemistry, Thrombosis & Hemostasis Treatment Center, University Hospital Schleswig-Holstein, Kiel, Germany (U.N.-G.).
authors.forename: Ulrike
authors.initials: U
authors.lastname: Nowak-Göttl
mesh_terms: D000071120:ADAMTS13 Protein / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D017668:Age of Onset; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D054643:INDEL Mutation; D007223:Infant; D007231:Infant, Newborn; D015810:Linkage Disequilibrium; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D015203:Reproducibility of Results; D012307:Risk Factors; D020521:Stroke / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D014841:von Willebrand Factor / Q000378:metabolism*
chemical_list: D014841:von Willebrand Factor; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human
keywords: genetic association studies; genetic variation; genetics; humans; stroke; thrombosis