title: Rare genetic variants in SMAP1, B3GAT2, and RIMS1 contribute to pediatric venous thromboembolism.
abstract: Recent genome-wide association studies (GWAS) have confirmed known risk mutations for venous thromboembolism (VTE) and identified a number of novel susceptibility loci in adults. Here we present a GWAS in 212 nuclear families with pediatric VTE followed by targeted next-generation sequencing (NGS) to identify causative mutations contributing to the association. Three single nucleotide polymorphisms (SNPs) exceeded the threshold for genome-wide significance as determined by permutation testing using 100 000 bootstrap permutations (P< 10-5). These SNPs reside in a region on chromosome 6q13 comprising the genes small ARF GAP1 (SMAP1), an ARF6 guanosine triphosphatase-activating protein that functions in clathrin-dependent endocytosis, and β-1,3-glucoronyltransferase 2 (B3GAT2), a member of the human natural killer 1 carbohydrate pathway. Rs1304029 and rs2748331 are associated with pediatric VTE with unpermuted/permuted values ofP= 1.42 × 10-6/2.0 × 10-6andP= 6.11 × 10-6/1.8 × 10-5, respectively. Rs2748331 was replicated (P= .00719) in an independent study sample coming from our GWAS on pediatric thromboembolic stroke (combinedP= 7.88 × 10-7). Subsequent targeted NGS in 24 discordant sibling pairs identified 17 nonsynonymous coding variants, of which 1 located inSMAP1and 3 inRIMS1, a member of the RIM family of active zone proteins, are predicted as damaging by Protein Variation Effect Analyzer and/or sorting intolerant from tolerant scores. Three SNPs curtly missed statistical significance in the transmission-disequilibrium test in the full cohort (rs112439957:P= .08326,SMAP1; rs767118962:P= .08326,RIMS1; and rs41265501:P= .05778,RIMS1). In conjunction, our data provide compelling evidence forSMAP1,B3GAT2, andRIMS1as novel susceptibility loci for pediatric VTE and warrant future functional studies to unravel the underlying molecular mechanisms leading to VTE.
authors.affiliation: Genetic Epidemiology, Institute for Human Genetics, Westfälische Wilhelms University, Muenster, Germany.
authors.forename: Frank
authors.identifier: 0000-0001-7688-2394
authors.initials: F
authors.lastname: Rühle
authors.affiliation: Genetic Epidemiology, Institute for Human Genetics, Westfälische Wilhelms University, Muenster, Germany.
authors.forename: Anika
authors.initials: A
authors.lastname: Witten
authors.affiliation: Genetic Epidemiology, Institute for Human Genetics, Westfälische Wilhelms University, Muenster, Germany.
authors.forename: Andrei
authors.initials: A
authors.lastname: Barysenka
authors.affiliation: Genetic Epidemiology, Institute for Human Genetics, Westfälische Wilhelms University, Muenster, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Huge
authors.affiliation: Genetic Epidemiology, Institute for Human Genetics, Westfälische Wilhelms University, Muenster, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Arning
authors.affiliation: Children's Hospital, University Hospital Frankfurt, Frankfurt, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Heller
authors.affiliation: Pediatric Hematology and Oncology and.
authors.forename: Anne
authors.initials: A
authors.lastname: Krümpel
authors.affiliation: Division of Hematology and Oncology, Department of Medicine A, University Hospital of Muenster, Muenster, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Mesters
authors.affiliation: Institute for Molecular Biology and.
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.affiliation: Institute of Epidemiology and Biobank PopGen, Christian-Albrechts University Kiel, Kiel, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Lieb
authors.affiliation: Genetic Epidemiology, Institute for Human Genetics, Westfälische Wilhelms University, Muenster, Germany.
authors.forename: Mona
authors.initials: M
authors.lastname: Riemenschneider
authors.affiliation: Genetic Epidemiology, Institute for Human Genetics, Westfälische Wilhelms University, Muenster, Germany.
authors.forename: Milan
authors.initials: M
authors.lastname: Hiersche
authors.affiliation: Thrombosis & Hemostasis Treatment Center, Institute of Clinical Chemistry, University Hospital Schleswig-Holstein, Lubeck, Germany; and.
authors.forename: Verena
authors.initials: V
authors.lastname: Limperger
authors.affiliation: Pediatric Hematology and Oncology and.|Thrombosis & Hemostasis Treatment Center, Institute of Clinical Chemistry, University Hospital Schleswig-Holstein, Lubeck, Germany; and.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Nowak-Göttl
authors.affiliation: Genetic Epidemiology, Institute for Human Genetics, Westfälische Wilhelms University, Muenster, Germany.|Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.
authors.forename: Monika
authors.identifier: 0000-0002-2711-4281
authors.initials: M
authors.lastname: Stoll
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D002896:Chromosomes, Human, Pair 6 / Q000737:chemistry*; D015331:Cohort Studies; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics*; D020690:GTPase-Activating Proteins / Q000235:genetics*; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D014453:Glucuronosyltransferase / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D035781:Siblings; D054556:Venous Thromboembolism / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology
chemical_list: D020690:GTPase-Activating Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C491492:RIMS1 protein, human; C107022:SMAP1 protein, human; C475472:B3GAT2 protein, human; D014453:Glucuronosyltransferase; D019204:GTP-Binding Proteins