title: Genome-wide linkage scan in affected sibling pairs identifies novel susceptibility region for venous thromboembolism: Genetics In Familial Thrombosis study.
abstract: BACKGROUND
  Venous thromboembolism (VTE) is a multicausal disorder involving environmental and genetic risk factors. In many thrombophilic families the clustering of thrombotic events cannot be explained by known genetic risk factors, indicating that some remain to be discovered.
  
  
  OBJECTIVE
  We aimed to identify novel thrombosis susceptibility alleles in a large panel of small thrombophilic families: the Genetics In Familial Thrombosis (GIFT) study.
  
  
  METHODS
  In the GIFT study, 201 families were recruited consisting of 438 siblings with an objectively confirmed VTE at a young age. Multipoint linkage analysis (402 SSR markers) and fine mapping were performed, followed by genotyping of tagging SNPs in positional candidate genes.
  
  
  RESULTS
  Established genetic risk factors such as factor V Leiden, ABO blood group non-O, prothrombin 20210A, fibrinogen gamma 10034T and deficiencies of antithrombin, protein C and protein S were more frequent in GIFT patients than in unselected VTE patients. Linkage supported the presence of novel thrombosis susceptibility loci on 7p21.3-22.2 (LOD score = 3.23) and Xq24-27.3 (LOD score = 1.95). Simulation analysis showed that the chr7 signal was genome-wide statistically significant (P = 0.022). Tagging SNPs (n = 157) in eight positional candidate genes (LOD drop 1.5 regions) were genotyped in GIFT patients and 332 healthy controls. Five chr7 SNPs associated with VTE. SNP THSD7A rs2074597 was responsible for part of the chr7 signal.
  
  
  CONCLUSIONS
  The GIFT panel is rich in established genetic risk factors for VTE, but genetic factors remain unidentified in many families. Genome-wide linkage failed to identify the previously established genetic risk factors for VTE, but identified a novel VTE susceptibility locus on chr7.
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands. mdvisser@lumc.nl
authors.forename: M C H
authors.initials: MC
authors.lastname: de Visser
authors.forename: R
authors.initials: R
authors.lastname: van Minkelen
authors.forename: V
authors.initials: V
authors.lastname: van Marion
authors.forename: M
authors.initials: M
authors.lastname: den Heijer
authors.forename: J
authors.initials: J
authors.lastname: Eikenboom
authors.forename: H L
authors.initials: HL
authors.lastname: Vos
authors.forename: P E
authors.initials: PE
authors.lastname: Slagboom
authors.forename: J J
authors.initials: JJ
authors.lastname: Houwing-Duistermaat
authors.forename: F R
authors.initials: FR
authors.lastname: Rosendaal
authors.forename: R M
authors.initials: RM
authors.lastname: Bertina
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D016022:Case-Control Studies; D005260:Female; D008040:Genetic Linkage; D005819:Genetic Markers / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D035781:Siblings; D011795:Surveys and Questionnaires; D019851:Thrombophilia / Q000235:genetics*; D013927:Thrombosis / Q000235:genetics*; D054556:Venous Thromboembolism / Q000235:genetics*; D055815:Young Adult
chemical_list: D005819:Genetic Markers
keywords: genetic linkage; siblings; thromboembolism; thrombophilia; thrombosis