title: A novel polymorphism in the factor XIII B-subunit (His95Arg): relationship to subunit dissociation and venous thrombosis.
abstract: BACKGROUND
  Factor (F)XIII B-subunit, which plays a carrier role for zymogen FXIIIA, is highly polymorphic, but the molecular basis for these polymorphisms and their relationship to disease remains unknown.
  
  
  OBJECTIVE
  To screen the FXIIIB gene coding region for common variation and analyze possible functional effects.
  
  
  RESULTS
  We examined the FXIIIB gene by PCR-SSCP and identified three common single nucleotide polymorphisms: A8259G, C29470T and A30899G. A8259G results in substitution of His95Arg in the second Sushi domain. An FXIII tetramer ELISA was developed to analyze B-subunit dissociation from A-subunit (leading to access to the catalytic site of FXIII). Increased subunit dissociation, 0.51 vs. 0.45 (fraction of total tetramer), was found in plasma from subjects possessing the Arg-allele. However, when the variants were purified to homogeneity and binding was analyzed by steady-state kinetics, no difference was observed. The relationship between His95Arg and venous thrombosis was investigated in 214 patients and 291 controls from Leeds. His/Arg + Arg/Arg genotypes were more frequent in patients than controls (22.4% vs. 15.1%). His95Arg was also investigated in the Leiden Thrombophilia Study, in which a similar difference was observed for 471 patients vs. 472 controls (18.5% vs. 14.0%), for a pooled odds ratio (OR) of 1.5 (CI95 1.1-2.0).
  
  
  CONCLUSIONS
  We have identified three FXIIIB polymorphisms, one of which codes for substitution of His95Arg. The Arg95 variant associates with a moderately increased risk for venous thrombosis, and with increased dissociation of the FXIII subunits in plasma, although in vitro steady-state binding between purified subunits was not affected.
authors.affiliation: Academic Unit of Molecular Vascular Medicine, Leeds Institute for Genetics, Health and Therapeutics, University of Leeds, UK.
authors.forename: N
authors.initials: N
authors.lastname: Komanasin
authors.forename: A J
authors.initials: AJ
authors.lastname: Catto
authors.forename: T S
authors.initials: TS
authors.lastname: Futers
authors.forename: A
authors.initials: A
authors.lastname: van Hylckama Vlieg
authors.forename: F R
authors.initials: FR
authors.lastname: Rosendaal
authors.forename: R A S
authors.initials: RA
authors.lastname: Ariëns
mesh_terms: D001665:Binding Sites; D005176:Factor XIII / Q000737:chemistry / Q000235:genetics* / Q000302:isolation & purification; D005260:Female; D005787:Gene Frequency; D005820:Genetic Testing; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007700:Kinetics; D008297:Male; D009154:Mutation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017434:Protein Structure, Tertiary / Q000235:genetics; D012307:Risk Factors; D013923:Thromboembolism / Q000209:etiology / Q000235:genetics*; D020246:Venous Thrombosis / Q000209:etiology / Q000235:genetics*
chemical_list: C064015:factor XIII subunit A; D005176:Factor XIII; C054380:factor XIIIb