title: Joint linkage and association of six single-nucleotide polymorphisms in the factor XIII-A subunit gene point to V34L as the main functional locus.
abstract: OBJECTIVE
  Activated factor XIII (FXIII) crosslinks fibrin to enhance the mechanical strength of a blood clot and increase its resistance to fibrinolysis. The prevalence of a common variant in the FXIII-A gene (V34L) has been reported to be lower in patients with myocardial infarction and ischemic stroke than in controls, suggesting a protective role for this polymorphism in vascular diseases. The current study investigated 6 single-nucleotide polymorphisms (SNPs) within the FXIII A-subunit gene to locate functional polymorphism(s) responsible for variation in FXIII activation.
  
  
  RESULTS
  A total of 201 dizygotic twin pairs were genotyped for 1 promoter and all common nonsynonymous coding polymorphisms in the FXIII A-subunit gene: -246G>A, V34L, Y204F, P564L, V650I, and E651Q. Tests of linkage, association, and combined linkage and association were performed using QTDT software. Significant linkage to the V34L polymorphism (P=5 x 10(-12)) as well as association (P=3 x 10(-49)) was observed. Adjusting for association while performing linkage made the linkage signal disappear for the V34L polymorphism (from chi2=47.55, P=5x10(-12) to chi2=1.30, P=0.25). Only haplotypes containing the 34L allele showed association with FXIII activation.
  
  
  CONCLUSIONS
  Testing multiple SNPs in the FXIII A-subunit gene indicates that V34L is the main functional polymorphism influencing FXIII activation.
authors.affiliation: Twin Research & Genetic Epidemiology Unit, St Thomas' Hospital, London, UK.
authors.forename: Marlies
authors.initials: M
authors.lastname: de Lange
authors.forename: Toby
authors.initials: T
authors.lastname: Andrew
authors.forename: Harold
authors.initials: H
authors.lastname: Snieder
authors.forename: Dongliang
authors.initials: D
authors.lastname: Ge
authors.forename: T Simon
authors.initials: TS
authors.lastname: Futers
authors.forename: Kristina
authors.initials: K
authors.lastname: Standeven
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Grant
authors.forename: Robert A S
authors.initials: RA
authors.lastname: Ariëns
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D002874:Chromosome Mapping; D005176:Factor XIII / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D006239:Haplotypes; D006801:Humans; D007930:Leucine; D008875:Middle Aged; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D014429:Twins, Dizygotic / Q000235:genetics*; D014633:Valine
chemical_list: D005176:Factor XIII; D007930:Leucine; D014633:Valine