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.

OBJECTIVES:

To screen the FXIIIB gene coding region for common variation and analyze possible functional effects.

METHODS AND 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: N Komanasin, A J Catto, T S Futers, A van Hylckama Vlieg, F R Rosendaal, R A S Ariëns
• Journal: Journal of thrombosis and haemostasis : JTH (J Thromb Haemost) Vol. 3 Issue 11 Pg. 2487-96 (Nov 2005) ISSN: 1538-7933 [Print] England
• PMID: 16241947 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• factor XIII subunit A
• Factor XIII
• factor XIIIb

Topics

• Binding Sites
• Factor XIII (chemistry, genetics, isolation & purification)
• Female
• Gene Frequency
• Genetic Testing
• Genotype
• Heterozygote
• Homozygote
• Humans
• Kinetics
• Male
• Mutation
• Phenotype
• Polymorphism, Single Nucleotide
• Protein Structure, Tertiary (genetics)
• Risk Factors
• Thromboembolism (etiology, genetics)
• Venous Thrombosis (etiology, genetics)