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Arteriosclerosis, Thrombosis, and Vascular Biology
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on June 8, 2006

Arteriosclerosis, Thrombosis, and Vascular Biology. 2006
Published online before print June 8, 2006, doi: 10.1161/01.ATV.0000231538.60223.92
A more recent version of this article appeared on August 1, 2006
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Submitted on January 20, 2005
Accepted on May 18, 2006

Joint Linkage and Association of Six Single-Nucleotide Polymorphisms in the Factor XIII-A Subunit Gene Point to V34L As the Main Functional Locus

Marlies de Lange ; Toby Andrew ; Harold Snieder ; Dongliang Ge ; T. Simon Futers ; Kristina Standeven ; Tim D. Spector ; Peter J. Grant ; and Robert A.S. Ariëns *

From the Twin Research & Genetic Epidemiology Unit (M.d.L., T.A., H.S., T.D.S.), St Thomas’ Hospital, London, UK; Department of Biological Psychology (M.d.L.), Vrije Universiteit, Amsterdam, The Netherlands; Georgia Prevention Institute (H.S., D.G.), Department of Pediatrics, Medical College Georgia, Augusta; and Academic Unit of Molecular Vascular Medicine (T.S.F., K.S., P.J.G., R.A.S.A.), The Leeds Institute for Genetics, Health and Therapeutics, Faculty of Medicine and Health, University of Leeds, UK.

* To whom correspondence should be addressed. E-mail: r.a.s.ariens{at}leeds.ac.uk.

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.

Methods and 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=5x10-12) as well as association (P=3x10-49) was observed. Adjusting for association while performing linkage made the linkage signal disappear for the V34L polymorphism (from {chi}2=47.55, P=5x10-12 to {chi}2=1.30, P=0.25). Only haplotypes containing the 34L allele showed association with FXIII activation.

Conclusion--Testing multiple SNPs in the FXIII A-subunit gene indicates that V34L is the main functional polymorphism influencing FXIII activation.
Key words: joint linkage and association analysis • functional locus • FXIIIV34L • FXIII activation • twins






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