Association of FXIII Val34Leu with decreased risk of myocardial infarction in Finnish males

Wartiovaara, Ulla; Perola, Markus; Mikkola, Hanna; Tötterman, K. J.; Savolainen, Vesa; Penttilä, Antti; Grant, Peter J.; Tikkanen, Matti J.; Vartiainen, Erkki; Karhunen, Pekka J.; Peltonen, Leena; Palotie, Aarno

doi:10.1016/s0021-9150(98)00241-x

Cited by 118 publications

(104 citation statements)

References 13 publications

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“…A study from Finland confirmed the protective association of factor XIII Leu34 in a combined postmortem and coronary angiography study but failed to demonstrate an interaction with the PAI-1 4G/5G promoter genotype. 127 Interestingly, the prevalence of the Leu allele was reported as being lowest in the Eastern Kainuu area, in which the highest risk of MI is found in Finland. These findings are similar to those described for Asians living in Britain, who both are at high vascular risk and have a low prevalence of the Leu34 allele.…”

Section: Factor XIII Val34leu and Coronary Artery Diseasementioning

confidence: 99%

Role of factor XIII in fibrin clot formation and effects of genetic polymorphisms

Ariëns

Lai

Weisel

et al. 2002

Blood

329

272

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Factor XIII and fibrinogen are unusual among clotting factors in that neither is a serine protease. Fibrin is the main protein constituent of the blood clot, which is stabilized by factor XIIIa through an amide or isopeptide bond that ligates adjacent fibrin monomers. Many of the structural and functional features of factor XIII and fibrin(ogen) have been elucidated by protein and gene analysis, site-directed mutagenesis, and x-ray crystallography. However, some of the molecular aspects involved in the complex processes of insoluble fibrin formation in vivo and in vitro remain unresolved. The findings of a relationship between fibrinogen, factor XIII, and cardiovascular or other thrombotic disorders have focused much attention on these 2 proteins. Of particular interest are associations between common variations in the genes of factor XIII and altered risk profiles for thrombosis. Although there is much debate regarding these observations, the implications for our understanding of clot formation and therapeutic intervention may be of major importance. In this review, we have summarized recent findings on the structure and function of factor XIII. This is followed by a review of the effects of genetic polymorphisms on protein structure/function and their relationship to disease. (Blood. 2002;100:743-754)

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Section: Factor XIII Val34leu and Coronary Artery Diseasementioning

confidence: 99%

Role of factor XIII in fibrin clot formation and effects of genetic polymorphisms

Ariëns

Lai

Weisel

et al. 2002

Blood

329

272

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“…Table I shows sequences for Fibrinogen A␣ (amino acids 7-20) (Fbg A␣- (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)), Factor XIII activation peptide (aa 28 -41) (FXIII AP-(28 -41)), D-Phe-Pro-Arg-chloromethylketone (PPACK), and thrombin receptor (aa 32-45) (PAR1- (32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)). In each peptide, there is an Arg residue at the P 1 position 2 that binds within the catalytic cleft of thrombin forming a salt bridge with thrombin amino acid 3 Asp 189 .…”

mentioning

confidence: 99%

“…X-ray crystal studies of PAR1- (32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45) and PPACK reveal that thrombin contains a hydrophobic surface that can accommodate this proline (9,10). Fbg A␣- (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20), by contrast, contains a Val at the P 2 position instead of the Pro. The Phe at the P 9 position, however, is proposed to compensate for the absence of the Pro.…”

mentioning

confidence: 99%

“…A mutation within the Factor XIII AP segment, Val 34 to a Leu (V34L), has been correlated with protection against myocardial infarction (15)(16)(17)(18). This protection may be mediated through the formation of weaker fibrin structures.…”

mentioning

confidence: 99%

“…An HPLC assay was used to compare the ability of thrombin to hydrolyze a segment of the Fibrinogen A␣ chain (Fbg A␣- (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)), the native Factor XIII Activation Peptide (FXIII AP-(28 -41)), and the mutant peptide (FXIII AP-(28 -41), V34L). The kinetic values K m , k cat , and k cat /K m were determined for each peptide.…”

mentioning

confidence: 99%

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Examining Thrombin Hydrolysis of the Factor XIII Activation Peptide Segment Leads to a Proposal for Explaining the Cardioprotective Effects Observed with the Factor XIII V34L Mutation

Trumbo

Maurer

2000

Journal of Biological Chemistry

130

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In the blood coagulation cascade, thrombin cleaves fibrinopeptides A and B from fibrinogen revealing sites for fibrin polymerization that lead to insoluble clot formation. Factor XIII stabilizes this clot by catalyzing the formation of intermolecular cross-links in the fibrin network. Thrombin activates the Factor XIII a 2 dimer by cleaving the Factor XIII activation peptide segment at the Arg 37 -Gly 38 peptide bond. Using a high performance liquid chromatography assay, the kinetic constants K m , k cat , and k cat /K m were determined for thrombin hydrolysis of fibrinogen A␣-(7-20), Factor XIII activation peptide-(28 -41), and Factor XIII activation peptide-(28 -41) with a Val 34 to Leu substitution. This Val to Leu mutation has been correlated with protection from myocardial infarction. In the absence of fibrin, the Factor XIII activation peptide-(28 -41) exhibits a 10-fold lower k cat /K m value than fibrinogen A␣-(7-20). With the Factor XIII V34L mutation, decreases in K m and increases in k cat produce a 6-fold increase in k cat /K m relative to the wild-type Factor XIII sequence. A review of the x-ray crystal structures of known substrates and inhibitors of thrombin leads to a hypothesis that the new Leu generates a peptide with more extensive interactions with the surface of thrombin. As a result, the Factor XIII V34L is proposed to be susceptible to wasteful conversion of zymogen to activated enzyme. Premature depletion may provide cardioprotective effects.Fibrinogen is composed of three chains A␣, B␤, and ␥ arranged into the dimer (A␣B␤␥) 2 . In blood coagulation, the serine protease thrombin cleaves the N-terminal portions of the A␣ and B␤ chains. For the A␣ chain, cleavage occurs at the Arg 16 -Gly 17 peptide bond and fibrinopeptide A (FpA) 1 is released; whereas, for the B␤ chain, cleavage occurs at the Arg 14 -Gly 15 peptide bond and fibrinopeptide B (FpB) is released. Removal of the fibrinopeptides leads to exposure of fibrin polymerization sites that react to form an insoluble blood clot (reviewed in Ref. 1).Activated Factor XIII helps stabilize this clot structure by catalyzing the formation of intermolecular ␥-glutamyl-⑀-lysine cross-links in the fibrin network and in fibrin-enzyme complexes. Factor XIII is a member of a family of enzymes known as transglutaminases that have a catalytic triad, similar to cysteine proteases, composed of amino acids Cys 314 , His 373, and Asp 396 . In plasma, Factor XIII is expressed as a zymogen of the form a 2 b 2 . In the presence of thrombin and calcium, the a 2 unit is released and activated. By contrast, platelet Factor XIII is expressed as the zymogen a 2 unit (reviewed in Ref. 2).The Factor XIII a 2 dimer contains in the N-terminal portion of each monomer a sequence known as the activation peptide (3, 4). Each activation peptide segment crosses the dimer interface and extends over the catalytic site of the opposing Factor XIII a subunit. Cleavage of the activation peptide segments by thrombin at the Arg 37 -Gly 38 peptide bond aids in exposure of the Fact...

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Racial and genetic determinants of plasma factor XIII activity

et al. 2000

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Factor XIII (F XIII), a plasma transglutaminase, is essential for normal hemostasis and fibrinolysis. Plasma F XIII consists of two catalytic A (F XIIIA) and two non‐catalytic B (F XIIIB) subunits. Activated F XIII is involved in the formation of fibrin gel by covalently crosslinking fibrin monomers. As the characteristics of the fibrin gel structure have been shown to be associated with the risk of coronary heart disease (CHD), F XIII activity may play a seminal role in its etiology. In this investigation, we determined plasma F XIII activity in two racial groups, including Asian Indians (n = 258) and Chinese (n = 385). Adjusted plasma F XIII activity was significantly higher in Indian men (142 vs. 110%; P < 0.0001) and women (158 vs. 111%; P < 0.0001) than their Chinese counterparts. As compared to Indians where the distribution of F XIII activity was almost normal, in Chinese it was skewed towards low activity. In both racial groups, bivariate and multivariate analyses showed strong correlation of F XIII activity with plasma fibrinogen and plasminogen levels. Race explained about 25% of the variation in F XIII activity even after the adjustment of significant correlates. We also determined the contribution of common genetic polymorphisms in the F XIIIA and F XIIIB genes in affecting plasma F XIII activity. Both loci showed significant and independent effects on plasma F XIII activity in Indians (F XIIIA, P < 0.01; F XIIIB, P < 0.05) and Chinese (F XIIIA, P < 0.0001; F XIIIB, P < 0.13) in a gene dosage fashion. This study shows that both racial and genetic components play a significant role in determining plasma F XIII activity, and consequently it may affect the quantitative risk of CHD. Genet. Epidemiol. 19:440–455, 2000. © 2000 Wiley‐Liss, Inc.

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Association of FXIII Val34Leu with decreased risk of myocardial infarction in Finnish males

Cited by 118 publications

References 13 publications

Role of factor XIII in fibrin clot formation and effects of genetic polymorphisms

Role of factor XIII in fibrin clot formation and effects of genetic polymorphisms

Examining Thrombin Hydrolysis of the Factor XIII Activation Peptide Segment Leads to a Proposal for Explaining the Cardioprotective Effects Observed with the Factor XIII V34L Mutation

Racial and genetic determinants of plasma factor XIII activity

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