Association of a Common Polymorphism in the Factor XIII Gene with Myocardial Infarction

Abstract

SummaryFactor XIII when activated by thrombin, crosslinks fibrin, however its role in thrombotic disorders is unknown. A common point mutation (G T) in exon 2 of the A-subunit gene which codes for an amino acid change three amino acids from the thrombin activation site (Factor XIIIVal34Leu) is a candidate for a role in the pathogenesis of acute myocardial infarction. Factor XIII genotype frequencies were determined in a case-control study of 398 caucasian patients and 196 healthy controls. Patients had undergone angiography for investigation of coronary artery disease and were evaluated for a history of myocardial infarction. The prevalence of the mutation was lower in patients with myocardial infarction than without (32% vs. 50%), p = 0.0009 and than in controls (32% vs. 48%), p = 0.005. Patients possessing the mutation with a history of myocardial infarction had higher PAI-1 concentrations (mean, 27.9 vs. 16.7 ng/ml, p = 0.004) and the PAI-1 4G/4G genotype was commoner (43% vs. 26%, p = 0.03). There was no difference in PAI-1 4G/4G genotype (33% vs. 32%) and PAI-1 levels (mean, 21.0 vs. 20.9 ng/ml) in patients possessing wild type with MI compared to those without MI. These results indicate that the G T mutation coding for factor XIIIVal34Leu is protective against myocardial infarction and suggest a mechanism whereby elevated levels of PAI-1 may contribute to vascular risk.

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

“…The first was carried out in a cohort of consecutive individuals undergoing coronary angiography and reported a highly significant underrepresentation of the Leu34 allele in subjects with a history of MI as compared with angiographic subjects who had no history of MI and as compared with controls. 108 These results suggested that possession of the Leu allele was protective against MI, an impression reinforced by the observation that, in carriers of the Leu allele, cardioprotection was lost in the presence of increasing degrees of insulin resistance as estimated by the homeostasis model assessment method 125 and in the presence of high levels of the fibrinolytic inhibitor plasminogen activator inhibitor-1 (PAI-1). 126 These findings indicated a major gene (factor XIII Leu34)-environment (insulin resistance) interaction that modulated vascular risk.…”

“…Val34Leu is relatively common, with an allele frequency of around 0.25 to 0.30 in the white population. [108][109][110] The Leu allele frequency varies among different populations, being highest in whites (0.25-0.30) and American Indians (0.29), with a maximum of 0.40 among Pima Indians. 109,110 In South Asians and in African populations, however, frequency of the Leu34 allele is lower, at around 0.13 and 0.17, respectively, 109,110 and it reaches its lowest point in the Japanese at 0.01.…”

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

“…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.…”

“…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 .…”

“…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.…”