A common mutation in the gene for coagulation factor XIII‐A (VAL34Leu): A risk factor for primary intracerebral hemorrhage is protective against atherothrombotic diseases

Abstract

The role of a common polymorphism in the factor XIII A-subunit gene (FXIII Val34Leu) has been recently investigated as a protective genetic factor against arterial and venous thrombosis. In addition, the less frequent Leu34 allele has been described as a risk factor for intracerebral hemorrhage. We evaluated the prevalence of this polymorphism by PCR in three case-control studies of patients diagnosed as having primary intracerebral hemorrhage (PCH, n = 130), coronary heart diseases (CHD, n = 240; myocardial infarction/no myocardial infarction, 120/120), and cerebrovascular diseases (CVD, n = 240; cerebral infarction/transient ischaemic attack, 120/120). The matched control groups consisted of patients admitted to the hospital without history of vascular disease. In addition, 200 healthy subjects were investigated. The frequency of the mutated allele (Leu34) was higher in patients with PCH than in controls (33.8% vs. 23.1%, P = 0.009) and lower in CHD and CVD patients compared to controls (18.1% vs. 25.2%, P = 0.010 and 17.3% vs. 24.2%, P = 0.011, respectively). Moreover, among the patients with CHD, the Leu34 allele was underrepresented in cases with myocardial infarction than without (12.9% vs. 23.3%, P = 0.004) and than in controls (12.9% vs. 25.2%, P < 0.001). Similar findings were obtained in patients with CVD comparing the cases with cerebral infarction versus cases with transient ischaemic attack (12.5% vs. 22.1%, P = 0.008) and versus controls (12.5% vs. 24.2%, P < 0.001). Finally, considering altogether the groups of ischaemic patients (CHD and CVD, n = 480), it was noted a trend towards a higher mean age of the clinical onset in homozygotes for the Leu allele than in the wild types (P = 0.078). This study indicates that in our population possession of the FXIII Val34Leu mutation predisposes to the occurrence of primary intracerebral hemorrhage and protects against cerebral and myocardial infarction. A wider modulatory role in the progression and onset of atherothrombotic diseases could be ascribed to FXIII Val34Leu. Am.

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

“…145 These findings were supported by a smaller study from Italy. 129 A more recent study from the United States did not find a protective effect of Leu34 in a limited number of young women with cerebral infarction. 130 Instead, the authors found that the Phe204 allele of factor XIII, which previously has been linked with an increased risk for miscarriage, 102 was associated with a mild increased risk of ischemic stroke.…”

“…109 Two further studies have reported a protective effect of Leu34 against MI, with similar odds ratios of around 0.6 (Table 3). 128,129 A third study, which investigated acute MI risk in young women, showed a relative risk of 0.8 for the Leu34 allele in this group of patients. 130 Four publications have reported no association between possession of Leu34 and risk of MI.…”

Genetics of stroke

“…However, the role of this polymorphism in ICH is still controversial. Previous reports found that the 34Leu allele predisposes individuals to an increased risk for PICH in an Italian cohort (OR=1.70) [103] . In addition, fibrinogen concentration was found to modify the effect of the polymorphism, such that carriers of the 34Leu allele with a high concentration of fibrinogen may be at risk of hemorrhage [104] .…”

Factor XIII Val34Leu polymorphism in patients with Cardiac Syndrome X

“…The studies focused on the assumption that the presence of FXIII Leu34 allele might have protective effects against arterial and venous thrombosis [21][22][23]. In a study including 398 patients with acute coronary syndrome and 196 healthy control subjects, it was demonstrated that FXIII Leu incidence was significantly low in the patient group and suggested that this polymorphism was protective against acute coronary syndrome [6].…”