Allele-allele interaction within the F13A1 gene: a risk factor for ischaemic heart disease in Spanish population.

Atherothrombotic diseases are a group of diseases that cause the majority of population morbidity in industrialized countries. Genetic variation in causative or susceptible genes constitutes the basis of molecular mechanisms, that together with environmental factors, lead to disease development [1]. Plasma coagulation factor XIII (FXIII) is a pro-transglutaminase essential for haemostasis which, after being activated by thrombin and Ca2+, plays an important role in the final stages of blood coagulation and in the regulation of fibrinolysis. Plasma FXIII consists of two A subunits and two B subunits (carrier molecule), encoded by genes located on chromosomes 6p25-p24 and 1q31-q32.1, respectively. Activated FXIII cross-links covalently adjacent fibrin monomers and stabilizes the structure of blood clot [2]. Genetic variation in the sequence of FXIII A subunit (F13A1) has been associated with atherothrombotic disease and functional changes in FXIII levels and activity. The Val34Leu polymorphism (rs5985) is a non-synonymous single-nucleotide polymorphism (SNP) located in exon 2 of F13A1, three residues away from the thrombin cleavage site [3]. Studies of fibrin structure and clot permeability showed how Leu34 allele modulates the association of loss of permeability with high fibrinogen concentrations [4]. Individuals carrying Leu34Leu34 genotype produced fibrin with thicker fibres at elevated fibrinogen concentrations, preventing physiological conditions associated with thrombotic risk and pointing out a gene-environment interaction. Controversial results on its potential role in coronary artery disease (CAD) susceptibility have been reported. Whereas some epidemiological studies indicated amain protective role of Leu34 against thrombosis in different populations in the UK, Finland, Northern France, Northern Italy, and Turkey [5–10], it has not been confirmed in other populations, such as Spain, Southern France, Netherlands, Italy, Sardinia, and Hungary [11–17], as reviewed by Vokó et al [18]. Another important non-synonymous SNP, Pro564Leu (rs5982), located in exon 11 of F13A1 on the barrel 1 domain of the FXIIIA subunit [3], is implicated in the interactions between the A and B subunits of FXIII [19], affecting the supply of activated FXIII. Although this polymorphism has been less studied, evidence of association of the Leu564 allele with hemorrhagic stroke has been reported [20]. As well as SNPs, two additional tetranucleotide microsatellite polymorphisms (STR) flanking the F13A1 coding sequence have also been described: the F13A1-STR [21] and the D6S477. The former is located 704 bp upstream from the transcription initiation site and the latter 3692 bp downstream the end of transcription. To date, there are nodata fromassociation studies for thesemicrosatellite polymorphisms. The lack of replication in genetic epidemiological studies could be attributed to gene-gene interactions. Moore [22] suggested that