With the advent of large-scale GWAS, a series of common obesity-associated gene loci were identified including FTO (fat mass and obesity associated) as a repeatedly confirmed susceptibility gene with profound relevance for common obesity (Scuteri et al. 2007; Frayling et al. 2007). FTO was found associated with T2DM and subsequently uncovered as a strong determinant of BMI (Scuteri et al. 2007; Frayling et al. 2007). The FTO gene product is an about 60 kD 2-oxoglutarate-dependent nucleic acid demethylase. Despite the strong impact of FTO polymorphisms on obesity risk, the underlying molecular mechanism is still not understood. Nonetheless, a strong association was found for potentially functional SNPs in FTO and early-onset, severe obesity (Frayling et al. 2007). Recent attempts to unravel the functional coupling of FTO to cellular signaling pathways revealed a potential linkage to neuronal plasticity by interference with the NTRK2/BDNF pathway via interaction with the transcription factor C/EBPb (Rask-Andersen et al. 2011). So far, this neuronal mechanism is rather speculative and needs confirmation by further functional studies. FTO has been suggested a common risk determinant for both obesity and T2DM, and linkage of FTO expression to insulin resistance has been reported (Perry and Frayling 2008). Another interesting aspect is the ­dependency of the impact of FTO risk alleles on physical activity. Physical activity may specifically attenuate obesity risk in risk A-allele carriers of the FTO rs9939609 genotype (Andreasen et al. 2008).

For some prominent candidate genes, GWAS has rather excluded a role in common obesity. One example are the leptin receptors, which play a pivotal role in neuroendocrine signaling for the control of energy balance and adiposity (Münzberg and Myers 2005; Bender et al. 2011). Leptin is formed in adipose tissue and communicates the requirements for food intake and energy expenditure to the central nervous system. Leptin signaling impacts on glucose metabolism by determining insulin sensitivity in a way independent of energy balance control. Thus, leptin is considered a crucial determinant of susceptibility for obesity, T2DM, and cardiovascular risk. Common obesity is associated with disturbances in leptin signaling, most prominently involving impaired leptin sensitivity.

Leptin resistance may originate not only from defects in the leptin receptor but also from impaired downstream signal transduction or availability of the hormone at its target sites within the central nervous system. Importantly, the blood–brain barrier represents the main anatomical structure that controls the traffic of adipose tissue-derived hormone(s) to its target receptors and might therefore be involved in leptin resistance (Münzberg et al. 2005). Moreover, leptin sensitivity may be impaired by defects in signaling elements downstream of the hormone/cytokine receptor. Downregulation of leptin sensitivity is considered as a physiological process in response to altered environmental conditions (Penas-Steinhardt et al. 2011), and this adaptive process involves the protein tyrosine phosphatase 1B (PTP1B) and the suppressor of cytokine signaling (SOCS3). Specifically SOCS appear(s) to play a crucial role in both leptin and insulin resistance. The involvement and relevance of genetic factors in leptin resistance, associated with common obesity, is still unclear. Recently, common variants in the gene encoding for the downstream leptin effector JAK2 (Table 4.2), a janus-type protein kinase, were found associated with susceptibility for metabolic syndrome, suggesting a causative role of this polymorphisms in leptin and/or insulin resistance (Penas-Steinhardt et al. 2011).

Another gene of which variants have been found to determine the risk for both obesity and T2DM is PPARG, which encodes a ligand-regulated transcription factor of the nuclear hormone receptor family (PPARγ) that is pivotal for adipogenesis, glucose homeostasis, and insulin resistance (Altshuler et al. 2000). Disturbances in PPARγ signaling and alterations in PPARγ-dependent gene expression have been identified as a hallmark of insulin resistance and T2DM, and a series of SNPs that associate with obesity and/or T2DM have been documented (Jeninga et al. 2009). PPARG harbors not only rare mutations potentially linked to T2DM in a causative manner but also a common variation that is clearly associated with T2DM risk. The common PPARγ P12A polymorphism (rs1801282) has been suggested to exert a profound impact on population risk while modestly affecting individual susceptibility. Interestingly, the less frequent 12A allele was found to confer a decreased risk for the disease although the proline to alanine mutation within the proteins N-terminus reduces transcriptional activity (Altshuler et al. 2000; Gouda et al. 2010). Consistently, another mutation in the N-terminal activation function-1 (AF-1) domain of PPARγ, P113Q, confers enhanced transcriptional activity, which promotes T2DM (Jeninga et al. 2009). This is interesting and unexpected, as impaired PPARγ function has repeatedly been demonstrated to promote insulin resistance due to lack of expression of PPARγ target genes required for insulin signaling. Moreover, pharmacological activation of PPARγ by thiazolidinediones has become an established strategy to increase insulin sensitivity in T2DM therapy. It may be speculated that the 12A variant, which displays modestly reduced transcriptional activity, confers a reduced T2DM risk due to a mildly suppressed function as regulator of adipogenesis. Hence, different functional modifications of PPARγ can result in similar metabolic and cardiovascular outcomes. Recently, this phenomenon was addressed and in part elucidated by resolving the crystal structure of PPARγ associated with its co-receptor RXRα and bound to DNA, ligands, and peptides (Chandra et al. 2008). Several unexpected interactions between missense mutations and specific functional domains were revealed. Furthermore, it is important to note that PPARγ has been recognized to govern also vascular remodeling and inflammatory processes, whereby the transcription factor may impact via this mechanism on atherogenesis and vascular dysfunction (Schiffrin 2005).

An adipose tissue-derived signaling molecule that plays a key role in metabolic and cardiovascular pathophysiology has been identified in the mid-1990s. A 30-kDa adipokine termed adipocyte complement-related protein (Acrp30) or adiponectin (AdiopQ) represents an endogenous regulator of insulin sensitivity and glucose and lipid metabolism. Adiponectin levels are inversely correlated not only with insulin resistance and hyperlipidemia but also with the risk to develop inflammatory diseases and certain types of cancer (Ziemke and Mantzoros 2010). Thus, adiponectin signaling has emerged as a factor involved in obesity-related malignancies. The adiponectin gene is located on chromosome 3q27, within a region that determines susceptibility to T2DM. Production and secretion of the antidiabetic adipokine is governed by PPARγ and is clearly upregulated by thiazolidinediones (Combs et al. 2002). Circulating adiponectin levels are typically low in obese humans (Arita et al. 1999) and are depending on nutrition and exercise. Cellular actions of adiponectin are mediated by two different G-protein-coupled receptors (GPCRs; AdiopR1/R2) and transduced into different signaling cascades including the mTOR, JNK, and STAT3 pathways (Ziemke and Mantzoros 2010). The adipokine was reported to exert cardiovascular protection via enhanced phosphorylation of AMP-activated protein kinase, resulting in phosphorylation and increased activity of NOS3 (eNOS, see Sect. 4.2.5; Morandi et al. 2010). Interestingly, AdipoR1-mediated activation of Ca²⁺ entry and Ca²⁺/calmodulin-­dependent kinase β has recently been suggested as a prominent mechanism by which the adipokine governs mitochondrial functions as well as insulin sensitivity (Iwabu et al. 2010). The adiponectin/AdipoR system may be seen as a critical signaling hub that integrates genetic and environmental/lifestyle factors into cardiovascular risk. Common as well as rare polymorphisms in the adiponectin gene have been found associated with the risk for obesity and T2DM development. Missense mutations as well as a silent mutation that is associated with decreased adiponectin levels were found to increase the risk for obesity and insulin resistance (Stumvoll et al. 2002; Yang et al. 2007b). Interestingly, a SNP (11391 G/A; rs17300539), which is associated with increased levels of the adipokine, apparently not only lacked protection against obesity-associated metabolic disturbances but even increased the risk for childhood obesity and insulin resistance (Morandi et al. 2010). Consequently, enhanced adiponectin levels may be excluded as the basis of the recently documented metabolically healthy state in humans (Karelis et al. 2004).

Besides PPARG two other genes were identified as potential basis of polygenic T2DM. These are calpain 10 (CAPN10) encoding for a cysteine protease (Evans et al. 2001) and TCF7L2, which encodes for a high mobility, box-containing transcription factor implicated in the control of glucose homeostasis and vascular functions. TCF7L2 was suggested to affect susceptibility to T2DM (Grant et al. 2006). This is most likely based on its role in regulation of the insulinotropic hormone glucagon like peptide-1 (GLP-1) as one of the TCF7L2 target genes. TCF7L2 functions as a nuclear receptor for β-catenin, which transduces upstream signals from the canonical Wnt pathway to transcriptional control (Prunier et al. 2004). Wnt signaling has been suggested essential for pancreatic β cell proliferation (Papadopoulou and Edlund 2005; Rulifson et al. 2007) and is linked to a variety of other transcriptional regulators (Mulholland et al. 2005). Interestingly, calpain has been proposed as a determinant of β-catenin activity, indicating potential convergence of the mechanisms by which mutations in CAPN10 and TCF7L2 determine insulin secretion and T2DM risk (Benetti et al. 2005). It is important to emphasize that among the currently identified susceptibility genes for T2DM, the majority impacts on β cell function rather than insulin sensitivity.

Two functionally well-understood gene products involved in glucose sensing and regulation of pancreatic insulin secretion are the ion channel subunits comprising the β cell ATP-sensitive K⁺ channel. KCNJ11 which encodes a 390 aa, two membrane spanning, pore forming channel subunit that combines with the ABC protein SUR1 to form a tetrameric K⁺ channel that is inhibited by intracellular ATP. This protein complex represents a paradigm metabolic sensor (Olson and Terzic 2010). Cellular ATP generation reports glucose supply of the pancreatic β cell and is translated by a membrane potential change and modulation of voltage-gated Ca²⁺ entry into appropriate insulin secretion. Gain-of-function mutations in KCNJ11 promote cell hyperpolarization and impair insulin secretion (Flanagan et al. 2009). Such gain-of-function mutations are the basis of rare forms of diabetes in neonates, and a common gain-of-function mutation E23K (rs5219) has been identified, which is associated with T2DM (Gloyn et al. 2003; Nielsen et al. 2003). As expected for a common gene variant, the functional consequence of this mutation on ATP sensitivity is moderate but leads to impaired glucose homeostasis and enhanced T2DM susceptibility.

This member of the apolipoprotein family is a 299aa (34 kDa) protein that is for a large part produced in hepatocytes.

The three major human isoforms apoE2/3/4 differ in aa positions 112 and 158 by polymorphisms resulting in C/C (apoE2), C/R (apoE3), or R/R (apoE4) containing proteins encoded by the APOEε2/3/4 allele. This polymorphism of APOE exhibits clear ethnic population dependence (Corbo and Scacchi 1999) with a higher frequency of the ε4 allele in Native Americans, Pygmies, and Papuans, while ε3 is prominent in societies of long agricultural history. Structural apoE diversity can be related to function and pathophysiology as the aa residues in positions 112 and 158 determine the interaction of apoE with lipoprotein particles and LDL receptors, thereby affecting blood cholesterol levels. ApoE2 confers an approximately 50-fold reduction in binding to LDL-R as compared to apoE3 and apoE4 (Raffai et al. 2001). Besides the impact on lipid homeostasis, APOE polymorphisms have been clearly demonstrated to affect signaling pathways involved in immune reactions and inflammatory responses (see Zhang et al. 2011). Polymorphism governs the ability of ApoE to modulate/suppress cytokine secretion such as TNF-α and IL-1b with E2 conferring highest and E4 lowest effectiveness. Consistently, APOE polymorphisms were found to affect mortality infectious diseases (Zhang et al. 2011). Moreover APOE genotype strongly impacts on endothelial function and signaling, and apoE4-VLDL has been shown to counteract the antiapoptotic activity of HDL in the endothelium by suppressing PI3K/Akt pathway via a mechanism involving interaction with LDL-R (DeKroon et al. 2006). Genetic variations of APOE are robustly associated with the risk for a variety of diseases that determine longevity, including not only atherosclerosis and cardiovascular events but also infections as well as neurodegenerative disorders such as Alzheimer’s disease (Kim et al. 2009). It is important to note that the role of apoE as a modulator of immune responses is certainly relevant for its significance in cardiovascular disease.

An example for a novel gene and molecular player in lipid homeostasis more recently identified via GWAS is sortilin 1. A genome-wide screen in patients with coronary artery disease identified 1p13.3 as locus associated with both elevated LDL-C levels and cardiovascular events. Among several SNPs within this locus, all residing in a noncoding region, rs12740374, an intronic SNP in CELSR2 (cadherin, EGF LAG-seven-pass G-type receptor), was found to generate a C/EBP transcription factor interaction site and was therefore considered a causative variation (Musunuru et al. 2010). The SNP results in enhanced expression of sortilin 1 in the liver. Sortilin 1 is a multi-ligand receptor and a member of the VSP10P domain receptor family also known as neurotensin receptor 3, which is capable of interaction with apolipoproteins, lipoprotein lipase, and LDL-R-associated protein (RAP). Cellular localization of sortilin 1 includes both the cell surface and intracellular compartments, and a role of the multi-ligand receptor in endocytosis and protein trafficking has been reported (Nielsen et al. 2001). Sortilin 1 is likely to interfere with hepatic secretion of apolipoproteins (Kjolby et al. 2010) and has been demonstrated to interfere with LDL uptake into cells (Linsel-Nitschke et al. 2010). However, diverging results have been obtained in various experimental models studying the effects of genetic manipulation of sortilin 1 expression on plasma cholesterol levels (Musunuru et al. 2010; Linsel-Nitschke et al. 2010). Thus, the mechanism linking hepatic expression of this novel player in lipid homeostasis and cardiovascular risk needs further investigations.

PCSK9 represents a typical example for a gene harboring both SNPs causing rare, severe mutations resulting in profound changes in LDL-C levels (>100 md/dl) but also more common variants (frequency 19 %) with mild effects (3 mg/dl) (Willer et al. 2008). Proprotein convertase subtilisin/kexin type 9 controls LDL-C plasma levels and influences the cellular fate of LDL-Rs. Representing a secreted proteinase, PCSK9 binds to LDL-Rs and targets the receptors to the lysosome promoting its degradation (Horton et al. 2007, 2009). Consistently, rare gain-of-function mutations are associated with hypercholesterinemia (Abifadel et al. 2003) and clearly increase the risk for cardiovascular events. Protective loss-of-function mutations are more common and reduce LDL-C levels. One example is the nonsynonymous R46L polymorphism (rs11591147, frequency about 3 %) which results in moderate reductions in plasma cholesterol (13 mg/dl) (Sanna et al. 2011) and a strong reduction in cardiovascular risk, which appears not sufficiently explained by the change in LDL-C (Benn et al. 2010). This discrepancy may be taken as an indication for an additional protective mechanism of the R46L mutation besides lowering plasma cholesterol (Benn et al. 2010). However, so far animal models have clearly demonstrated the impact of PCSK9 on lipid metabolism (Frank-Kamenetsky et al. 2008) while lipid-independent effects potentially related to cardioprotection are speculation. Importantly, PCSK9 has recently been demonstrated as a highly attractive target for pharmacological intervention. For example, a monoclonal antibody against PCSK9 has been tested which produces significant reductions of LDL-C in patients with familial hypercholesterinemia (Stein et al. 2012).

Epidemiology has identified plasma Lp(a) levels as a predictor of cardiovascular risk (De la Peña-Díaz et al. 2000; Kamstrup 2010). Lp(a) contains the glycoprotein apo(a), which is linked by a disulfide bond to ApoB-100 (Guevara et al. 1993, see also Chap. 13). Apo(a) is structurally related to a family of serine proteases, displaying a high degree of similarity with plasminogen. The apoA gene is localized in close proximity to the plasminogen gene on chromosome 6, and its expression is strongly determined by polymorphisms in the 5′-flanking region of the gene (Suzuki et al. 1997). Moreover, structural polymorphism in apo(a) leading to isoforms with size differences has been recognized as basis of variability in Lp(a) plasma levels. The apo(a) size variation arises from the presence of a variable number of repetitive domains, which are homologous to the plasminogen kringle-4 (K4). The structural similarity to plasminogen combined with a lack of fibrinolytic protease function results in a substantial antifibrinolytic potential based on competitive interference with the plasminogen-fibrin interaction (Loscalzo et al. 1990). Apo(a) polymorphism affects both Lp(a) plasma levels and antifibrinolytic activity and thereby cardiovascular risk. Size polymorphism based on a copy number variant has been reported as a basis of variation of plasma Lp(a) levels among ethnic groups (Kraft et al. 1996a, b), and a common nonsense mutation in the K4-2 domain was identified, which results in low Lp(a) levels (Parson et al. 2004). More recently, a nonsynonymous SNP (rs3798220) encoding an Ile>Met exchange in the pseudoprotease domain was found associated with elevated circulating Lp(a) and cardiovascular risk (Luke et al. 2007). Notably, apo(a) polymorphism represents an established paradigm for overlap in the genetic basis of disturbances in lipid metabolism and hemostasis, specifically affecting the fibrinolytic system.

VF is closely related to changes in the structure and function of HERG (KCNQ1, KCNH2, KCNE1) and/or its regulatory subunits (Amin et al. 2012; Nishio et al. 2009; Sinner et al. 2008). A polymorphism of KCNH2 (SNP rs1805123) associated with VF leads to the substitution of lysine 897 by threonine in the delayed rectifier potassium channel. The exact effect of the genetic variant on channel function is still a matter of controversy (Bezzina et al. 2003; Männikkö et al. 2010; Paavonen et al. 2003). However, a rather rare SNP (rs1805128) affecting KCNE1 (D85N) has been demonstrated to be associated with functional defects in delayed rectifiier potassium channel (IKr, Nishio et al. 2009) and a large gene survey identified the KCNE1-D85N as a possible modulator of drug-induced torsades de pointes (Kääb et al. 2012).

Another intermediate phenotype involved in VF and SCD is represented by the mechanisms responsible for PR interval and QRS duration. Here, voltage-gated sodium channels (Nav1.5, SCN5A) (Shinlapawittayatorn et al. 2011) have been demonstrated to be affected by polymorphisms that are also targets of Mendelian traits leading to cardiac conduction disease (Schott et al. 1999). SCN10A, encoding Nav1.8, is the gene affected by SNP rs6795970, a single-nucleotide polymorphism responsible for changes in PR interval and QRS duration (Holm et al. 2010).

GWAS studies have identified a series of genetic loci that confer susceptibility to AF. Among these loci in particular, 4q25 near the developmental transcription factor PITX2 has received particular attention (Liu et al. 2012). PITX2 is essential in embryonic development and governs development of cardiac left-right asymmetry, pulmonary myocardium, and the sleeve of cardiomyocytes that reaches into the pulmonary vein, which represents a critical origin of triggered activities leading to AF. PITX2 is a downstream target of Wnt/β-catenin signaling and, in the heart, a pivotal player in developmental signaling pathways involving factors such as Nodal, Shox2, and Tbx3 (Poelmann et al. 2008; Tessari et al. 2008; Christoffels et al. 2010).

PITX2 is the closest gene to common risk variants on chromosome 4q25 with the first identified by Gudbjartsson et al. (2007) (rs2200733 and rs2220464; see Table 4.4).

The gene is responsible for development and identity of atrial and ventricular excitability properties as well as pulmonary myocardium. This key role has been established by genetic mouse models demonstrating a potential role in AF (Wang et al. 2010a). PITX2 is considered as an inhibitor of genetic programs essential for pacemaker functions and to govern the potential for ectopic activity. Human atrium displays expression of the PITX2c isoform which was found downregulated in AF patients (Kirchhof et al. 2011). Moreover, PITX2c-deficient mice were shown to display increased sensitivity to programmed stimulation-induced AF. Importantly, lack of PITX2c was suggested to affect ion channel expression in the atrium (Chinchilla et al. 2011), including KCNQ1 and may be also other K⁺ channels essential for atrial repolarization.

Cardiac electrophysiologists have for a long time ignored the presence and/or significance of small-/intermediate-type Ca²⁺-activated K⁺ channels. Only recently these channels got into the spotlight of cardiology since expression in human hearts (Xu et al. 2003) specifically in atrium has been demonstrated. Ellinor et al. (2012) recently identified a polymorphism (rs133763339) on chromosome 1q21 that is associated with lone AF. This common variation affects a member of the intermediate/small conductance Ca²⁺-activated K⁺ channel family that appears of importance for atrial action potential morphology (KCNN3). In fact, pharmacological experiments suggest that inhibition of KCNN3 prolongs atrial action potential duration and is able to terminate AF (Diness et al. 2010). Thus, KCNN3 has emerged as an attractive target for AF therapy. It is important to note that AF is of pivotal importance as a cardiovascular risk factor promoting heart failure and stroke due to disturbances in cardiac mechanics, hemodynamics, and hemostasis.

Thrombotic events in coronary arteries are central for the development of MI. Twin and sibling studies have shown that inherited risk factors contribute significantly to the development of coronary artery disease (CAD) and ischemic stroke (Brass et al. 1996, 1992). The formation of blood clots that occlude major arteries represents the leading complication of arteriosclerosis. In the 1990s it became evident that besides mutations in coding regions of genes, polymorphisms in regulatory elements of coagulation factor genes, particularly in the promoter regions, have an important impact on blood coagulation because of their effect on the concentration of the proteins (Franco and Reitsma 2001; Blake et al. 2001). For some coagulation factors, reproducible data exist regarding the contribution of various SNPs to the variability of plasma concentration and consequently an effect on the clinical phenotype.

Fibrinogen is a 340-kDa glycoprotein consisting of three nonidentical polypeptide chains (α, β, and γ) linked by disulfide bridges. The three genes encoding fibrinogen Bβ (FGB), Aα (FGA), and γ (FGG) are clustered in a region of ∼50 kilobases (kb) on human chromosome 4. Each gene is separately transcribed and translated to produce the nascent Aα, Bβ, and γ-polypeptides, which assemble to form fibrinogen. Fibrinogen levels are subject to biological variation. They are upregulated during acute phase reactions via the activation of the IL-6 responsive elements in the promoter region of all three fibrinogen chains. High levels of fibrinogen have been associated with the development of arterial thrombosis. Prospective studies such as the Northwick Park Heart Study, the Gothenburg study, and the PROCAM study have related elevated fibrinogen levels to MI and stroke (Heinrich et al. 1994; Wilhelmsen et al. 1984). Fibrinogen levels cluster with other cardiovascular risk factors including hypertension, diabetes, smoking, and peripheral arterial disease (Lee et al. 1993; Endler and Mannhalter 2003).

Genetic factors contribute to the variability of fibrinogen plasma levels. The two most frequently studied polymorphisms are the −455G>A (rs1800790) polymorphism located in the promoter region of the fibrinogen beta chain (FGB) and the 312Thr>Ala (rs6050) polymorphism in the fibrinogen alpha chain (FGA). −455G>A is in complete linkage disequilibrium with the −148C>T polymorphism in the IL-6 responsive element and leads to increased plasma fibrinogen levels, while 312Thr>Ala is associated with modestly lower plasma fibrinogen levels. The FGA rs6050 single-nucleotide polymorphism (SNP) indicates a decreased risk, whereas the FGB −455G>A SNP seems to increase the risk of stroke. The risk of myocardial infarction does not seem to be altered by either SNP (Siegerink et al. 2009). Interestingly, an association between poststroke mortality and the 312Thr>Ala polymorphism in patients with atrial fibrillation had been observed by Carter et al. (1999). Thus, although the general risk for MI or stroke apparently is not significantly affected by fibrinogen polymorphisms, they may play a role in subgroups of patients.

Currently, the role of fibrinogen polymorphisms in thrombotic disease has still not been definitely proven. The available results suggest that plasma fibrinogen levels could be more important as risk factors for ischemic stroke than for myocardial infarction.

Fibrinogen is cleaved by thrombin leading to the generation of fibrin monomers which have to polymerize and be cross-linked by factor XIII. This cross-linking of the fibrin polymers is essential for clot stability and its resistance to fibrinolysis (Siebenlist et al. 2001). Fibrin structure and stability have been linked to thrombotic diseases. Biochemical studies of fibrinogens have examined the interactions that mediate the conversion of soluble fibrinogen to the insoluble fibrin network. These studies show that fibrin structure modulates the enzymatic lysis of the fibrin network. Thus, the molecular mechanisms that control structure also control stability. FXIII which catalyzes the formation of covalent ε(γ-glutamyl)-lysyl bonds between the γ and α chains of fibrin plays an important role in this process. Factor XIII ­circulates in plasma as a heterotetramer consisting of two catalytic A-subunits and two carrier protein B-subunits (A2B2). Monocytes and megakaryocytes synthesize FXIII, and it has also been identified in platelets. In the F13 gene, a common G>T polymorphism at nt163 (rs5985, c.103G>T), leading to a valine (Val) to leucine (Leu) substitution at amino acid position 35 (nomenclature according to HGVS, three amino acids away from the thrombin activation site in exon 2 of the FXIII A-subunit gene), was described (Mikkola et al. 1994). Due to the close proximity of the thrombin activation site, this polymorphism is thought to impair FXIII activation and contribute to the pathogenesis of thrombotic disorders (Kohler and Grant 1999). The Val35Leu polymorphism leads to faster activation of FXIII. In vitro, the 35Leu allele confers an increased catalytic activity to FXIII but decreases clot stability and resistance to fibrinolysis by alterations of the clot structure (Ariens et al. 2000). A lower prevalence of the 35Leu allele has been found in subjects with MI or deep vein thrombosis compared to healthy controls (Corral et al. 2000; Bereczky and Muszbek 2011). In spite of some positive reports, the importance of the FXIII 35Leu genetic variant for premature coronary artery disease (CAD) and thrombotic events remains controversial. The evaluation of its effect on long-term clinical outcome defined as a composite of cardiovascular death, recurrent MI, and revascularization indicated no association of FXIII 35Leu with premature CAD or clinical outcome. However, carriage of factor XIII 35Leu leads to a stepwise decrease in the rate of fibrinolysis with a significant gene dose effect in patients (Silvain et al. 2011). The role of the FXIII Val35Leu polymorphism in ischemic stroke is still unclear. Our group found no differences in genotype distribution between patients with ischemic stroke and healthy controls. This suggests that an association of the FXIII Val35Leu polymorphism with a decreased risk of ischemic stroke or an increased risk of intracerebral hemorrhage is unlikely (Endler et al. 2003). The results were recently confirmed by Shemirani et al. (2010) who also found no association between the risk of acute ischemic stroke and FXIIIA 35Leu carriership in either gender. Thus, while there is increasing evidence that the 35Leu allele protects from MI, its role in the development of stroke needs to be clarified.

In mammalian blood the fibrinolytic system is essential for the dissolution of blood clots and the maintenance of a patent vascular system. Abnormalities in the fibrinolytic system have been implicated in the pathogenesis of atherosclerotic diseases such as myocardial infarction and stroke (Babu et al. 2012). Fibrinolysis is initiated by specific interactions between its main components, the inactive proenzyme plasminogen, which is converted to the active enzyme plasmin, which degrades fibrin. Two plasminogen activators exist in blood: tissue-type plasminogen activator (tPA) and urokinase. Activation of plasminogen by tPA is enhanced in the presence of fibrin or at the endothelial cell surface. Inhibition of fibrinolysis occurs either at the level of plasminogen activation by a plasminogen activator inhibitor or at the level of plasmin by a2-antiplasmin.