**14. MTHFR (C677T and A1298C) and MTR A2756G gene polymorphisms**

Hyperhomocysteinemia plays an important role in the pathogenesis of nonvalvular AF. Hyperhomocysteinemia develops as a result of polymorphisms occurring in genes encoding


PCR, polymerase chain reaction; SNP, single nucleotide polymorphism; MTHFR, methylenetetrahydrofolate reductase; MTR, methionine synthase reductase.

**Table 9.** Primer sequences used in PCR for MTHFR C677T and A1298C, MTR A2756G.

homocysteine metabolism. These polymorphisms are thought to be effective in the development of nonvalvular AF, which is the most common arrhythmia in clinical practice. Homocysteine is a highly reactive, sulfur-containing amino acid that occurs as a product of the essential amino acid methionine. Gene polymorphisms known to be associated with homocysteine occur in genes encoding enzymes that play a role in the metabolism of homocysteine. Of these polymorphisms, MTHFR C677T and A1298C gene polymorphisms are associated with a decrease in MTHFR enzyme activity. In addition to these polymorphisms, there is also the MTR A2756G gene polymorphism. Homocysteine plays an important role in the pathogenesis of AF and there are studies showing that there is a significant relationship between increased homocysteine levels and AF. In some studies, there was a significant relationship between MTHFR C677T gene polymorphism and increased plasma homocysteine levels in patients with low folate levels. There are few studies related to MTHFR A1298C and MTR A2756G polymorphisms. In a study conducted by Betti Guisti et al., there was a significant relationship between plasma total homocysteine levels and MTHFR C677T gene polymorphism genotype distributions in patients with nonvalvular AF. Furthermore, no significant relationship was observed between plasma total homocysteine levels and MTHFR 1298AA and MTR 2756GG genotypes in nonvalvular AF patients. Given the combined genotype distributions, it is known that the MTHFR C677T and A1298C gene polymorphisms are related to each other [31]. It is presented primer sequences that used to determine MTHFR (C677T and A1298C) and MTR A2756G gene polymorphisms in **Table 9**.

## **15. Conclusion**

**13. β-fibrinogene 455G/A gene polymorphism**

18 Cardiac Arrhythmias

Various studies have been conducted to investigate the relationship between β-fibrinogen 455G/A polymorphism and ischemic stroke in different populations. In a study conducted by Kessler et al., the AA genotype of the β-fibrinogen 455G/A polymorphism was more observed in patients with major vascular infarction. In a study conducted by Nishiuma et al., in a Japanese population, A allele of β-fibrinogen 455G/A polymorphism was identified as an independent risk factor for hypertensive patients. In a study conducted by Martiskainen et al., a significant association was found between the A-allele and the lacunar infarction susceptibility in the β-fibrinogen 455G/A polymorphism. In a study conducted by Zhang et al., in the Chinese population, β-fibrinogen 455G/A polymorphism was found to be a genetic risk factor in the development of ischemic stroke. There are some meta-analysis studies showing that β-fibrinogen 455G/A polymorphism is associated with ischemic stroke in Chinese or Asian populations. A number of studies have been conducted to determine the association between this polymorphism and ischemic stroke, but no study has shown genetic effects in the pathogenesis of cardioembolic stroke in AF patients. The role of β-fibrinogen 455G/A polymorphism in cardioembolic stroke pathology is unclear. Promoter elements play an important role in regulating gene transcription. Transcription factor binding sites and transcription initiation rates can be varied by a promoter variant. β-fibrinogen 455G/A polymorphism has an important stimulatory effect on the rate of basal and induced transcription rate of the β-fibrinogen gene. There is a significant association between A allele of this polymorphism and increased promoter activity. β-Fibrinogen 455G/A polymorphism is one of the genetic polymorphisms associated with an increase in plasma fibrinogen. The increase in fibrinogen levels of individuals with A allele is greater than the increase in fibrinogen levels of individuals with G allele. Therefore, A allele of β-fibrinogen 455G/A polymorphism was found to be associated with higher fibrinogen level. Platelet aggregation, fibrinogen, an important determinant of blood viscosity, is a component that plays a role in the coagulation cascade. As a result of elevated fibrinogen levels, thrombosis progresses and coagulation increases. In animal studies, fibrinogen applications have been shown to increase thrombosis and embolic status at increasing doses. In addition, it is known that fibrinogen has been implicated in triggering various inflammatory processes. As a basic component of inflammation, fibrinogen can cause impairment of thrombus plaque and is effective in the development of ischemic stroke. As a result of all these events, hemorheological disorders occur. As a result of all these events, hemorheological disorders occur. Other polymorphisms that occur in the fibrinogen gene may also cause high fibrinogen concentrations such as β-fibrinogen 455G/A polymorphism β-fibrinogen 455G/A polymorphism has also been proven to be ineffective in the development of thrombotic events. In a study carried out by Xiaofeng Hu et al., in Chinese AF patients, proved that there is a relationship between

increased risk of cardioembolic stroke and β-fibrinogen 455G/A polymorphism [30].

Hyperhomocysteinemia plays an important role in the pathogenesis of nonvalvular AF. Hyperhomocysteinemia develops as a result of polymorphisms occurring in genes encoding

**14. MTHFR (C677T and A1298C) and MTR A2756G gene** 

**polymorphisms**

Different results have been obtained in gene polymorphism studies to explain the pathogenesis of AF in which environmental and genetic factors play a role together. Differences in the results of these studies may result from different selection criteria for patients and control groups. Moreover, the findings obtained from these studies are different from each other because they are carried out with different races and populations. Identification of genes associated with AF and polymorphisms that occur in these genes will allow us to have information about the underlying mechanisms of the disease in susceptibility to this disease. Identification of candidate genes that play a role in genetic susceptibility to AF will be mentor to the prevention of this disease and the development of new therapies for disease. In order to be able to explain the pathogenesis of AF and to develop appropriate therapies for this disease, comprehensive studies should be conducted with different populations and with a large number of patients and control groups.
