**Mechanisms**

[16] Afeltra A, Galeazzi M, Ferri GM, Amoroso A, De Pità O, Porzio F, Bonomo L. Expres‐ sion of cd69 antigen on synovial fluid t cells in patients with rheumatoid arthritis and

[17] Ferenczi K, Burack L, Pope M, Krueger JG, Austin LM. Cd69, hla-dr and the il-2r identify persistently activated t cells in psoriasis vulgaris lesional skin: Blood and

[18] McDonald GB, Jewell DP. Class ii antigen (hla-dr) expression by intestinal epithelial

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[20] Oczenski W, Krenn H, Jilch R, Watzka H, Waldenberger F, Köller U, Schwarz S, Fitz‐ gerald RD.Hla-dr as a marker for increased risk for systemic inflammation and septic

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**Chapter 4**

**New Candidate Genes in Atrial Fibrillation**

**of Different Etiological Origins**

Additional information is available at the end of the chapter

Svetlana Nikulina, Vladimir Shulman, Ksenya Dudkina, Anna Chernova and

Oksana Gavrilyuk

**1. Introduction**

http://dx.doi.org/10.5772/53527

**Polymorphisms of the Alpha 2-Beta-Adrenoceptor and**

**the Endothelial NO Synthase Genes in Atrial Fibrillation**

Molecular and genetic bases of atherosclerosis, cardiomyopathy, hypertension are the most studied among cardiovascular diseases. Recently, search for genetic markers associated with various rhythm disorders and conduction attracts researchers. The greatest attention is paid to the genetic aspects of atrial fibrillation as the most frequent and dangerous arrhythmia. Atrial fibrillation represents the most common type of arrhythmia in clinical practice. The prevalence of atrial fibrillation is 0.4% in the general population and it increases with age [1]. According to the Framingham study atrial fibrillation doubles mortality in cardiac pa‐ tients and is responsible for 1 \ 3 thromboembolic episodes [2-4]. That's why finding of ge‐ nealogical and genetic aspects of atrial fibrillation predictors of its occurrence is relevant and

In most cases, this rhythm disorder is secondary, i.e. it's caused by a disease. But at least in the 1 \ 3 cases etiology of atrial fibrillation cannot be established. Such arrhythmia is known to refer to the terms - idiopathic atrial fibrillation, primary atrial fibrillation, or "isolated at‐ rial fibrillation» (lone atrial fibrillation). It is believed that a significant number of primary atrial fibrillation cases are caused by a hereditary factor [5-10]. However, even in the secon‐ dary atrial fibrillation a hereditary component is not excluded in the development of ar‐ rhythmia. In the 90s of the 20th century many papers associated with the genealogy of atrial

and reproduction in any medium, provided the original work is properly cited.

© 2013 Nikulina et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

offers opportunities for early diagnosis and timely prevention of this pathology.

**New Candidate Genes in Atrial Fibrillation Polymorphisms of the Alpha 2-Beta-Adrenoceptor and the Endothelial NO Synthase Genes in Atrial Fibrillation of Different Etiological Origins**

Svetlana Nikulina, Vladimir Shulman, Ksenya Dudkina, Anna Chernova and Oksana Gavrilyuk

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/53527

**1. Introduction**

Molecular and genetic bases of atherosclerosis, cardiomyopathy, hypertension are the most studied among cardiovascular diseases. Recently, search for genetic markers associated with various rhythm disorders and conduction attracts researchers. The greatest attention is paid to the genetic aspects of atrial fibrillation as the most frequent and dangerous arrhythmia.

Atrial fibrillation represents the most common type of arrhythmia in clinical practice. The prevalence of atrial fibrillation is 0.4% in the general population and it increases with age [1]. According to the Framingham study atrial fibrillation doubles mortality in cardiac pa‐ tients and is responsible for 1 \ 3 thromboembolic episodes [2-4]. That's why finding of ge‐ nealogical and genetic aspects of atrial fibrillation predictors of its occurrence is relevant and offers opportunities for early diagnosis and timely prevention of this pathology.

In most cases, this rhythm disorder is secondary, i.e. it's caused by a disease. But at least in the 1 \ 3 cases etiology of atrial fibrillation cannot be established. Such arrhythmia is known to refer to the terms - idiopathic atrial fibrillation, primary atrial fibrillation, or "isolated at‐ rial fibrillation» (lone atrial fibrillation). It is believed that a significant number of primary atrial fibrillation cases are caused by a hereditary factor [5-10]. However, even in the secon‐ dary atrial fibrillation a hereditary component is not excluded in the development of ar‐ rhythmia. In the 90s of the 20th century many papers associated with the genealogy of atrial

© 2013 Nikulina et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

fibrillation described some families whose members had atrial fibrillation and / or atrial flut‐ ter [7-9, 11, 12].

tion. Researchers have shown particular interest to families that had an accumulation of in‐ traventricular conduction disturbances, combined with a variety of tachyarrhythmias. Families whose members in several generations suffered from atrial fibrillation and/or atrial flutter in a combination with a blockade of various branches of His bundle or atrio-ventricu‐

New Candidate Genes in Atrial Fibrillation Polymorphisms of the Alpha 2-Beta-Adrenoceptor and the Endothelial…

http://dx.doi.org/10.5772/53527

61

C.S. Fox et al. indicated that atrial fibrillation in the parents increases the risk of atrial fibril‐ lation for posterity. Among the examined 2243 patients with atrial fibrillation 681patients (30%) had at least one parent with the registered atrial fibrillation [9]. Postulational piority of the autosomal dominant model atrial fibrillation belongs to J. Girona et al. (1997). They presented two families in which 20 out of 70 members had paroxysmal or persistent atrial fibrillation [28]. A. Gillor, E. Korsch in 1992 [29] described a family case of idiopathic atrial flutter. In this family, two male children were diagnosed with atrial flutter; they were the third and sixth children of seven. Other five children were girls. Two daughters died, the first daughter died at the age of twenty days, parents do not know the cause of death, the

In 1996 French scientists P. Poret, P. Mabo, C. Deplace et al. studied a family with congenital tachyarrhythmia. In three generations five members of the family were diagnosed with idio‐ pathic atrial fibrillation since the young age. The examination of the sick relatives revealed hypertrophy of both atria, mitral and tricuspid regurgitation [27]. In 1997 R. Brugada et al. [30, 31] carried out clinical, electrophysiological and genetic study of three Spanish families

Genetic analysis revealed that the gene responsible for atrial fibrillation in this family is lo‐ calized on chromosome 10q in the area 10q22-24. Abnormal gene locus was placed between D10S1694 and D10S1786. The authors supposed that candidate genes of this pathology were genes of beta- adrenoreceptors (ADRB1), alpha- adrenoreceptors (ADRA2) and genes of Gprotein coupled receptor-kinase (GPRR5) as localized on the same chromosome 10 in locus 23 - 26. In these families atrial fibrillation was revealed in 21 out of 49 relatives. One of the sick relatives (II-8) died at the age of 68 from stroke. The other relative (III-2) with paroxys‐ mal AF since 20 years' age, died suddenly at the age of 36, but an autopsy was not per‐ formed. 18 out of 19 living family members had chronic atrial fibrillation and 1 - paroxysmal

Finally, Chinese scientists H. Yang et al. identified 2 genes responsible for heredity of atrial fibrillation. They appeared to be genes of proteins of potassium channels in myocytes. In particular, H. Yang et al. [32] reported about replacement of arginine to cysteine in position 27 of gene KCNE2 on chromosome 21q22.1-22, encoding the beta subunit of potassium channels. These mutations appeared in 2 out of 28 examined Chinese families with familial atrial fibrillation. H. Yang et al. identified the mutation of (S140G) gene on chromosome 11p15.5, encoding the alpha subunit of the cardiac potassium channel. Atrial fibrillation oc‐ currence in these cases is due to the fact that in these genes function of the corresponding potassium channels increases, leading to the shortening of potential action and atrial effec‐ tive refractory period. It should be recalled that paroxysmal atrial fibrillation is one of the major phenotypic manifestations of the syndrome of short interval QT, in which the func‐

lar block [24-27] were described.

with atrial fibrillation.

atrial fibrillation.

fourth - at the age of 5 years, probably from meningitis.

Molecular researches of AF are concentrated generally in 2 directions: 1. Identification of genes which mutations lead to arrhythmia (inheritance of such mutations occurs according to the classical Mendel type). 2. Studying of polymorphisms of various genes, so-called genes of susceptibility or genes – candidates.

In this regard, some of the most promising genetic markers are polymorphisms of gene al‐ pha 2-beta-adrenoceptor (ADRA2V). Gene ADRA2V is located on the long arm of chromo‐ some 2 (2q11.2), it has no introns. It encodes a2β-adrenergic receptor [13]. Adrenergic receptors - a class of receptors coupled to G-proteins activated by catecholamines [13, 14]. There are at least four groups of receptors that differ in their mediated effects, localization and affinity for different substances: alpha-1, alpha 2, beta 1 and beta-2 adrenergic receptors [15, 16]. A2 - adrenergic receptors include three subtypes: α2a, a2β and α2c [17].

All these proteins have a similar structure and are associated with G-protein [13]. Receptors of α2 family are important components of vegetative nervous system and provide a physio‐ logical response to sympathetic stimulation. A role of the sympathoadrenal stimulation of the atria in the pathogenesis of AF was shown in the works of P. Coumel et al. [18] in 1982.

Molecules of nitric oxide (NO) can play a definite role in the pathogenesis of AF. Nitric ox‐ ide in the human body is continuously produced by fermentation from L - arginine and serves as a universal messenger inside and intercellular signaling [19]. The catalyst of this reaction is synthase NO (NO-synthase, or NOS, the enzyme code 1.14.13.39) [19]. Influenced by NO-synthase oxidation of L - arginine and nitric oxide synthesis in endothelial cells of blood vessels take place. Then, getting out of endothelial cells into the smooth muscle cells, nitric oxide activates soluble guanylate cyclase, that leads to increased level of cyclic GMP, activation of cyclic GMP - dependent protein kinases, changes in calcium concentration and sensitivity of conducting cardiac myocytes receptors to the level of catecholamines. In 2005 M. Kim showed that the decrease in the production of NO-synthase can cause oxidative stress and lead to changes in myocardial conduction system, thereby contributing to the de‐ velopment of AF [20]. Polymorphism rs1799983 in exon 7 of the gene NOS3, replacement of G to T in position 894 of the nucleotide sequence leads to the replacement glu298-to-asp (E298D) in the amino acid sequence. So far, the influence of polymorphisms of gene ADRA2B and gene of endothelial NO-synthase on the development of atrial fibrillation has not been investigated.

#### **1.1. Genealogical and genetic aspects of atrial fibrillation**

The first familial cases of atrial fibrillation were described in 1943 [21]. In 1950 for the first time Gould pointed out a significant role of heredity in the atrial fibrillation development. He described the family susceptibility to atrial fibrillation, monitored the history of atrial fi‐ brillation in several generations of this family for 36 years [22]. In 1998 T. Tikanoja et al. [23] have published data about the development of familial atrial fibrillation in two fetuses at 23 and 25 weeks of fetal development, and both babies were born with ongoing atrial fibrilla‐ tion. Researchers have shown particular interest to families that had an accumulation of in‐ traventricular conduction disturbances, combined with a variety of tachyarrhythmias. Families whose members in several generations suffered from atrial fibrillation and/or atrial flutter in a combination with a blockade of various branches of His bundle or atrio-ventricu‐ lar block [24-27] were described.

fibrillation described some families whose members had atrial fibrillation and / or atrial flut‐

Molecular researches of AF are concentrated generally in 2 directions: 1. Identification of genes which mutations lead to arrhythmia (inheritance of such mutations occurs according to the classical Mendel type). 2. Studying of polymorphisms of various genes, so-called

In this regard, some of the most promising genetic markers are polymorphisms of gene al‐ pha 2-beta-adrenoceptor (ADRA2V). Gene ADRA2V is located on the long arm of chromo‐ some 2 (2q11.2), it has no introns. It encodes a2β-adrenergic receptor [13]. Adrenergic receptors - a class of receptors coupled to G-proteins activated by catecholamines [13, 14]. There are at least four groups of receptors that differ in their mediated effects, localization and affinity for different substances: alpha-1, alpha 2, beta 1 and beta-2 adrenergic receptors

All these proteins have a similar structure and are associated with G-protein [13]. Receptors of α2 family are important components of vegetative nervous system and provide a physio‐ logical response to sympathetic stimulation. A role of the sympathoadrenal stimulation of the atria in the pathogenesis of AF was shown in the works of P. Coumel et al. [18] in 1982.

Molecules of nitric oxide (NO) can play a definite role in the pathogenesis of AF. Nitric ox‐ ide in the human body is continuously produced by fermentation from L - arginine and serves as a universal messenger inside and intercellular signaling [19]. The catalyst of this reaction is synthase NO (NO-synthase, or NOS, the enzyme code 1.14.13.39) [19]. Influenced by NO-synthase oxidation of L - arginine and nitric oxide synthesis in endothelial cells of blood vessels take place. Then, getting out of endothelial cells into the smooth muscle cells, nitric oxide activates soluble guanylate cyclase, that leads to increased level of cyclic GMP, activation of cyclic GMP - dependent protein kinases, changes in calcium concentration and sensitivity of conducting cardiac myocytes receptors to the level of catecholamines. In 2005 M. Kim showed that the decrease in the production of NO-synthase can cause oxidative stress and lead to changes in myocardial conduction system, thereby contributing to the de‐ velopment of AF [20]. Polymorphism rs1799983 in exon 7 of the gene NOS3, replacement of G to T in position 894 of the nucleotide sequence leads to the replacement glu298-to-asp (E298D) in the amino acid sequence. So far, the influence of polymorphisms of gene ADRA2B and gene of endothelial NO-synthase on the development of atrial fibrillation has

The first familial cases of atrial fibrillation were described in 1943 [21]. In 1950 for the first time Gould pointed out a significant role of heredity in the atrial fibrillation development. He described the family susceptibility to atrial fibrillation, monitored the history of atrial fi‐ brillation in several generations of this family for 36 years [22]. In 1998 T. Tikanoja et al. [23] have published data about the development of familial atrial fibrillation in two fetuses at 23 and 25 weeks of fetal development, and both babies were born with ongoing atrial fibrilla‐

[15, 16]. A2 - adrenergic receptors include three subtypes: α2a, a2β and α2c [17].

ter [7-9, 11, 12].

60 Atrial Fibrillation - Mechanisms and Treatment

not been investigated.

**1.1. Genealogical and genetic aspects of atrial fibrillation**

genes of susceptibility or genes – candidates.

C.S. Fox et al. indicated that atrial fibrillation in the parents increases the risk of atrial fibril‐ lation for posterity. Among the examined 2243 patients with atrial fibrillation 681patients (30%) had at least one parent with the registered atrial fibrillation [9]. Postulational piority of the autosomal dominant model atrial fibrillation belongs to J. Girona et al. (1997). They presented two families in which 20 out of 70 members had paroxysmal or persistent atrial fibrillation [28]. A. Gillor, E. Korsch in 1992 [29] described a family case of idiopathic atrial flutter. In this family, two male children were diagnosed with atrial flutter; they were the third and sixth children of seven. Other five children were girls. Two daughters died, the first daughter died at the age of twenty days, parents do not know the cause of death, the fourth - at the age of 5 years, probably from meningitis.

In 1996 French scientists P. Poret, P. Mabo, C. Deplace et al. studied a family with congenital tachyarrhythmia. In three generations five members of the family were diagnosed with idio‐ pathic atrial fibrillation since the young age. The examination of the sick relatives revealed hypertrophy of both atria, mitral and tricuspid regurgitation [27]. In 1997 R. Brugada et al. [30, 31] carried out clinical, electrophysiological and genetic study of three Spanish families with atrial fibrillation.

Genetic analysis revealed that the gene responsible for atrial fibrillation in this family is lo‐ calized on chromosome 10q in the area 10q22-24. Abnormal gene locus was placed between D10S1694 and D10S1786. The authors supposed that candidate genes of this pathology were genes of beta- adrenoreceptors (ADRB1), alpha- adrenoreceptors (ADRA2) and genes of Gprotein coupled receptor-kinase (GPRR5) as localized on the same chromosome 10 in locus 23 - 26. In these families atrial fibrillation was revealed in 21 out of 49 relatives. One of the sick relatives (II-8) died at the age of 68 from stroke. The other relative (III-2) with paroxys‐ mal AF since 20 years' age, died suddenly at the age of 36, but an autopsy was not per‐ formed. 18 out of 19 living family members had chronic atrial fibrillation and 1 - paroxysmal atrial fibrillation.

Finally, Chinese scientists H. Yang et al. identified 2 genes responsible for heredity of atrial fibrillation. They appeared to be genes of proteins of potassium channels in myocytes. In particular, H. Yang et al. [32] reported about replacement of arginine to cysteine in position 27 of gene KCNE2 on chromosome 21q22.1-22, encoding the beta subunit of potassium channels. These mutations appeared in 2 out of 28 examined Chinese families with familial atrial fibrillation. H. Yang et al. identified the mutation of (S140G) gene on chromosome 11p15.5, encoding the alpha subunit of the cardiac potassium channel. Atrial fibrillation oc‐ currence in these cases is due to the fact that in these genes function of the corresponding potassium channels increases, leading to the shortening of potential action and atrial effec‐ tive refractory period. It should be recalled that paroxysmal atrial fibrillation is one of the major phenotypic manifestations of the syndrome of short interval QT, in which the func‐ tion of potassium channels is increased. Thus, the data of Chinese researchers suggest that certain variants of familial atrial fibrillation can be attributed to channelopathies.

rial fibrillation (AF); however, results have been conflicting. In subgroup analysis, stratified by ethnicity, we observed a positive association between the eNOS 786T/C polymorphism and AF risk among Caucasians but not among mixed populations[42]. Meta-analysis sug‐ gests that there is insufficient evidence to demonstrate an association between ACE I/D polymorphism and AF risk. However, there seems to be a significant association between

New Candidate Genes in Atrial Fibrillation Polymorphisms of the Alpha 2-Beta-Adrenoceptor and the Endothelial…

http://dx.doi.org/10.5772/53527

63

ACE I/D gene polymorphic variation and AF in patients with hypertension [43].

**2.1. Clinical polymorphism of atrial fibrillation in probands and their relatives**

diographic manifestations of cardio-vascular diseases (control group).

patients with primary atrial fibrillation are specified in Table 1.

A total of 100 probands with atrial fibrillation and 150 of their relatives of the I st, II nd and III rd degree of relationship were examined. These families composed the study base

The probands were searched during the course of their in-patient and out-patient treatment in the Cardiological center of the Krasnoyarsk Regional clinical hospital № 20 named after I.S. Berzon. The patients' relatives were examined during doctors' home visits and subse‐ quent check-ups in the Cardiological center. We also studied 91 patients without electrocar‐

The families of the probands with atrial fibrillation were divided into two groups according

**1.** Families of the probands with primary atrial fibrillation, in which clinical and instru‐ mental examination revealed no evident cause-effect relation with any cardio-vascular diseases as well as other diseases which may have atrial fibrillation as a complication;

**2.** Families of the probands with secondary atrial fibrillation, in which the onset of this dysrhythmia was due to specific diseases as ischemic heart disease, arterial hyperten‐

The first group (families of the probands with primary atrial fibrillation) included 40 pro‐ bands (24 males and 16 females) and 79 of their relatives (23 males and 56 females), and the second one (families of the probands with secondary atrial fibrillation) included 60 pro‐ bands (28 males and 32 females) and 71 of their relatives (20 males and 51 females). Atrial fibrillation was revealed in 5 out of 79 relatives of the first group and in 1 out of 71 relatives of the second group. Differentiated clinical and electrocardiographic characteristics of the

Paroxysmal atrial fibrillation was revealed in 38 probands with primary atrial fibrillation (95,0±3,4%) and paroxysmal atrial flutter was revealed in 2 persons (5,0±3,4%). Among the sick relatives with primary atrial fibrillation (5 persons) paroxysmal atrial fibrillation was re‐

sion, dilated cardiomyopathy, gastroesophageal hernia and thyrotoxicosis.

**2. Results**

for our research.

to the atrial fibrillation etiology:

vealed in 5 persons (100%).

H. Yang et al. [32] in their work also showed an increase in the amount of protein connexin 43 with atrial fibrillation, the highest in the left atrium. Christiansen J. et al. [33] found that mutation in gene 1q21.1, which leads to a decrease in connexin 40, promotes the develop‐ ment of abnormalities of the aortic arch with atrial fibrillation. Somatic mutations in the gene encoding gap - junction protein connexin 40 (GJA5), myocardial protein involved in the coordination of the electrical activity of the atria, can be a cause of idiopathic atrial fibril‐ lation in some cases [34].

"A significant part of patients have no obvious cause for the development of atrial fibrilla‐ tion and it is possible that 1/3 of these cases actually occurs due to mutations in GJA5 ", Mi‐ chael R. and H. Gollob wrote (University of Ottawa Heart Institute, Ontario, Canada). The findings, published in New England Journal of Medicine, are based on analysis of GJA5 in cardiac tissue and lymphocytes taken from 15 patients with idiopathic atrial fibrillation. Four out of all these patients had heterozygous mutations in GJA5. Three patients had muta‐ tions in heart tissue but not in lymphocytes, that indicates a somatic origin of the defects. The fourth patient's mutation was detected in both types of cells that suggest an embryonic mutation. Dr. H. Gollob believes that connexin 40 may become the object of search for new drugs to treat atrial fibrillation. The findings, according to the authors' opinion, suggest that the so-called idiopathic atrial fibrillation may have a genetic basis in the form of the defect, limited by the sick tissue.

By the present moment a large quantity of data is stored that activity of renin-angiotensinaldosterone system (RAAS) is of great importance for formation of this peculiar «cardio‐ myopathies of auricles». A key component of RAAS, significantly affecting its activity through the synthesis of angiotensin - II is a angiotensin-converting enzyme (ACE). ACE gene, located on chromosome 17q23, consists of 26 exons and 25 introns [35, 36]. ACE gene polymorphism concerns a fragment of intron 16 and it is connected with the insertion / dele‐ tion of 287 pairs of nucleotides and determines three genotypes - I / I, D / D and I / D. V.I. Tseluyko et al. showed that ACE levels in plasma are significantly higher in patients with genotype D / D than in genotype I / I. Heterozygotes have intermediate levels of ACE [37]. L.O. Minushkina, E.S. Gorshkova et al. (2010) studied association of genes β-adrenoceptors of types 1, 2, and 3 (ADRB1, ADRB2, ADRB3), connexin (CX40) and a voltage - locked potas‐ sium channel of type 2 (KCNH2) with the occurrence of atrial fibrillation in patients with hypertension. This study shows that for polymorphic marker Trp64Arg of gene ADRB3 Trp allele frequency was significantly higher and the frequency of the Arg allele was significant‐ ly lower in patients with atrial fibrillation. In patients with atrial fibrillation frequency of the homozygous genotypes Arg / Arg appeared to be significantly less [38, 39].

According to the analysis conducted by J.D. Roberts, M.H. Michael, M.H. Gollob [10] at present a connection between atrial fibrillation and gene polymorphism of ion channels sub‐ units KCNQ1 [40], KCNA5 [41], KCNE2, KCNJ2, SCN5A, GJA5, NPPA is established. [10]. Several recent studies have focused on the association between the promoter polymor‐ phisms 786T/C of the endothelial nitric oxide synthase (eNOS) gene and susceptibility to at‐ rial fibrillation (AF); however, results have been conflicting. In subgroup analysis, stratified by ethnicity, we observed a positive association between the eNOS 786T/C polymorphism and AF risk among Caucasians but not among mixed populations[42]. Meta-analysis sug‐ gests that there is insufficient evidence to demonstrate an association between ACE I/D polymorphism and AF risk. However, there seems to be a significant association between ACE I/D gene polymorphic variation and AF in patients with hypertension [43].
