**4.2** *CYP11B2* **genotypic variants and atrial fibrillation**

Atrial fibrillation (AF) is the most clinically prevalent type of cardiac arrhythmia which may be precipitated due to the presence of underlying heart disease such as valvular dysfunction, ventricular dysfunction, and hypertension. However, AF does not exist in some patients with one or more of these risk factors and presents in others without any risk factors. Accordingly, the genetic role had been emerged in the predisposition for AF. A positive family history of AF in at least one parent was suggested by a recent Framingham Heart study on 2243 participants to be associated with an 85% increased relative risk for AF [71].

Taking together this genetic role, two types of AF have been identified regarding the heredity characteristics as familial and non-familial AF. Recent studies have detected several candidate genes which were suggested to be associated with the familial AF type such as genes encoding for subunits of potassium or sodium channels, sarcolipin, connexin 40, endothelial nitric oxide synthase, interleukin 10, and RAAS [72].

Association of genetic variants of renin angiotensin aldosterone system (RAAS) system with non-familial AF was suggested by Tsai et al. [73] using a risk-factor matched design. *CYP11B2* −344C/T polymorphism was reported to be associated with the susceptibility of AF by Amir et al. [74] in a cohort of 196 patients with symptomatic systolic heart failure. They found that the −344 CC genotype to be a strong independent predictor for AF (adjusted OR 2.35, 95% CI 1.57–3.51, *P* = 0.03). Therefore, *CYP11B2* −344C/T polymorphism may predispose to AF in patients with HF. Another study by Lu et al. [75] on 359 of Han and Kazak population with non-valvular AF and 527 non-AF patients as a control reported that −344C/T polymorphism of *CYP11B2* was associated with AF risk as the frequencies of TT genotype, and co-dominant model (CC + TT genotype) in Han population and of TT genotype, and dominant model (CT + TT genotype) in Kasak population were significantly higher in AF group than in the control group. Furthermore, a meta-analysis by Li et al. [76] involving 2758 subjects from six distinct studies reported that *CYP11B2* T−344C gene polymorphism was significantly associated with AF in all genetic models; allelic (OR: 1.26, *P* = 0.0002), recessive (OR: 1.99, *P* = 0.003), dominant (OR: 0.903, *P* = 0.036), and homozygous (OR: 1.356, 95% CI: 1.130–1.628, *P* = 0.001), and additive (OR: 1.153, *P* = 1.0 × 10<sup>−</sup>10). On the other hand, no significant association was detected by Zhang et al. [77] between different genotype and alleles of −344 T/C polymorphism and lone AF patients.

The possible mechanisms for the association of *CYP11B2* polymorphism and AF are mainly related to increased aldosterone production. Aldosterone exerts its effect via direct and indirect ways. Indirect effect of aldosterone on the heart arise from its role on increasing blood volume, blood pressure, left ventricular pressure, left ventricular hypertrophy, left atrial pressure, and left atrial volume. However, aldosterone can directly act on the heart inducing cardiac hypertrophy and fibrosis [78, 79] via the proliferation and differentiation of myocardial cells, vascular smooth muscle cells, and fibroblasts, leading to a significant increase in collagen production. These effects lead to cardiac fibrosis and structural remodeling leading to heart rhythm disorders. Specifically, in the atrium, aldosterone may directly or indirectly cause atrial enlargement and fibrosis, leading to structural and electrical atrial remodeling resulting in atrial fibrillation. Based on these findings, aldosterone antagonists as angiotensin II receptor antagonists may be used clinically in the patients with AF to control and minimize the incidence and persistence of AF [80].

**29**

−344C/T allele.

*Aldosterone Synthase Gene (*CYP11B2*) Polymorphisms and Enhanced Cardiovascular Risk*

Coronary artery disease (CAD) is a complex disorder comprised two major subsequent events: coronary atherosclerosis and myocardial infarction (MI). Despite the major progress in diagnosis of CAD, the pathogenesis and possible risk factors need further evaluation. The classical risk factors including positive family history, smoking, high body mass index, and disorders as hyperlipidemia, hypertension, and diabetes mellitus have been reported to be responsible for no more than 50% of total risk factors for CAD. Accordingly, genetic background seems also to partici-

Among the different polymorphisms described for *CYP11B2* gene, several studies have shown that the *CYP11B2* gene ˗344T>C polymorphism is associated with CAD in different ethnic groups with controversial results. Previous study on 201 CAD patients and 201 controls form Italian population have detected that *CYP11B2* polymorphism and CC genotype were associated with CAD risk in crude analysis with borderline significance which is lost by stratification to the confounding factors as smoking and family history [82]. A meta-analysis suggested that the −344T>C polymorphism in the *CYP11B2* gene might be associated with susceptibility to CAD in Caucasians and Asians [83]. A study on 609 Taiwanese male and female subjects who were unrelated and received coronary catheterization found that the C/C allele occurred more frequently in females who had CAD, and that it was associated with higher left ventricular mass (LVM) and left ventricular end diastolic diameter (LVEDD) [84]. Sharma et al. [85] also reported the association of the *CYP11B2* −344C>T polymorphism with the size of atherosclerotic plaque in the carotid artery. Neal et al. [86] suggested that −344C/T polymorphism is a cardiovascular risk factor due to its association with LV hypertrophy and decreased baroreflex sensitivity which predict the morbidity and mortality rates of MI. Others failed to find any significant association of *CYP11B2* with CAD in different popula-

**4.3** *CYP11B2* **genotypic variants and coronary artery disease**

tions as in an Indian population and other populations [87–89].

**4.4** *CYP11B2* **genotypic variants and hypertrophic cardiomyopathy**

the predisposition for left ventricular hypertrophy (LVH) and HCM [92].

Evidences suggested that aldosterone seems to play a major role in the progression of LVH and HCM as it is produced locally in the heart and *CYP11B2*

The underlying mechanism by which the *CYP11B2* ˗344T>C polymorphism can increase the risk for CAD remains unclear. However, it is related to its effect on increasing expression of *CYP11B2*, thereby increasing aldosterone secretion [83]. Also, the influence of gene-environment interaction has been involved as an etiological factor for CAD risk. Growing evidence has suggested the interaction between ˗344T>C polymorphism and positive smoking for enhanced CAD risk [90]. Also, Hautanen et al. [91] detected that smoking and dyslipidemia are associated risk factors for non-fatal MI in males who were carriers for *CYP11B2*

Hypertrophic cardiomyopathy (HCM) is a clinical cardiac dysfunction characterized mainly by hypertrophy of left ventricle. HCM is an autosomal dominant disorder and its diagnosis needs to exclude other cardiac or systemic causes of increased ventricular wall thickening. HCM comprises different histological features as cardiomyocyte hypertrophy, myofibrillar disarray, and fibrosis. Several factors are involved in the pathogenesis of HCM, with the genetic element has an upper hand. Mutations and polymorphisms in genes encoding the sarcomere proteins and renin-angiotensin-aldosterone system (RAAS) seem to be related to

*DOI: http://dx.doi.org/10.5772/intechopen.89133*

pate in the predisposition for CAD [81].
