**4. Genotypic variants and haplotypes in** *CYP11B2* **gene**

Several polymorphisms have been identified in *CYP11B2* and are associated with enhanced *CYP11B2* transcription, increased aldosterone production, and the progression of many cardiovascular disorders (**Figure 8**). About 227 singlenucleotide polymorphisms (SNPs) have been detected in different population worldwide according to National Center for Biotechnology Information (NCBI) database (https://www.ncbi.nlm.nih.gov/) [43]. However, only few SNPs are evaluated in different studies. The first and most extensively studied polymorphism is −344 C/T which exists in the 5′ promoter region of *CYP11B2* gene. It occupies the putative binding site for the transcription factor SF-1 which is responsible for the expression of several enzymes involved in steroid biosynthesis framework in the adrenal cortex. The two alternative bases at this position are thymine (T) and cytosine (C) [44]. *CYP11B2* −344C/T polymorphism is associated with increased aldosterone synthesis and secretion in serum [45] or urine [46] and increased aldosterone renin ratio [47, 48] with either C allele or T allele were suggested to be involved among different studies. The mechanisms that stand behind this association are conflicting. Functional studies showed that T allele binds to SF-1 with four folds lower affinity than the C allele. This results in stimulation of the expression of enzymes responsible for steroidogenesis leading to increased aldosterone synthase activity in C allele carriers [41]. However, in T allele carrier, the increased aldosterone production was explained by lower affinity for SF1 binding leading to the increased availability of this transcription factor in other parts of the gene with subsequent activation of the steroidogenic acute regulatory gene [45]. On the other hand, others suggest that this polymorphism exert its effect via a strong linkage disequilibrium with functional polymorphisms in *CYP11B1*, a substitution (T to C) in codon 75 and (G to A) in intron 6 that result in 11 β hydroxylase deficiency [49]. This results in sustained elevation of ACTH [50] with subsequent increases in the expression of a number of genes required for aldosterone synthesis including StAR, *CYP11A*, and *CYP21* leading to enhanced aldosterone synthesis [31, 50].

The second polymorphism is a gene intronic conversion (IC) whereby a fragment of the "wild-type (Wt)" intron 2 of *CYP11B2* is replaced by the corresponding intronic fragment of *CYP11B1* conversion (Conv). Due to the nature of this variation and difficulty in genotyping it, its frequency has not been reported in

**27**

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

public databases. The −344 T/C and intron conversion polymorphisms are in tight linkage disequilibrium and three common haplotypes have been reported: T/Conv (38%), C/Wt (45%), and T/Wt (13%), where the first allele corresponds to the −344 polymorphism (T or C) and the second to the intron 2 conversion (Wt or

Beside the previously described polymorphisms of *CYP11B2*, other interesting polymorphisms have been reported and associated with increased aldosterone production as missense mutation in exon 3, where a lysine is replaced by an arginine (K173R) and *CYP11B2* (T4991C) SNP in exon 7 [51]. However, the haplotype including −344T and K173 was associated with higher *CYP11B2* expression in adrenal tissue than the −344C and R173 haplotype [52]. Moreover, other polymorphisms have been studied as G5937C and A4550C and were associated with

Hypertension is a complex progressive cardiovascular disorder, not just a scale of threshold blood pressure values, with many causes that result in both functional and structural cardiac and vascular system abnormalities that damage the heart, kidneys, brain, vasculature, and other organs, and lead to premature morbidity and death [54]. Essential hypertension is a multifactorial disorder, predisposed by genetic and environmental factors [55]. Growing evidences suggest the potential role of genetic alteration affecting genes encoding the aldosterone synthesis pathway enzymes with associated enhanced aldosterone production resulting in

Several polymorphic variants of *CYP11B2* have been identified as potential genetic contributor in patients with essential hypertension with −344C/T was extensively studied among different ethnic groups, with conflicting results. Public databases reported that the T allele is more frequent than the C allele in highlanders compared with lowlanders Indian [57], African Americans and Japanese

subjects [48], Caucasian [58], Tamil population [59], Chinese Han population [38], Taiwanese females [60], and recently in the Egyptian population [61]. C allele has been suggested to be associated with hypertension by Tsukada et al. [62], Kumar et al. [63], Ji et al. [64], Li et al. [65], and in the meta-analysis by Cheng et al. [66]. No association was detected in the Japanese population [67] and in the meta-analysis by Chen et al. [68]. These discrepancies reflect the influence of different genetic and environmental factors as well as the age and gender in geographically separated

The *CYP11B2* gene intronic conversion (IC) was also described in a small study of essential hypertensive subjects; the conversion allele frequency was much lower in black subjects compared with white [69]. However, several studies proved the more frequent association of *CYB11B2* −344T/IC haplotype with hypertensive subjects than normotensives, especially those with a high aldosterone renin ratio (ARR) and increased aldosterone levels in plasma [45, 47], although this finding is not supported in all studies [67]. IC has also associated with a better therapeutic

On the other hand, *CYP11B2* (K173R) and *CYP11B2* (T4991C) polymorphisms were found to be associated with hypertension [51, 52]. A strong synergistic effect has existed among different genotypes of *CYP11B2* C−344T, IC, and K173R polymorphisms with the haplotype (−344T-Conv-K173) associated with a higher risk for essential hypertension progression [43]. Despite the use of several polymorphisms in *CYP11B2,* their causal relationship with hypertension and inappropriate aldoste-

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

**4.1** *CYP11B2* **genotypic variants and hypertension**

progression to essential hypertension [56].

response to anti-hypertensive treatment [70].

rone production remains unclear.

Conv) [31].

heart size [53].

populations [61].

**Figure 8.** *Common CYP11B2 polymorphisms associated with increased aldosterone production.*

#### *Aldosterone Synthase Gene (*CYP11B2*) Polymorphisms and Enhanced Cardiovascular Risk DOI: http://dx.doi.org/10.5772/intechopen.89133*

public databases. The −344 T/C and intron conversion polymorphisms are in tight linkage disequilibrium and three common haplotypes have been reported: T/Conv (38%), C/Wt (45%), and T/Wt (13%), where the first allele corresponds to the −344 polymorphism (T or C) and the second to the intron 2 conversion (Wt or Conv) [31].

Beside the previously described polymorphisms of *CYP11B2*, other interesting polymorphisms have been reported and associated with increased aldosterone production as missense mutation in exon 3, where a lysine is replaced by an arginine (K173R) and *CYP11B2* (T4991C) SNP in exon 7 [51]. However, the haplotype including −344T and K173 was associated with higher *CYP11B2* expression in adrenal tissue than the −344C and R173 haplotype [52]. Moreover, other polymorphisms have been studied as G5937C and A4550C and were associated with heart size [53].
