The angiotensins are peptides (substances smaller than proteins) that act as vasoconstricting agents (causing blood vessels to narrow) that send up the blood pressure. Angiotensin I-converting enzyme, or kininase II, is a dipeptidyl carboxypeptidase that plays an important role in blood pressure regulation and electrolyte balance by hydrolyzing angiotensin I into angiotensin II, a potent vasopressor, and aldosterone-stimulating peptide. The enzyme is also able to inactivate bradykinin, a potent vasodilator.
Although angiotensin-converting enzyme has been studied primarily in the context of its role in blood pressure regulation, this widely distributed enzyme has many other physiologic functions. The ACE gene encodes 2 isozymes. The somatic ACE isozyme is expressed in many tissues, including vascular endothelial cells, renal epithelial cells, and testicular Leydig cells, whereas the testicular or germinal ACE isozyme is expressed only in sperm.
The importance of ACE in circulatory homeostasis is well documented. Besides being present as a membrane-bound enzyme on the surface of vascular endothelial cells, ACE also circulates in plasma. The plasma enzyme may be synthesized in vascular endothelium. In normal individuals, plasma ACE levels can show as much as a 5-fold interindividual variation; on the other hand, intra-individual variation is small.
The exact nature of the pathogeny of the disease is not known. BD is considered, at least in part, a genetic disease, due to the small number of familial cases of the syndrome seen around the world. This genetic susceptibility has been shown to be associated with certain genes of the major histocompatibility complex (MHC). The most prominent of these are: the HLAB5, HLAB51, TNF, and MICA genes that are linked to the ocular symptoms. Similarly, HLAB12 and HLAB27 have been shown to be associated with the mucocutaneous and joint lesions, respectively. The exact nature of the relationships of BD with the HLA types and non-MHC genes remains largely unexplored.
Al Jishi et al. (2005) described, for the first time, a 41-year-old married woman with a combination of Takayasu arteritis (TA) and primary antiphospholipid antibodies (aPL) syndrome who underwent carotid stenting. She carried the D/D genotype of the insertion- deletion mutation of Angiotensin converting enzyme and was E3/E3 genotype carrier of apolipoprotein E.
Salem and Batzer (2009) studied the intronic AluYa5 insertion/deletion polymorphic state in the ACE gene among Arabs. ACE genes of 112 Egyptians from Ismailia and 52 from the Sinai were studied by PCR amplification. The D allelic frequency was found to be 0.674 among the Egyptians (0.679-Ismailia, 0.663-Sinai). This was comparable to values reported from other Arab countries and higher than most reports on Caucasians and other Asian populations.
Hamdy et al. (2002) studied the frequencies of the dipeptidyl carboxypeptidase (DCP1), cholesteryl ester transfer protein (CETP), beta-2 adrenergic receptor (ADRB2), and 5-hydroxy tryptamine 2A receptor (HTR2A) genes in 242 unrelated Egyptian subjects. In DCP1, the frequency of the insertion allele (I) was 0.32 compared to 0.68 for the deletion allele (D).
Al-Harbi et al. (2013) investigated the association between ACE polymorphisms and Type 2 Diabetes Mellitus in Bahrain. The case-control study involved 171 unrelated adult Bahraini T2DM patients and 188 age-matched Bahraini control subjects. PCR was used to detect two alleles: the 190 bp deletion (D allele) and 490 bp insertion (I allele). The frequencies of the II, ID, and DD genotypes were 13%, 39%, and 48%, respectively, in the T2DM patients, and 18%, 47%, and 35%, respectively, in the control subjects. DD genotype and D allele frequencies were significantly higher in the patients than in the controls. Al-Harbi et al. (2013) opined that the high level of D allele and DD genotype in the Bahraini population might be responsible for the high prevalence of T2DM in the country.
[See also: Jordan, Syria > Salem and Batzer, 2009].
Verity et al. (2000) investigated the frequency of the R/G 241 and K/E 469 ICAM-1 gene polymorphisms in 83 patients with Behcet's disease (BD) and 103 healthy controls, all of Palestinian and Jordanian descent. They demonstrated an association between BD and the ICAM-1 E469 allele (Pc = 0.046, OR = 2.1).
Al-Eisa et al. (2000) studied the polymorphism within intron 16 of the angiotensin-converting enzyme in 47 Kuwaiti children with different urological abnormalities leading to variable degrees of renal impairment and in 48 healthy control subjects with a similar ethnic background. Al-Eisa et al. suggested an association of the D allele of the angiotensin-converting enzyme gene insertion/deletion polymorphism and congenital urological abnormalities, which result in parenchymal damage in Kuwaiti Arab children. In 2001, Al-Eisa et al. further investigated the association of the angiotensin-converting enzyme gene I/D polymorphism with the clinical presentation of idiopathic nephrotic syndrome in Kuwaiti children and found an association of the D-allele with the clinical manifestation of idiopathic nephrotic syndrome in Kuwaiti Arab children. Later, Al-Eisa et al. (2001) compared ACE gene polymorhisms in 54 Kuwaiti Arab children with idiopathic nephrotic syndrome with those in 48 healthy controls. The patients were found to have a significantly higher percentage of the DD genotype (70%) compared to the controls (52%). In addition, the D-allele frequency was higher in the patient group (0.81 vs. 0.75). Al-Eisa et al. (2001) speculated that the DD allele contributed to the pathogenesis of the disease by producing elevated levels of angiotensin II.
Haider et al. (2002) compared the ACE in/del polymorphisms in a group of 74 premature Kuwaiti infants with Retinopathy of Prematurity (ROP) with those in 107 control premature infants without ROP. The DD genotype was found to be similar in both groups. However, the incidence of the ID genotype was higher in the controls, while the II genotype was significantly higher in the cases. Haider et al. (2002) divided the case group into two sub-groups, one in which the disease regressed spontaneously, and the other in which the ROP progressed to advanced stages. They found that the incidence of the DD genotype was significantly higher in the second sub-group compared to the spontaneously regressing group. No significant difference between the ID and II genotypes was found between the two sub-groups.
Alsaeid et al. (2003) investigated the incidence of angiotensin converting enzyme (ACE) gene insertion-deletion (I/D) polymorphism genotypes in 82 children with juvenile rheumatoid arthritis (JRA) and in 48 ethnically matched healthy controls. A considerably higher incidence of II genotype was observed in the JRA patients compared to controls (p < 0.003). In contrast, no statistically significant difference was detected in the incidence of DD and ID genotypes in JRA patients and controls (p = 0.276 and 0.460, respectively). By analyzing the incidence of ACE gene polymorphism genotypes with regard to the clinical subclasses of JRA, the incidence of II genotype was found to be significantly higher in all the 3 JRA subclasses compared to controls. The strongest association between II genotype and JRA subclasses was detected in systemic JRA, followed by oligoarticular and polyarticular JRA. This was also reflected in a higher prevalence of I-allele in the systemic JRA cases (13/26, 50%) compared to the D-allele (11/26, 42%). Later, Alsaeid et al. (2004) compared ACE gene polymorphisms, Lp(A) levels, and other lipid profiles between 125 Kuwaiti children with type I diabetes and an equal number of age and sex-matched controls. The ACE genotype distribution did not show any significant difference between the two groups. However, the mean total cholesterol and HDL cholesterol levels were significantly higher in diabetic children in the DD group compared to the controls with the DD genotype. ApoA1 levels were also significantly higher in the diabetic children among both the DD and ID groups. In addition, within the DD group, there was a higher percentage of diabetic children with a family history of cardiovascular disease. Alsaeid et al. (2004) concluded that in children with type I diabetes, ACE genotype acts as a probable contributor to cardiovascular disease and that this contribution is partially mediated through other factors, including poor glycemic control, total cholesterol levels, and Lp(a) levels.
Al-Awadhi et al. (2007) compared ACE gene in/del polymorphisms genotypes in 92 patients with Systemic Lupus Erythematosus (SLE) and a group of 100 ethnically matched healthy controls. They did not find any significant difference in the distribution of these genotypes and the allele frequencies between the patients and the controls. However, the ACE DD genotype was found to be significantly associated with Raynaud's phenomenon in the patients, suggesting that it might confer a genetic susceptibility to the development of vascular morbidity.
Uppal et al. (2007) studied the association between RA and ACE gene polymorphism in 60 RA patients. They found a significant overrepresentation of the DD genotype and the D allele in the study group. Logistic regression analysis indicated that the DD genotype conferred a relative risk for development of RA of a multitude of 3.
Chmaisse et al. (2006) used PCR-RFLP to study the association between Behcets disease and two ICAM1 SNPs; (T/C) 469 and (G/A) 241 in Lebanese patients. Only the T469C polymorphism was found to be associated with the disease.
Bayoumi et al. (2006) determined the frequencies of insertion-deletion (*I and *D) alleles of the ACE gene in two Arabian (Omanis and Emiratis) and two African populations (Sudanese and Somalis). DNA was extracted from 124 Omani subjects and subjected to PCR amplification. Further reanalysis of the samples with *D/*D genotype was done with an insertion-specific primer pair which would obtain 335-bp band in the presence of *I allele and no band in the presence of *D allele. The differences in the results of allele counting between the different ethnic groups was tested by chi square test which was also used along with goodness-of-fit test to assess the deviation from the Hardy-Weinberg equation. The observed genotype and heterozygosity level within the Omani population did not deviate significantly from the Hardy-Weinberg equation as the observed number of individuals with *I/*I, *I/*D, and *D/*D genotype were 8, 55, and 61, respectively, versus the expected numbers of 10.4, 51.1 and 62.5, respectively. The allele frequencies of *I and *D were 0.29 and 0.71, respectively, and these frequencies were similar to those of other studied ethnic groups, except for a slight difference with the Emiratis. The allele frequencies of *I and *D were 0.29 and 0.71, respectively, and these frequencies were similar to those of other studied ethnic groups, except for a slight difference with the Emiratis. Bayoumi et al. (2006) suggested that this lack of difference was probably due mixing of gene pools, attributed to the close proximity of Oman and the UAE, as well as the significant interaction between Omanis and East Africans through trade routes. The authors also highlighted that their study revealed *D allele preponderance among the Arab and African populations.
Bowirrat et al. (2006) investigated whether the ACE gene insertion-deletion (ID) polymorphism is associated with risk of developing dementia of Alzheimer's type (DAT) in an Arab community residing in Wadi Ara, a unique genetic isolate where there is a high prevalence of DAT. Bowirrat et al. (2006) found no evidence of an association between this polymorphism and either DAT or age-related cognitive decline (ARCD).
Meng et al. (2006) evaluated the association between 15 SNPs in the ACE gene and AD in a sample of 92 patients with Alzheimer's disease and 166 non-demented controls from an inbred Arab community. They observed significant association with two adjacent SNPs and with a combination of the two. Their haplotype 'GA' had a frequency of 0.21 in cases and 0.01 in controls. Individuals with this haplotype had a 45-fold increased risk of developing Alzheimer's disease compared with those possessing any of the other three haplotypes. Longer range haplotypes including I/D were even more significant.
El-Hazmi & Warsy, (2003) conducted a study which included 199 Saudi males and 258 Saudi females, to investigate the insertion/deletion (I/D) polymorphisms of the ACE gene in normal, overweight, and obese individuals. Of the 457 total individuals, 117 were categorized as obese, 185 as overweight, and 155 as normal, based on their BMI values. The frequency of DD genotype was 76.9%, 73.5% and 58.7% in the obese, overweight and normal groups, respectively. The frequency of ID genotype was 19.66%, 24.86% and 40% in the obese, overweight and normal groups, respectively. The frequencies of the D and I alleles in the obese individuals were 0.867 and 0.133, respectively. In the overweight individuals, the frequencies of these alleles were 0.859 and 0.141, respectively, while the frequencies were 0.787 and 0.213 in the normal weight individuals. The frequencies of the D allele were significantly higher in the obese and overweight individuals compared to normal individuals, suggesting that this allele may have a role in fat accumulation.
Ali et al. (2013) partly investigated the association of ACE insertion/deletion (I/D) polymorphism with hypertension in Saudi subjects. This study involved 250 controls and 120 cases with hypertension- among which 51 were obese and diabetic. ACE I/D dimorphism was identified through the absence or presence of a 278bp Alu repetitive intronic sequence. Genotypic and allelic frequencies were obtained through a PCR-based reaction assay using hybridization probes specific to the polymorphic variant. All cases showed a higher carrier frequency of the mutant ACE D allele than controls (98% vs 92%, p=0.028) and significant association was described using the odds ratio (OR=4.8, 95% CI 1.1-21.2). Filtering hypertensive cases with obesity and diabetes, 100% carriage of the mutant D allele was found, albeit with a near-significant association (p=0.052). Filtering hypertensive cases with combined genotypes of the ACE I/D and eNOS E298D alleles, only the mutant ACE D allele showed significant association. Genotype data was filtered through gender, age, parental consanguinity, and smoking, each of which showed no significant association with susceptibility to hypertension (p>0.05). Results suggested that the ACE I/D polymorphism may predispose to hypertension.
Bayoumi et al. (2006) determined the frequencies of insertion-deletion (*I and *D) alleles of the ACE gene in two Arabian (Omanis and Emiratis) and two African populations (Sudanese and Somalis). The allele frequencies of *I and *D were found to be 0.27 and 0.73, respectively in the 53 Somalian subjects studied [See Also: Oman > Bayoumi et al., 2006].
Bayoumi et al. (2006) determined the frequencies of insertion-deletion (*I and *D) alleles of the ACE gene in two Arabian (Omanis and Emiratis) and two African populations (Sudanese and Somalis). The allele frequencies of *I and *D were found to be 0.36 and 0.64, respectively in the 121 Sudanese subjects studied [See Also: Oman > Bayoumi et al., 2006].
In their study on the AluYa5 In/Del polymorphism in the ACE gene, Salem and Batzer (2009) calculated the D allelic frequency in a sample of 70 Syrians as being 0.600 [See also: Egypt> Salem and Batzer, 2009].
In 1997, Frossard et al. (1997) studied an insertion/deletion dimorphism in the human angiotensin-converting enzyme (ACE) gene amongst United Arab Emirates (UAE) nationals from the Abu Dhabi Emirate. There was a lack of association between the I/D allele marker system and clinical diagnosis of essential hypertension, suggesting that variations of the angiotensin-converting enzyme gene do not play a major role in the determination of elevated blood pressure in this Arab population. This agrees with results reported on other ethnic groups. In 1998, Frossard et al. (1998) carried out a retrospective case-control study of the angiotensin-converting enzyme insertion/deletion dimorphism in relation to circulating angiotensin-converting enzyme activity, as well as to hypertension, ischemic heart disease, myocardial infarction, and left ventricular hypertrophy in a sample population of 285 United Arab Emirates nationals. The analyzed group comprised controls and patients with clinical diagnoses of hypertension, ischemic heart disease, myocardial infarction, and left ventricular hypertrophy. Frossard et al. (1998) found out that the D allele was associated with increased circulating angiotensin-converting enzyme activity, and the angiotensin-converting enzyme insertion/deletion marker accounted for 28% of the variance of the phenomenon determining angiotensin-converting enzyme levels. However, Frossard et al. (1998) did not find an association between angiotensin-converting enzyme insertion/deletion and clinical diagnoses of hypertension, ischemic heart disease, myocardial infarction, and left ventricular hypertrophy. Frossard et al. (1998) concluded that the angiotensin-converting enzyme insertion/deletion dimorphism does not constitute a predictive marker for cardiovascular diseases in the population of the United Arab Emirates.
In 2001, Obineche et al. carried out an association (case-control) study of five candidate genes, including the angiotensin converting enzyme gene, with clinical left ventricular hypertrophy in a genetically homogenous Emirati group. No significant differences in the genotype distribution of the angiotensin converting enzyme gene markers were found between the left ventricular hypertrophy and non- left ventricular hypertrophy groups.
In 2003, Saeed Mahmood and colleagues assessed the value of genotyping the ACE G2350A dimorphism in a retrospective case-control study for a putative association with essential hypertension in the UAE population. Polymerase chain reaction and restriction endonuclease analyses were used to investigate a sample population of 254 Emirati from Abu Dhabi, comprising 136 normotensive controls, and 118 patients with clinical diagnoses of essential hypertension. Detailed analysis revealed that the ACE G/G 2350 genotype was positively associated with essential hypertension. According to the literature, this was the first association study of the ACE G2350A dimorphism with essential hypertension. Saeed Mahmood et al. (2003) concluded that this positive result might indicate that ACE could be a quantitative trait locus for essential hypertension as originally thought.
Bayoumi et al. (2006) determined the frequencies of insertion-deletion (*I and *D) alleles of the ACE gene in two Arabian (Omanis and Emiratis) and two African populations (Sudanese and Somalis). The allele frequencies of *I and *D were found to be 0.39 and 0.61, respectively in the 111 Emirati subjects studied [See Also: Oman > Bayoumi et al., 2006].
Laks and Passwell (1987) described an infant of Arab extraction with the Type II form of Gaucher's disease. In addition to the extensive neurological involvement and marked hepatosplenomegaly, the child's clinical presentation also included a marked hypergammaglobulinemia and raised serum angiotensin converting enzyme levels. Frishberg et al. (1998) compared the frequency of three polymorphisms of the renin-angiotensin system, including the angiotensin converting enzyme gene insertion/deletion polymorphism in intron 16, in Arab and Jewish children with focal segmental glomerulosclerosis with that in healthy controls of matching ethnic groups. Arab patients showed a greater tendency towards progressive renal disease than their Jewish counterparts. Frishberg and colleagues concluded that homozygosity for the angiotensin converting enzyme gene insertion allele may have a protective effect in children with focal segmental glomerulosclerosis and can serve as a positive prognostic indicator at diagnosis.
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