English abstract
High blood pressure affects 12–24 % of the world's population and recent studies in Oman showed it has affected 21 % of Omanis (Hassan et al., 2005). Essential hypertension is a complex disease where both genetic and environmental factors interact to produce the phenotype. Arterial blood pressure is regulated by several systems each performing a specific function. Our aim was to examine the contribution of certain genes in blood pressure regulation. Our criteria in gene selection were: a gene with a product (a protein or an enzyme) that is involved in blood pressure regulation, while its polymorphisms should alter this function. Also, this gene should have proven association with BP in previous studies or proven linkage to a chromosomal locus. The renin angiotensin aldosterone system (RAAS) is an important regulator of blood pressure. Some of the genes in this pathway have fulfilled our criteria. Angiotensin II, which is part of the RAAS, is a powerful vasoconstrictor and indirectly increases mean arterial pressure. Also, it has a range of other effects: (1) It increases cardiac contractility; (2) reduces renal plasma flow, enhancing Nat reabsorption in the kidney; (3) stimulate adrenal cortex to release aldosterone; (4) in the central nervous system (CNS), angiotensin II stimulates thirst and leads to the release of another vasoconstrictor, arginine vasopressin (AVP); (5) it also facilitates the release of norepinephrine by postganglionic sympathetic nerve terminals; and (6) finally, it acts as a cardiac growth factor.
To investigate the effect of the polymorphisms of the RAAS genes on blood pressure regulation, 294 subjects from one Omani family were genotyped for the following polymorphism: A-20C and G-6A of the angiotensinogen gene (AGT), the I/D of the angiotensin converting enzyme gene (ACE), A1166C of the angiotensin II type 1 receptor gene (ATIIRI) and the T-344C of the aldosterone synthase gene (CYP11B2). Haplotypes of the single polymorphisms of RAAS genes were also tested. The effect of these polymorphisms (as single polymorphism or as haplotypes) on blood pressure variables were investigated together with obesity related variables (waist circumference and body mass index) and several other biochemistry variables. The allele's frequency of these polymorphisms were found to be:
0.094 for the C allele (A-20C) of the AGT gene, 0.59 for the A allele (G-6A) of the AGT gene, 0.69 for the D allele (I/D) of the ACE gene, 0.182 for the Callele (A1166C) of the ATIR1 gene and 0.49 for the Callele (T-344C) of the CYP11B2 gene.
Our results showed that in the Omani study group the most important gene polymorphism that regulates blood pressure is the ACE gene (I/D) polymorphism. The D allele of the ACE gene was found to be associated with an increase in SBP, and total peripheral resistance index at rest and higher decrease in nocturnal dBP
dip (%). Total peripheral resistance was found to be associated with the D allele in males and not in females. However, SBP at rest and nocturnal dBP dip were found to be associated with the D allele in females and not in males. Insulin basal level was also found to be decreased in subjects carrying the D allele.
The C allele of the A-20C polymorphism in the AGT gene was found to be associated with a decrease in PSDHR, VLFHR and LFHR, that causes an excitation of the sympathetic nervous system to increases heart rate. In this study we also
found that the C allele is possibly associated with development of obesity, decrease in serum triglycerides and insulin basal level.
The A allele of the G-6A polymorphism in the AGT gene was found to be associated with an increase in total cholesterol and LDL cholesterol.
The C allele of the A1166C polymorphism of the ATIR1 gene was found to be associated with an increase in fasting and in 2-hour plasma glucose level. Also, this allele was found to be associated with an increase in total cholesterol level.
The C allele of the T-344C of the CYP11B2 gene was found to be associated with a decrease in insulin basal level and thyroid stimulating hormone level.
The most frequent haplotype was DAGCA (D of ACE, -20A of AGT, -6G of AGT, -344C of CYP11B2 and 1166A of ATIR1), which is associated with better regulation of blood pressure, protection from obesity and regulation of cholesterol and glucose levels.
Hypertension aggregates with other cardiovascular risk factors, such as abdominal obesity, dyslipideamia, glucose intolerance, hyperinsulinaemia, as is commonly known as "Metabolic Syndrome" possibly because of a common underlying cause and our results confirmed this, since the polymorphisms of the RAAS genes were found to affect blood pressure variables together with BMI, waist circumference, total cholesterol, LDL-cholesterol, glucose, insulin and thyroid stimulating hormone.
