Angiotensin II type 1 receptor gene polymorphisms in human essential hypertension.

Abstract

We conducted the present study to determine whether the angiotensin II type I receptor (AT,) gene might be implicated in human essential hypertension by using case-control and linkage studies. The entire coding and 3' untranslated regions of the AT, receptor gene (2.2 kb) were amplified by polymerase chain reaction and submitted to single-strand conformation polymorphism in 60 hypertensive subjects with a familial susceptibility. We identified five polymorphisms (T 573 -»C, A 1062 -*G, A" 6 6^C , G 1 5 "^T, and A' 878 -»G). However, no mutations that alter the encoded amino acid sequence were detected. A case-control study performed on white hypertensive (n=206; blood pressure, 168±16/103±9 mm Hg) and normotensive (n=298; blood pressure, 122±10/75±9 mm Hg) subjects using three of five polymorphisms showed a significant increase in allelic fre-H uman essential hypertension is thought to result from the interaction of environmental and genetic factors, with approximately 30% of the interindividual variability in blood pressure being genetically determined.1 The renin-angiotensin system is an important component of blood pressure regulation, playing roles in saltwater homeostasis and vascular tone, 2 and has been suspected to be involved in hypertension. Indeed, evidence for a genetic linkage of human essential hypertension to the angiotensinogen locus was recently obtained in an extensive collaborative study.3 However, linkage and association studies of the human renin and angiotensin I (Ang I)-converting enzyme loci have given negative results. 49Ang II receptors, which mediate the vasoconstrictive and salt-conserving actions of the renin-angiotensin system, also represent interesting candidate genes for essential hypertension. Two subtypes of cell surface

Genes of renin angiotensin system and coronary heart disease

“…In the AT1 receptor gene five polymorphisms have been identified. However only A/C transversion at nucleotide position 1166 in the 3' un-translated region of the AT1R gene was found to be associated with human essential hypertension as reported by Bonnardeaux et al (27). A significant increase in the allele frequency of C 1166 in hypertensive subjects was seen (0.36 versus 0.28 in normotensive subjects; x 2 = 6.8, p<0.01).…”

“…Despite this, it is postulated that the AT1 receptor polymorphism may be associated with functional alterations in the responsiveness of this receptor. Some authors (28-30) confirmed these results of Bonnardeaux et al (27) but others did not (31-33). Benetos et al (33) did not show association of this polymorphism with essential hypertension; but reported an association with aortic stiffness and with ratio of total to high-density lipoprotein cholesterol.…”

“…This phenomenon can result from various mechanisms including receptor protein modifications and down regulation of gene expression (38). As no polymorphism was detected that modified the encoded amino acid sequence (27), they further speculated that the AT1R C allele is in linkage disequilibrium with a functional variant that could alter the down regulation of/~T1R gene in response to All, which is present in increased concentration with ACE DD genotype. Similar kind of studies carried out, where the synergistic interaction between ACE DID and AT1R NC on MI was reported (39) while it was disapproved by others (40).…”

Association of polymorphisms of the renin–angiotensin system and bradykinin B2 receptor with ACE-inhibitor-related cough

“…The ACE I/D polymorphism and the angiotensin II type 1 receptor 1166 A/C and type 2 receptor 3123C/A polymorphisms are suspected to be markers in linkage disequilibrium with an unidentified functional variant that could affect the regulation of the gene in response to angiotensin II. 34 Moreover, the cellular effects of angiotensin II are mediated by two structurally distinct receptor subtypes, angiotensin II type 1 and type 2 receptors, and angiotensin II type 1 and type 2 receptors have opposite functions. [35][36][37] It is also suspected that angiotensin II receptor stimulates the kininogenkinin system and induces cough; therefore it was interesting for us to examine the association between angiotensin II receptor polymorphisms and ACE-inhibitor-related cough.…”

Genetics of arterial hypertension and hypotension

“…These efforts resulted in the identification of an A1166C variant that is confined to the 3′ untranslated region of the AT1R cDNA (Bonnardeaux et al 1994;Wang et al 1997) and has been implicated in determining mRNA stability and, ultimately, receptor expression (Thekkumkara and Linas 2003; Fig. 13).…”