Angiotensin-converting Enzyme Locus Research Articles

Renin???angiotensin sysiem gene polymorphisms influence blood pressure and the response to angiotensin converting enzyme inhibition

To investigate the relationship between polymorphisms in the angiotensin converting enzyme (ACE), angiotensinogen (AGT) and type 1 angiotensin-II (AT1R) genes and (1) quantitative variations in blood pressure and (2) the blood pressure response to ACE inhibition in a hypertensive cohort. We administered monotherapy with ACE inhibitors to 125 previously untreated essential hypertensives. Genotypes for ACE insertion and deletion, AGT M235T and AT1R A1166-->C polymorphisms were determined in DNA extracted from peripheral blood leucocytes. The influence of genotype on pretreatment blood pressure and the ACE inhibitor-induced decrease in blood pressure was tested by analysis of variance and multiple regression analysis, adjusting for age, sex, body mass index, alcohol intake and, where appropriate, pretreatment blood pressure. ACE and AT1R genotypes were independent predictors of pretreatment systolic and diastolic blood pressure, with an apparent interaction between these two gene loci. Although it did not influence pretreatment blood pressure in this population, AGT genotype was an independent predictor of the blood pressure response to ACE inhibition. The ACE and AT1R gene loci (chromosomes 17q and 3q, respectively) may carry alleles influencing blood pressure variation in this hypertensive population, with a possible epistatic interaction between the two loci. The AGT T235 allele does not appear to be a marker for blood pressure variation in this group, but variants on chromosome 1q lying in or near the AGT gene may contribute to individual differences in the blood pressure response to ACE inhibition. Among essential hypertensives, differences in the ACE inhibitor response appear, in part, to be genetically determined.

Renin-angiotensin system gene polymorphisms influence blood pressure and the response to angiotensin converting enzyme inhibition

Objectives To investigate the relationship between polymorphisms in the angiotensin converting enzyme (ACE), angiotensinogen (AGT) and type 1 angiotensin-II (AT1R) genes and (1) quantitative variations in blood pressure and (2) the blood pressure response to ACE inhibition in a hypertensive cohort. Design and methods We administered monotherapy with ACE inhibitors to 125 previously untreated essential hypertensives. Genotypes for ACE insertion and deletion, AGT M235T and AT1R A1166±C polymorphisms were determined in DNA extracted from peripheral blood leucocytes. The influence of genotype on pretreatment blood pressure and the ACE inhibitor-induced decrease in blood pressure was tested by analysis of variance and multiple regression analysis, adjusting for age, sex, body mass index, alcohol intake and, where appropriate, pretreatment blood pressure. Results ACE and AT1R genotypes were independent predictors of pretreatment systolic and diastolic blood pressure, with an apparent interaction between these two gene loci. Although it did not influence pretreatment blood pressure in this population, AGT genotype was an independent predictor of the blood pressure response to ACE inhibition. Conclusions The ACE and AT1R gene loci (chromosomes 17q and 3q, respectively) may carry alleles influencing blood pressure variation in this hypertensive population, with a possible epistatic interaction between the two loci. The AGT T235 allele does not appear to be a marker for blood pressure variation in this group, but variants on chromosome 1q lying in or near the AGT gene may contribute to individual differences in the blood pressure response to ACE inhibition. Among essential hypertensives, differences in the ACE inhibitor response appear, in part, to be genetically determined.

Genetic Linkage of the ACE Gene to Plasma Angiotensin-Converting Enzyme Activity but Not to Blood Pressure

An allelic variant of the ACE gene has been found to be linked to plasma angiotensin-converting enzyme (ACE) activity in humans and has been implicated in the etiology of some common cardiovascular disorders. Previously, we have shown significant genetic linkage of blood pressure to a region on rat chromosome 10 that contains ACE in an experimental F2-intercross between the stroke-prone spontaneously hypertensive rat (SHRSPHD) and the normotensive Wistar-Kyoto (WKYHD-0) reference strain. Subsequent investigations revealed marked differences in plasma ACE activity among the SHRSPHD and WKYHD-0 strains. Nonetheless, the physiological relevance of these findings remained obscure. We therefore investigated the genetic determination of plasma ACE activity and its relation to blood pressure and dietary NaCl exposure in a model of experimental genetic hypertension, the SHRSPHD. We conducted a further crossbreeding experiment between SHRSPHD and a congenic reference strain, WKYHD-1, that carries a 6-centimorgan (cM) long, SHRSP-homologous segment introgressed in chromosome 10, 26 cM remote from ACE. This allowed us to contrast effects on blood pressure and ACE activity conferred by the ACE locus with other more remote loci within the congenic chromosomal region. Genetic analysis in this F2 (WKYHD-1 x SHRSPHD) cross revealed that plasma ACE activity was determined almost entirely by genetic effects of the ACE gene locus (lod score = 43). However, neither plasma ACE nor the ACE locus showed any cosegregation with blood pressure before or after dietary NaCl exposure. These results demonstrate that a molecular variant of the ACE gene determines plasma ACE activity but exhibits no direct effect on blood pressure. Moreover, the findings also exclude the possibility that plasma ACE is secondarily affected by blood pressure or excess dietary NaCl exposure. Our results reconcile the previous discrepancy between findings in human and experimental hypertension.

The genetics of hypertension

In the past few years, a number of key insights have been made concerning the genetic basis of hypertension and blood pressure regulation. The genes responsible for two Mendelian forms of hypertension, glucocorticoid-remediable aldosteronism and Liddle's syndrome, were identified. In addition, research into the role of the renin—angiotension system in blood pressure regulation has further implicated the angiotensinogen and angiotensin-converting enzyme loci in hypertension and its complications, such as myocardial infarction. Finally, several new candidate genes for hypertension have been identified through the use of genome scanning and contemporary gene expression assays in model organisms.

Genetic associations with human longevity at the APOE and ACE loci

In an effort to dissect the genetic components of longevity, we have undertaken case-control studies of populations of centenarians (n = 338) and adults aged 20-70 years at several polymorphic candidate gene loci. Here we report results on two genes, chosen for their impact on cardiovascular risk, encoding apolipoprotein E (ApoE), angiotensin-converting enzyme (ACE). We find that the epsilon 4 allele of APOE, which promotes premature atherosclerosis, is significantly less frequent in centenarians than in controls (p < 0.001), while the frequency of the epsilon 2 allele, associated previously with type III and IV hyperlipidemia, is significantly increased (p < 0.01). A variant of ACE which predisposes to coronary heart disease is surprisingly more frequent in centenarians, with a significant increase of the homozygous genotype (p < 0.01). These associations provide examples of genetic influences on differential survival and may point to pleiotropic age-dependent effects on longevity.

Vascular conversion of angiotensin I in stroke-prone spontaneously hypertensive and Wistar-Kyoto rats.

Linkage studies have shown that the gene locus for angiotensin converting enzyme (ACE) is associated with the expression of hypertension in stroke-prone spontaneously hypertensive rats (SHRSP). We tested the hypothesis that the conversion of angiotensin I (Ang I) to angiotensin II (Ang II) in blood vessels is elevated in SHRSP. We measured the conversion rate of Ang I to Ang II during one pass through an isolated resistance vessel bed. We used the same substrains of SHRSP and Wistar-Kyoto control rats (WKY) that had been employed in the earlier linkage studies. Isolated hindquarters from young and adult (10- to 12- and 36- to 38-week-old) rats were perfused with an artificial medium and then infused with Ang I at 0.5 and 2 pmol/ml. Ang I and II were measured with high-performance liquid chromatography and radioimmunoassay in hindquarter effluent and in blank control channels. Conversion and extraction rates were calculated from angiotensin levels in hindquarter and blank perfusion channels, respectively. The conversion rates of Ang I to Ang II did not differ between SHRSP and WKY in young or in adult rats. Captopril completely abolished the formation of Ang II in all groups of rats. During infusion at the higher dose of Ang I, the extraction of Ang I was significantly decreased in SHRSP compared with WKY. Our results are consistent with the notion that the metabolism of angiotensin is decreased in spontaneously hypertensive rats. However, we found no support for the hypothesis that vascular ACE is responsible for high blood pressure in SHRSP. These findings suggest that other genes close to the ACE locus or the hyperexpression of the enzyme in other areas may contribute to hypertension in these rats.

Deletion polymorphism in angiotensin-converting enzyme gene associated with parental history of myocardial infarction

In a European study an insertion (/)/deletion (D) polymorphism in the angiotensin converting enzyme (ACE) gene has been shown to be associated with the risk of myocardial infarction (Ml). In the same study, we investigated the association of the polymorphism with a parental history of fatal MI. There was an excess of both DD (odds ratio 2·6, p=0·02) and ID (odds ratio=1·9, p=0·08) genotypes among those having a parental history of Ml, confirming that genetic variation in the ACE locus could be involved in the risk of MI.

A new genetic locus cosegregating with blood pressure in F2 progeny obtained from stroke-prone spontaneously hypertensive rats and Wistar-Kyoto rats.

Segregation studies using genomic polymorphisms on F2 progeny obtained from hypertensive rat models showed that a putative hypertensive gene is located close to the angiotensin converting enzyme (ACE) gene. However, it was suggested that additional major genes should contribute to the pathogenesis of hypertension. F2 rats were obtained from stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto (WKY) rats of Izumo colony. Blood pressure was measured with a photoelectronic oscillometric tail-cuff method before and during salt loading. Genomic DNA was extracted from livers and digested with HaeIII or Rsal. DNA fingerprinting was performed with 26 32P-labelled human variable number of tandem repeats markers. Eighty-seven fingerprint bands polymorphic between SHRSP and WKY were obtained. When the distribution of these bands in the F2 progeny was studied, one fingerprint band (1/MCT96.1) showed a distorted distribution between the high- and low-blood pressure subpopulations of the F2 rats, suggesting that the band cosegregated with blood pressure. When blood pressure was compared between the F2 rats with [(+) rats] and without [(-) rats] the 1/MCT96.1 band, it was found that (-) rats had significantly higher basal and salt-loaded blood pressures than (+) rats. The 1/MCT96.1 locus was also shown to have no positive linkage with the ACE locus. The present study showed that examination of the allele distribution between subpopulations with extreme phenotype can be used in the screening of loci cosegregating with blood pressure. Furthermore, a locus not in the ACE region, showing cosegregation with blood pressure in F2 progeny from SHRSP and WKY rats, was found.

Cosegregation of blood pressure with angiotensin converting enzyme and atrial natriuretic peptide receptor genes using Dahl salt-sensitive rats.

We have evaluated the genes for angiotensin converting enzyme (ACE) and guanylyl cyclase A/atrial natriuretic peptide receptor (GCA) for genetic effects on blood pressure response to high salt diet. In F2 rats derived from Milan normotensive and Dahl salt-hypertension sensitive (S) rats, both ACE and GCA cosegregated with blood pressure, and rats that were homozygous for the S allele at both the ACE and GCA loci had inordinately high blood pressure. In F2 derived from Wistar Kyoto (WKY) and S rats, GCA revealed positive cosegregation with blood pressure, but ACE did not. We conclude that certain alleles at the GCA and ACE loci (or at loci closely linked to them) have a significant genetic impact on blood pressure response to high salt in specific rat strains.

Absence of linkage between the angiotensin converting enzyme locus and human essential hypertension.

The angiotensin converting enzyme (ACE) is a key component of the renin angiotensin system that contributes to the regulation of blood pressure (BP). Recent demonstration of linkage between the ACE locus and elevated BP in a rat model of hypertension has further emphasized ACE as a candidate gene in human hypertension. We report the localization of the ACE gene on the genetic map of chromosome 17, and identify an extremely polymorphic marker at the human growth hormone (hGH) locus which shows no recombination with ACE. We have found no evidence to support linkage between the ACE locus and hypertension, which suggests that mutations at the ACE locus do not commonly contribute to the pathogenesis of hypertension in our test population.