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1.  Murine double nullizygotes of the angiotensin type 1A and 1B receptor genes duplicate severe abnormal phenotypes of angiotensinogen nullizygotes. 
Journal of Clinical Investigation  1998;101(4):755-760.
Rodents are the unique species carrying duplicated angiotensin (Ang) type 1 (AT1) receptor genes, Agtr1a and Agtr1b. After separately generating Agtr1a and Agtr1b null mutant mice by gene targeting, we produced double mutant mice homozygous for both Agtr1a and Agtr1b null mutation (Agtr1a-/-; Agtr1b-/-) by mating the single gene mutants. Agtr1a-/-, Agtr1b-/- mice are characterized by normal in utero survival but decreased ex utero survival rate. After birth they are characterized by low body weight gain, marked hypotension, and abnormal kidney morphology including delayed maturity in glomerular growth, hypoplastic papilla, and renal arterial hypertrophy. These abnormal phenotypes are quantitatively similar to those found in mutant mice homozygous for the angiotensinogen gene (Agt-/-), indicating that major biological functions of endogenous Ang elucidated by the abnormal phenotypes of Agt-/- are mediated by the AT1 receptors. Infusion of Ang II, AT1 blockers, or an AT2 blocker was without effect on blood pressure in Agtr1a-/-; Agtr1b-/- mice, indicating that AT2 receptor does not exert acute depressor effects in these mice lacking AT1 receptors. Also, unlike Agt-/- mice, some Agtr1a-/-; Agtr1b-/- mice have a large ventricular septum defect, suggesting that another receptor such as AT2 is functionally activated in Agtr1a-/-, Agtr1b-/- mice.
PMCID: PMC508622  PMID: 9466969
2.  Common Genetic Variation, Residential Proximity to Traffic Exposure, and Left Ventricular Mass: The Multi-Ethnic Study of Atherosclerosis 
Environmental Health Perspectives  2010;118(7):962-969.
Elevated left ventricular mass (LVM) is a strong predictor of negative cardiovascular outcomes, including heart failure, stroke, and sudden cardiac death. A relationship between close (< 50 m compared with > 150 m) residential proximity to major roadways and higher LVM has previously been described, but the mechanistic pathways that are involved in this relationship are not known. Understanding genetic factors that influence susceptibility to these effects may provide insight into relevant mechanistic pathways.
We set out to determine whether genetic polymorphisms in genes affecting vascular and autonomic function, blood pressure, or inflammation influence the relationship between traffic proximity and LVM.
This was a cross-sectional study of 1,376 genotyped participants in the Multi-Ethnic Study of Atherosclerosis, with cardiac magnetic resonance imaging performed between 2000 and 2002. The impact of tagged single-nucleotide polymorphisms (tagSNPs) and inferred haplotypes in 12 candidate genes (ACE, ADRB2, AGT, AGTR1, ALOX15, EDN1, GRK4, PTGS1, PTGS2, TLR4, VEGFA, and VEGFB) on the relationship between residential proximity to major roadways and LVM was analyzed using multiple linear regression, adjusting for multiple potential confounders.
After accounting for multiple testing and comparing homozygotes, tagSNPs in the type 1 angiotensin II receptor (AGTR1, rs6801836) and arachidonate 15-lipoxygenase (ALOX15, rs2664593) genes were each significantly (q < 0.2) associated with a 9–10% difference in the association between residential proximity to major roadways and LVM. Participants with suboptimal blood pressure control demonstrated stronger interactions between AGTR1 and traffic proximity.
Common polymorphisms in genes responsible for vascular function, inflammation, and oxidative stress appear to modify associations between proximity to major roadways and LVM. Further understanding of how genes modify effects of air pollution on CVD may help guide research efforts into specific mechanistic pathways.
PMCID: PMC2920916  PMID: 20308035
AGTR1; ALOX15; cardiac structure; cardiac MRI; gene-environment interactions; left ventricular mass; traffic, air pollution
3.  Molecular and clinical analysis of TRPC6 and AGTR1 genes in patients with pulmonary arterial hypertension 
Pulmonary arterial hypertension (PAH) is a rare and progressive vascular disorder characterized by increased pulmonary vascular resistance and right heart failure. The aim of this study was to analyze 5′UTR region in canonical transient receptor potential isoform 6 (TRPC6) and 3′UTR region in Angiotensin II type I receptor (AGTR1) genes in patients with idiopathic and associated PAH. Correlation among mutations and clinical and functional parameters was further analyzed.
Analysis of TRPC6 and AGTR1 genes was performed by polymerase chain reaction (PCR) and direct sequencing. We used a non-parametric test to determine if significant differences were found between the groups studied and chi-square test to compare clinical and hemodynamic variables among genotypes.
Fifty five patients and fifty two controls were included in this study. We found statistically significant differences for c.1-361A > T (p = 0.0077), c.1-254C > G (p < 0.0001) and c.1-218C > T (p = 0.0021) in TRPC6 gene and c.1166A > C (p < 0.001) in AGTR1 gene, between patients and controls. Idiopathic PAH patients (IPAH) and controls presented significant differences for all 3 TRPC6 polymorphisms (p = 0.020), (p = 0.002) and (p = 0.008) respectively, and also showed differences for AGTR1 gene (p < 0.001). In associated PAH (APAH) patients we found statistical differences for c.1-254C > G (p < 0.001) and c.1-218C > T (p = 0.001) in TRPC6 gene and c.1166A > C (p = 0.001) in AGTR1 gene. Several clinical and hemodynamic parameters showed significant differences between carriers and non-carriers of these single nucleotide polymorphisms (SNPs). Nineteen patients were carriers of all 3 SNPs in TRPC6 gene and presented a more severe phenotype with differences in mean pulmonary arterial pressure (p = 0.016), systolic pulmonary arterial pressure (p = 0.040), cardiac index (p < 0.001) and 6 minute walking test (p = 0.049). 16 of these patients harbored the SNP in AGTR1 gene. These patients showed differences in age at diagnosis (p = 0.049), mean pulmonary arterial pressure (p = 0.033), cardiac index (p = 0.002) and 6 minute walking test (p = 0.039).
PAH is a rare disease with pulmonary vascular remodeling caused in part by a heterogeneous constellation of genetic arrangements. This study seems to suggest that c.1-361A > T, c.1-254C > G and c.1-218C > T polymorphisms in TRPC6 gene and c.1166A > C polymorphism in AGTR1 could have a role in the development of this disease.
PMCID: PMC4307182  PMID: 25603901
Pulmonary Arterial Hypertension; TRPC6; AGTR1; Polymorphism; Correlation genotype/phenotype
4.  Genetic polymorphisms of angiotensin-2 type 1 receptor and angiotensinogen and risk of renal dysfunction and coronary heart disease in type 2 diabetes mellitus 
BMC Nephrology  2009;10:9.
Increased activation of the renin-angiotensin system (RAS) may be important in promoting coronary heart disease (CHD) and renal dysfunction, but limited data are available on associations between angiotensin type 1 receptor (AGT1R) and angiotensinogen (AGT) genotypes in type 2 diabetes.
Study participants were diabetics from the Health Professionals Follow-Up Study (HPFS) and the Nurses' Health Study (NHS). We analyzed single nucleotide polymorphisms (SNPs) associated with cardiovascular pathophysiology (including AGT1R T573C, AGT1R A1166C, and AGT M235T) and presence of renal dysfunction (eGFR<60 ml/min/1.73 m2) or history of CHD.
The AGT1R 1166 C-allele was associated with eGFR<60 ml/min/1.73 m2 (multivariable OR 1.63 [1.01, 2.65]) in the HPFS men (n = 733) and in the combined dataset (n = 1566) (OR 1.42 [1.02, 1.98]). The AGT1R 1166 C-allele was also associated with CHD in men (OR 1.57 [1.10, 2.24]). In NHS women (n = 833), AGT 235T-allele was associated with CHD (OR 1.72 [1.20, 2.47]). Removal of hypertension from the fully adjusted models did not influence results, suggesting that the associations may not be mediated by hypertension. There were significant interactions between sex and AGT1R 1166 C-allele (p = 0.008) and AGT M235T (p = 0.03) in models for CHD. No significant associations were seen between AGT1R T573 C-allele and renal dysfunction or CHD.
Polymorphisms in AGT1R and AGT genes are associated with renal dysfunction and CHD in type 2 diabetes and further support the important role of the RAS in these complications. Sex may modify associations between AGT1R 1166 C-allele and AGT 235T and CHD in type 2 diabetes.
PMCID: PMC2669070  PMID: 19327134
5.  Polymorphism in the Angiotensin II Type 1 Receptor (AGTR1) is Associated with Age at Diagnosis in Pulmonary Arterial Hypertension 
Pulmonary arterial hypertension (PAH) is a rare, lethal disease associated with single gene disorders, connective tissue disease, exposures to anorexigens, and often idiopathic etiology. There is evidence that genes can modify the risk of PAH: 1) monogenic disorders associated with PAH are incompletely penetrant, and 2) not all patients with associated conditions at increased risk for PAH develop the disease. The renin angiotensin aldosterone system (RAAS) provides a set of candidate genes that could modulate pulmonary vascular disease similar to its effects on renal and peripheral vasculature.
We studied 247 subjects with PAH (177 subjects with idiopathic PAH (IPAH); 63 subjects with PAH/connective tissue disease (CTD); and 7 subjects with PAH associated with anorexigens). Subjects were genotyped for five common polymorphisms in angiotensinogen (AGT), angiotensin converting enzyme (ACE), cardiac chymase A (CMA1), angiotensin II type 1 receptor (AGTR1) and aldosterone synthase (CYP11B2). Genotypes were tested for associations with age at diagnosis, hemodynamic parameters at diagnosis, and/or response to acute pulmonary vasodilator testing at diagnosis.
Associations were demonstrated for AGTR1 and age at diagnosis in IPAH (p=0.005). Homozygotes for the C1166 allele (n=13) were associated with an age at diagnosis 26 years later than subjects with A/A (n=139) or A/C (n=90) genotypes. No associations were demonstrated for AGT, ACE, CMA1, or CYP11B2.
The 1166C polymorphism in AGTR1 appears to be associated with a later age at diagnosis in IPAH suggesting that this pathway could be involved in the biologic variability that is known to occur in PAH.
PMCID: PMC3712279  PMID: 19332265
genetic; pulmonary hypertension; renin; angiotensin; aldosterone
6.  Genetic Variation in ACE-related pathways associated with Sudden Cardiac Arrest Risk 
Angiotensin converting enzyme (ACE)-related pathways influence arrhythmias and sudden cardiac arrest (SCA) risk.
We investigated whether genetic variation in ACE-related pathways are associated with SCA risk. Because these pathways are sex-dependent and influenced by estrogen, we examined these genotype-SCA associations in the full study population, and tested for interaction with gender.
In a population-based case-control study set in King County WA, we genotyped 211 SCA cases (mean age 59, 80% male) and 730 age- and gender-matched controls of European descent for 47 single nucleotide polymorphisms (SNPs) in eight genes (ACE, AGT, REN, AGTR1, AGTR2, ACE2, KNG1, BDKRB2). We examined association of SNPs and haplotypes with SCA risk using logistic regression.
AGTR1 SNP rs1492099 (allele frequency=15%) was associated with decreased SCA risk (OR=0.62, 95%CI=0.4–0.9). Haplotype variation in AGTR2 was associated with SCA risk (global haplotype test p=0.001), with haplotype 2 (allele frequency=27%) associated with increased risk (OR=1.26, 95%CI=1.1–1.5). There was interaction with gender on SCA risk for variation in KNG1 (interaction p-value range=0.0004–0.017 for 6/8 SNPs). KNG1 SNP rs710448 (allele frequency=42%) was associated with decreased risk (OR=0.44, 95%CI=0.3–0.8) among women but not men. Other SNPs and haplotypes in the eight genes examined were not associated with SCA risk after multiple testing correction.
Variation in AGTR1 and AGTR2 are associated with SCA risk in a population-based case-control study. There was evidence of interaction with gender on SCA risk for variation in KNG1. Our findings, if replicated, suggest that variation in genes in ACE-related pathways influence SCA risk.
PMCID: PMC2757102  PMID: 19716087
sudden death; cardiac arrest; epidemiology; genetics; polymorphism; renin-angiotensin system
7.  Susceptibility and Gene Interaction Study of the Angiotensin II Type 1 Receptor (AGTR1) Gene Polymorphisms with Non-Alcoholic Fatty Liver Disease in a Multi-Ethnic Population 
PLoS ONE  2013;8(3):e58538.
Angiotensin II type 1 receptor (AGTR1) has been reported to play a fibrogenic role in non-alcoholic fatty liver disease (NAFLD). In this study, five variants of the AGTR1 gene (rs3772622, rs3772627, rs3772630, rs3772633, and rs2276736) were examined for their association with susceptibility to NAFLD. Subjects made up of 144 biopsy-proven NAFLD patients and 198 controls were genotyped using TaqMan assays. The liver biopsy specimens were histologically graded and scored according to the method of Brunt. Single locus analysis in pooled subjects revealed no association between each of the five variants with susceptibility to NAFLD. In the Indian ethnic group, the rs2276736, rs3772630 and rs3772627 appear to be protective against NAFLD (p = 0.010, p = 0.016 and p = 0.026, respectively). Haplotype ACGCA is shown to be protective against NAFLD for the Indian ethnic subgroup (p = 0.03). Gene-gene interaction between the AGTR1 gene and the patatin-like phospholipase domain-containing 3 (PNPLA3) gene, which we previously reported as associated with NAFLD in this sample, showed a strong interaction between AGTR1 (rs3772627), AGTRI (rs3772630) and PNPLA3 (rs738409) polymorphisms on NAFLD susceptibility (p = 0.007). Further analysis of the NAFLD patients revealed that the G allele of the AGTR1 rs3772622 is associated with increased fibrosis score (p = 0.003). This is the first study that replicates an association between AGTR1 polymorphism and NAFLD, with further details in histological features of NAFLD. There is lack of evidence to suggest an association between any of the five variants of the AGTR1 gene and NAFLD in the Malays and Chinese. In the Indians, the rs2276736, rs3772630 and rs3772627 appear to protect against NAFLD. We report novel findings of an association between the G allele of the rs3772622 with occurrence of fibrosis and of the gene-gene interaction between AGTR1gene and the much-studied PNPLA3 gene.
PMCID: PMC3590220  PMID: 23484035
8.  Renin angiotensin system gene polymorphisms and cerebral blood flow regulation: The MOBILIZE Boston study 
Background and purpose
Our objective was to investigate the associations between polymorphisms in representative genes of the renin angiotensin system with measures of cerebral blood flow regulation in older adults.
Participants in this analysis were white subjects (n=335) in the MOBILIZE Boston study, an observational study of community-dwelling elders who underwent transcranial Doppler while sitting and standing and during hypercapnea and hypocapnea. Autoregulation phenotype was the change in cerebrovascular resistance from sit to stand. Vasoreactivity (VR) phenotype was the slope of the change in cerebrovascular conductance vs change in end-tidal CO2. Total of 33 tagged single nucleotide polymorphisms (SNP) were selected in the angiotensinogen gene (AGT), the angiotensin converting enzyme (ACE) gene and the angiotensin receptor gene (AGTR). Regression analyses adjusted for age, gender, body mass index, mean arterial blood pressure, stroke and use of antihypertensives were conducted for each SNP and outcome. Bonferroni corrections were used to adjust p-values for multiple testing.
In the AGT gene, only the rs699 SNP was associated with VR after Bonferroni correction (p=0.00028). Homozygous carriers of the CC genotype of this SNP had lower VR compared to the CT or TT genotypes. There were no significant associations with autoregulation measures. None of the SNP’s in the other genes was associated with our phenotypes.
This analysis suggests that the AGT gene may be involved in vasoreactivity independent of blood pressure. Larger studies are needed to confirm the role of this gene in cerebrovascular health and aging.
PMCID: PMC3563282  PMID: 20185782
Angiotensin; cerebral blood flow; vasoreactivity
9.  Association between angiotensin II receptor gene polymorphism and serum angiotensin converting enzyme (SACE) activity in patients with sarcoidosis 
Thorax  1998;53(6):459-462.
BACKGROUND—Serum angiotensin converting enzyme (SACE) is considered to reflect disease activity in sarcoidosis. SACE activity is increased in many patients with active sarcoid lesions. The mechanism for the increased SACE activity in this disease has not been clarified. ACE insertion/deletion (I/D) gene polymorphism has been reported to have an association with SACE levels in sarcoidosis, but no evidence of an association between angiotensin II receptor gene polymorphism and SACE in this disease has been found. A study of the association of angiotensin II receptor gene polymorphisms with sarcoidosis was therefore undertaken.
METHODS—ACE (I/D), angiotensin II type 1 receptor (AGTR1), and angiotensin II type 2 receptor (AGTR2 ) gene polymorphisms were investigated by polymerase chain reaction (PCR) and SACE levels were measured in three groups of patients: those with sarcoidosis or tuberculosis and normal controls.
RESULTS—There was no difference in allele frequency of AGTR1 and AGTR2 polymorphism among the three groups. Neither AGTR1 nor AGTR2 polymorphisms were associated with sarcoidosis. SACE activity was higher in patients with sarcoidosis with the AGTR1 A/C genotype than in others. However, this tendency was not detected in patients with tuberculosis.
CONCLUSIONS—The AGTR1 allele C is associated with high activity of SACE in patients with sarcoidosis. It is another predisposing factor for high levels of SACE in patients with sarcoidosis and is considered to be an independent factor from the ACE D allele for high levels of SACE in sarcoidosis. This fact could be one of the explanations for the increased SACE activity in sarcoidosis.

PMCID: PMC1745244  PMID: 9713444
10.  Polymorphisms of the renin–angiotensin system are associated with blood pressure, atherosclerosis and cerebral white matter pathology 
The renin–angiotensin system is involved in the development of hypertension, atherosclerosis and cardiovascular disease. We studied the association between the M235T polymorphism of the angiotensinogen gene (AGT) and the C573T polymorphism of the angiotensin II type 1 receptor (AT1R) and blood pressure, carotid atherosclerosis and cerebrovascular disease.
We genotyped over 6000 subjects from the Rotterdam Study and more than 1000 subjects from the Rotterdam Scan Study. We used logistic regression and univariate analyses, adjusting for age and sex with, for AGT, the MM and, for AT1R, the TT genotype as reference.
We found that AGT−235T increased systolic (p for trend = 0.03) and diastolic blood pressure (p for trend = 0.04). The prevalence of carotid plaques was increased 1.25‐fold (95% CI 1.02–1.52) in AGT‐TT carriers. There was a significant increase in mean volume deep subcortical white matter lesions (WML) for AGT‐TT carriers (1.78 ml vs 1.09 ml in the reference group; p = 0.008). A significant interaction was found between AGT and AT1R, further increasing the effect on periventricular and subtotal WML (p for interaction = 0.02). We found a non‐significant increased risk of silent brain infarction for AGT‐TT carriers and AT1R‐CC carriers, but no effect on stroke.
We found an association between AGT and blood pressure, atherosclerosis and WML. Also, we found synergistic effects between AGT and AT1R on the development of WML. These findings raise the question of whether the renin–angiotensin system may be a therapeutic target for the prevention of cerebral white matter pathology.
PMCID: PMC2117548  PMID: 17220293
11.  Genetic variants in the renin-angiotensin system and blood pressure reactions to the cold pressor test 
Journal of hypertension  2010;28(12):2422-2428.
The purpose of this study was to examine the association between genetic variants in the renin-angiotensin system (RAS) and blood pressure (BP) responses to cold pressor test (CPT).
The CPT was conducted among 1,998 Han Chinese participants. BP measurements were obtained before and after the CPT using a standard sphygmomanometer according to a standard protocol. The association between SNP genotypes and BP responses to the CPT was assessed using a mixed linear model.
Of 68 SNPs genotyped in 6 RAS genes, two were strongly associated with diastolic BP (DBP) responses to CPT (P ≤ 0.001; false discovery rate q-value < 0.05): rs2006765 and rs943580 in the angiotensinogen (AGT) gene. Compared to C allele carriers of rs2006765, the TT homozygotes had a significantly decreased DBP response to the CPT. For participants with the TT genotype, percent DBP responses were 5.68% (4.25%, 7.10%), compared to corresponding responses of 9.17% (8.66%, 9.68%) among participants with the CC+CT genotype. In addition, SNP rs4681443 of the angiotensin type 1 receptor (AGTR1) gene was significantly associated with percent SBP responses to CPT (P≤0.001; q-value <0.05).
Briefly, our study identified variants in the AGT and AGTR1 genes that may influence BP responses to CPT in Han Chinese population. These results show that genetic variants in the RAS play an important role in BP responses to CPT, and therefore in predicting future hypertension.
PMCID: PMC3029492  PMID: 20811292
blood pressure; cold pressor test; renin-angiotensin system; genetics; polymorphism
12.  HNF4alpha Dysfunction as a Molecular Rational for Cyclosporine Induced Hypertension 
PLoS ONE  2011;6(1):e16319.
Induction of tolerance against grafted organs is achieved by the immunosuppressive agent cyclosporine, a prominent member of the calcineurin inhibitors. Unfortunately, its lifetime use is associated with hypertension and nephrotoxicity. Several mechanism for cyclosporine induced hypertension have been proposed, i.e. activation of the sympathetic nervous system, endothelin-mediated systemic vasoconstriction, impaired vasodilatation secondary to reduction in prostaglandin and nitric oxide, altered cytosolic calcium translocation, and activation of the renin-angiotensin system (RAS). In this regard the molecular basis for undue RAS activation and an increased signaling of the vasoactive oligopeptide angiotensin II (AngII) remain elusive. Notably, angiotensinogen (AGT) is the precursor of AngII and transcriptional regulation of AGT is controlled by the hepatic nuclear factor HNF4alpha. To better understand the molecular events associated with cyclosporine induced hypertension, we investigated the effect of cyclosporine on HNF4alpha expression and activity and searched for novel HNF4alpha target genes among members of the RAS cascade. Using bioinformatic algorithm and EMSA bandshift assays we identified angiotensin II receptor type 1 (AGTR1), angiotensin I converting enzyme (ACE), and angiotensin I converting enzyme 2 (ACE2) as genes targeted by HNF4alpha. Notably, cyclosporine represses HNF4alpha gene and protein expression and its DNA-binding activity at consensus sequences to AGT, AGTR1, ACE, and ACE2. Consequently, the gene expression of AGT, AGTR1, and ACE2 was significantly reduced as evidenced by quantitative real-time RT-PCR. While RAS is composed of a sophisticated interplay between multiple factors we propose a decrease of ACE2 to enforce AngII signaling via AGTR1 to ultimately result in vasoconstriction and hypertension. Taken collectively we demonstrate cyclosporine to repress HNF4alpha activity through calcineurin inhibitor mediated inhibition of nuclear factor of activation of T-cells (NFAT) which in turn represses HNF4alpha that leads to a disturbed balance of RAS.
PMCID: PMC3029342  PMID: 21298017
13.  Complementation of reduced survival, hypotension, and renal abnormalities in angiotensinogen-deficient mice by the human renin and human angiotensinogen genes. 
Journal of Clinical Investigation  1997;99(6):1258-1264.
The aim of this study was to determine whether elements of the human renin-angiotensin system (RAS) could functionally replace elements of the mouse RAS by complementing the reduced survival and renal abnormalities observed in mice carrying a gene-targeted deletion of the mouse angiotensinogen gene (mAgt). Double transgenic mice containing the human renin (HREN) and human angiotensinogen (HAGT) genes were bred to mice heterozygous for the mAgt deletion and the compound heterozygotes were identified and intercrossed. The resulting progeny (n = 139) were genotyped at each locus and the population was stratified into two groups: the first containing both human transgenes (RA+) and the second containing zero or one, but not both human transgenes (RA-). Despite appropriate Mendelian ratios of RA- mice that were wildtype (+/+), heterozygous (+/-), and homozygous (-/-) for the deletion of mAgt at birth, there was reduced survival of RA- mAgt-/- mice to adulthood (P < 0.001 by chi2). In contrast, we observed appropriate Mendelian ratios of RA+ mAgt+/+, RA+ mAgt+/-, and RA+ mAgt-/- mice at birth and in adults (P > 0.05 by chi2). These results demonstrate that the presence of both human transgenes rescues the postnatal lethality in mAgt-/- mice. The renal histopathology exhibited by RA- mAgt-/- mice, including thickened arterial walls, severe fibrosis, lymphocytic infiltration, and atrophied parenchyma, was also rescued in the RA+ mAgt-/- mice. Direct arterial blood pressure recordings in conscious freely moving mice revealed that BP (in mmHg) varied proportionally to mAgt gene copy number in RA+ mice (approximately 20 mmHg per mAgt gene copy, P < 0.001). BP in RA+ mAgt-/- mice (132+/-3, n = 14) was intermediate between wild-type (RA- mAgt+/+, 105+/-2, n = 9) and RA+ mAgt+/+ (174+/-3, n = 10) mice. These studies establish that the human renin and angiotensinogen genes can functionally replace the mouse angiotensinogen gene, and provides proof in principle that we can examine the regulation of elements of the human RAS and test the significance of human RAS gene variants by a combined transgenic and gene targeting approach.
PMCID: PMC507940  PMID: 9077534
14.  Factors Influencing Blood Pressure Response to Trandolapril Add-On Therapy in Patients Taking Verapamil SR (from the International Verapamil SR/Trandolapril [INVEST] Study) 
The American journal of cardiology  2007;99(11):1549-1554.
Factors such as age and race/ethnicity might influence blood pressure (BP) response to drugs. Therapeutic response to the angiotensin-converting enzyme inhibitor trandolapril used as add-on therapy to stable calcium channel blocker therapy with verapamil sustained release 240 mg was addressed in a racially/ethnically diverse group of 1,832 hypertensive patients with coronary artery disease. Furthermore, the association with a polymorphism (1166A→C) in the angiotensin II type 1 receptor gene (AGTR1) was tested. BP response was compared between groups using analysis of covariance after adjustment for covariates associated with BP response. Genotyping was performed using polymerase chain reaction and pyrosequencing. Trandolapril decreased mean unadjusted systolic and diastolic BPs by −9.1 ± 17.3 (SD) and −4.1 ± 10.1 mm Hg, respectively. The percentage of patients with BP under control (<140/90 mm Hg) increased from 6.7% to 41.3% (p <0.0001). Adjusted BP response was significantly associated with age and baseline systolic and diastolic BP (p <0.0001). Whereas the decrease in systolic BP was more pronounced in younger patients, the opposite was observed for diastolic BP decrease. Diastolic BP response was also significantly associated with race. Specifically, the adjusted diastolic BP decrease was significantly smaller in Hispanics and blacks than whites (p = 0.0032 and p = 0.0069, respectively). However, Hispanics achieved a decrease in systolic BP and an increase in BP control similar to the other ethnic groups. There was no genetic association between AGTR1 1166A→C genotype and BP response. In conclusion, trandolapril add-on therapy was effective in increasing BP control, with age and baseline BP associated with both systolic and diastolic BP response. Race was associated with diastolic BP response, although the difference is likely not to be clinically significant and AGTR1 genotype was not associated with BP response.
PMCID: PMC2720593  PMID: 17531579
15.  Chronic renal insufficiency among Asian Indians with type 2 diabetes: I. Role of RAAS gene polymorphisms 
BMC Medical Genetics  2006;7:42.
Renal failure in diabetes is mediated by multiple pathways. Experimental and clinical evidences suggest that renin-angiotensin-aldosterone system (RAAS) has a crucial role in diabetic kidney disease. A relationship between the RAAS genotypes and chronic renal insufficiency (CRI) among type 2 diabetes subjects has therefore been speculated. We investigated the contribution of selected RAAS gene polymorphisms to CRI among type 2 diabetic Asian Indian subjects.
Twelve single nucleotide polymorphisms (SNPs) from six genes namely-renin (REN), angiotensinogen (ATG), angiotensin converting enzyme I (ACE), angiotensin II type 1 receptor (AT1) and aldosterone synthase (CYP11B2) gene from the RAAS pathway and one from chymase pathway were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and tested for their association with diabetic CRI using a case-control approach. Successive cases presenting to study centres with type 2 diabetes of ≥2 years duration and moderate CRI diagnosed by serum creatinine ≥3 mg/dl after exclusion of non-diabetic causes of CRI (n = 196) were compared with diabetes subjects with no evidence of renal disease (n = 225). Logistic regression analysis was carried out to correlate various clinical parameters with genotypes, and to study pair wise interactions between SNPs of different genes.
Of the 12 SNPs genotyped, Glu53Stop in AGT and A>T (-777) in AT1 genes, were monomorphic and not included for further analysis. We observed a highly significant association of Met235Thr SNP in angiotensinogen gene with CRI (O.R. 2.68, 95%CI: 2.01–3.57 for Thr allele, O.R. 2.94, 95%CI: 1.88–4.59 for Thr/Thr genotype and O.R. 2.68, 95%CI: 1.97–3.64 for ACC haplotype). A significant allelic and genotypic association of T>C (-344) SNP in aldosterone synthase gene (O.R. 1.57, 95%CI: 1.16–2.14 and O.R. 1.81, 95%CI: 1.21–2.71 respectively), and genotypic association of GA genotype of G>A (-1903) in chymase gene (O.R. 2.06, 95%CI: 1.34–3.17) were also observed.
SNPs Met235Thr in angiotensinogen, T>C (-344) in aldosterone synthase, and G>A (-1903) in chymase genes are significantly associated with diabetic chronic renal insufficiency in Indian patients and warrant replication in larger sample sets. Use of such markers for prediction of susceptibility to diabetes specific renal disease in the ethnically Indian population appears promising.
PMCID: PMC1479320  PMID: 16672053
16.  The role of renin–angiotensin–aldosterone system polymorphisms in phenotypic expression of MYBPC3-related hypertrophic cardiomyopathy 
European Journal of Human Genetics  2012;20(10):1071-1077.
The phenotypic variability of hypertrophic cardiomyopathy (HCM) in patients with identical pathogenic mutations suggests additional modifiers. In view of the regulatory role in cardiac function, blood pressure, and electrolyte homeostasis, polymorphisms in the renin–angiotensin–aldosterone system (RAAS) are candidates for modifying phenotypic expression. In order to investigate whether RAAS polymorphisms modulate HCM phenotype, we selected a large cohort of carriers of one of the three functionally equivalent truncating mutations in the MYBPC3 gene. Family-based association analysis was performed to analyze the effects of five candidate RAAS polymorphisms (ACE, rs4646994; AGTR1, rs5186; CMA, rs1800875; AGT, rs699; CYP11B2, rs1799998) in 368 subjects carrying one of the three mutations in the MYBPC3 gene. Interventricular septum (IVS) thickness and Wigle score were assessed by 2D-echocardiography. SNPs in the RAAS system were analyzed separately and combined as a pro-left ventricular hypertrophy (LVH) score for effects on the HCM phenotype. Analyzing the five polymorphisms separately for effects on IVS thickness and Wigle score detected two modest associations. Carriers of the CC genotype in the AGT gene had less pronounced IVS thickness compared with CT and TT genotype carriers. The DD polymorphism in the ACE gene was associated with a high Wigle score (P=0.01). No association was detected between the pro-LVH score and IVS thickness or Wigle score. In conclusion, in contrast to previous studies, in our large study population of HCM patients with functionally equivalent mutations in the MYBPC3 gene we did not find major effects of genetic variation within the genes of the RAAS system on phenotypic expression of HCM.
PMCID: PMC3449069  PMID: 22569109
hypertrophic; cardiomyopathy; renin–angiotensin–aldisterone system; echocardiography
17.  Gene-Gene Interactions in Renin-Angiotensin-Aldosterone System Contributes to End-Stage Renal Disease Susceptibility in a Han Chinese Population 
The Scientific World Journal  2014;2014:169798.
Objective. In this study, we investigated whether RAAS gene single nucleotide polymorphisms (SNPs) and their interactions were associated with end-stage renal stage (ESRD). Methodology and Results. This was a case-control study for 647 ESRD cases and 644 controls. AGT (M235T (rs699) and T174M (rs4762)), AGTR1 (A1166C (rs5186) and C573T (rs5182)), ACE (I/D (rs1799752) and G2350A (rs4343)), and CYP11B2 C-344T (rs1799998) were genotyped and compared between cases and controls to identify SNPs associated with ESRD susceptibility. Multifactor dimensionality reduction (MDR) was used to identify gene-gene interactions. Several RAAS genes were associated with ESRD: AGT M235T, ACE I/D, ACE G2350A, and CYP11B2 C-344T. By MDR analysis, a three-locus model (ACE ID/ACE G2350A/CYP11B2 C-344T) of gene-gene interaction was the best for predicting ESRD risk, and its maximum testing accuracy was 56.08% and maximum cross-validation consistency was 9/10. ESRD risk was higher with the simultaneous occurrence of ACE I/D DD-ACE G2350A AA. AGT, ACE, and CYP11B2 gene polymorphisms are associated with ESRD. Conclusions. The gene-gene interaction effects of ACE I/D, ACE G2350A, and CYP11B2 C-344T polymorphisms are more important than individual factors for ESRD development among Han Chinese.
PMCID: PMC4003748  PMID: 24977181
18.  The role of genetic polymorphisms of the Renin–Angiotensin System in renal diseases: A meta-analysis 
Renal failure has a complex phenotype resulting from an underlying kidney disease as well as environmental and genetic factors. In the present study we performed a systematic review and meta-analyses to evaluate the association of the A1166C polymorphism of Angiotensin II type 1 Receptor gene (AGTR1) with Chronic Kidney Disease (CKD), End Stage Renal Disease (ESRD), IgA Nephropathy (IgAN) and Vesicoureteral Reflux (VUR) as well as the association of A1332G polymorphism of Angiotensin II type 2 Receptor (AGTR2) gene with Vesicoureteral Reflux (VUR). We found that neither AGTR1 Α1166C, nor AGTR2 A1332G polymorphisms were significantly associated with any of the aforementioned renal diseases, suggesting that they cannot be used as predictive markers in either general or subgroup ethnic populations.
PMCID: PMC4151998  PMID: 25210592
ESRD; CKD; Kidney disease; Angiotensin receptor; Polymorphism; Genetic association
19.  Screening the Single Nucleotide Polymorphisms in Patients with Internal Carotid Artery Stenosis by Oligonucleotide-Based Custom DNA Array 
Early screening of individuals considered to be at risk for severe internal carotid artery (ICA) stenosis is an important strategy for preventing ischemic cerebral stroke. The purpose of this study is to screening candidate single nucleotide polymorphisms (SNPs) associated with severe ICA stenosis using a newly developed oligonucleotide-based custom DNA array. The subjects consisted of 47 controls and 46 patients with severe ICA stenosis (≥70%) who underwent carotid endarterectomy (CEA). Subjects gave informed consent and we obtained samples of blood and genomic DNA. We studied 8 candidate genes: renin-angiotensin system [angiotensinogen (AGT), angiotensin II receptor type 1 (AGTR1), nitric oxide synthase 3 (NOS3)]; growth factor [hepatocyte growth factor (HGF)]; transgelin (SM22); cytokine [chemokine receptor 2 (CCR2)]; coagulation-fibrinolysis system [5,10-methylenetetrahydrofolate reductase (MTHFR)]; and plasminogen activator inhibitor 1 (PAI-1). Genotyping of candidate SNPs was done with a line probe assay (LiPA) based on an oligonucleotide-based DNA array. Results: The allele frequency of PAI-1 –1965 delG (odds ratio (OR), 0.3; 95% confidence interval (CI), 0.2–0.6) and MTHFR (OR 1.3, 95% CI, 1.0–1.5) were significantly different between controls and cases with ICA stenosis by Fisher’s exact test. Multiple logistic analysis revealed that diabetes mellitus (DM), SNPs in PAI-1 –1965 delG and MTHFR were an independent risk for ICA stenosis. In conclusion, genetic factors of coagulation-fibrinolysis as well as diabetes mellitus (DM) were relevant in ICA stenosis.
PMCID: PMC2789695  PMID: 20066125
atherosclerosis; carotid artery stenosis; polymorphism; plasminogen activator inhibitor 1; 5; 10-methylenetetra hydrofolate reductase
20.  Expression of the AT2 receptor developmentally programs extracellular signal-regulated kinase activity and influences fetal vascular growth 
Angiotensin II type 2 (AT2) receptor is abundantly expressed in vascular smooth muscle cells (VSMC) of the fetal vasculature during late gestation (embryonic day 15–20), during which the blood vessels undergo remodeling. To examine directly the influence of AT2 receptor expression in the developmental biology of VSMC, we studied cultures of VSMC from fetal and postnatal wild-type (Agtr2+) and AT2 receptor null (Agtr2–) mice. Consistent with in vivo data, AT2 receptor binding in cultured Agtr2+ VSMC increased by age, peaking at embryonic day 20, and decreased dramatically after birth. Angiotensin II–induced growth in Agtr2+ VSMC (embryonic day 20) was increased by the AT2 receptor blocker PD123319, indicating that the AT2 receptors are functional and exert an antigrowth effect in Agtr2+ VSMC. Growth of VSMC in response to serum decreased age dependently and was higher in Agtr2– than in Agtr2+, inversely correlating with AT2 receptor expression. However, serum-induced growth in Agtr2+ and Agtr2– VSMC and the exaggerated Agtr2– VSMC growth was maintained even in the presence of PD123319 or losartan, an AT1 receptor blocker. Moreover, Agtr2– VSMC showed greater growth responses to platelet-derived growth factor and basic fibroblast growth factor, indicating that Agtr2– cells exhibit a generalized exaggerated growth phenotype. We studied the mechanism responsible for this phenotype and observed that extracellular signal-regulated kinase (ERK) activity was higher in Agtr2– VSMC at baseline and also in response to serum. ERK kinase inhibitor PD98059 inhibited both growth and ERK phosphorylation dose–dependently, while the regression lines between growth and ERK phosphorylation were identical in Agtr2+ and Agtr2– VSMC, suggesting that increased ERK activity in Agtr2– VSMC is pivotal in the growth enhancement. Furthermore, the difference in ERK phosphorylation between Agtr2+ and Agtr2– was abolished by vanadate but not by okadaic acid, implicating tyrosine phosphatase in the difference in ERK activity. These results suggest that the AT2 receptor expression during the fetal vasculogenesis influences the growth phenotype of VSMC via the modulation of ERK cascade.
PMCID: PMC407869  PMID: 9884335
21.  Absence of angiotensin II type 1 receptor in bone marrow–derived cells is detrimental in the evolution of renal fibrosis 
The Journal of Clinical Investigation  2002;110(12):1859-1868.
We examined the in vivo function of the angiotensin II type 1 receptor (Agtr1) on macrophages in renal fibrosis. Fourteen days after the induction of unilateral ureteral obstruction (UUO), wild-type mice reconstituted with marrow lacking the Agtr1 gene (Agtr1–/–) developed more severe interstitial fibrosis with fewer interstitial macrophages than those in mice reconstituted with Agtr1+/+ marrow. These differences were not observed at day 5 of UUO. The expression of profibrotic genes — including TGF-β1, α1(I) collagen, and α1(III) collagen — was substantially higher in the obstructed kidneys of mice with Agtr1–/– marrow than in those with Agtr1+/+ marrow at day 14 but not at day 5 of UUO. Mice with Agtr1–/– marrow were characterized by reduced numbers of peripheral-blood monocytes and macrophage progenitors in bone marrow. In vivo assays revealed a significantly impaired phagocytic capability in Agtr1–/– macrophages. In vivo treatment of Agtr1+/+ mice with losartan reduced phagocytic capability of Agtr1+/+ macrophages to a level comparable to that of Agtr1–/– macrophages. Thus, during urinary tract obstruction, the Agtr1 on bone marrow–derived macrophages functions to preserve the renal parenchymal architecture, and this function depends in part on its modulatory effect on phagocytosis.
PMCID: PMC151648  PMID: 12488436
22.  Association of angiotensinogen gene T235 variant with progression of immunoglobin A nephropathy in Caucasian patients. 
Journal of Clinical Investigation  1997;100(4):814-820.
Genetic variability in the renin-angiotensin system may modify renal responses to injury and disease progression. We examined whether the M235T polymorphism of the angiotensinogen (AGT) gene, the insertion/deletion polymorphism of the angiotensin-converting enzyme (ACE) gene, and the A1166--> C polymorphism of the angiotensin II type 1 receptor gene may be associated with disease progression in 168 Caucasian patients with IgA nephropathy. All patients had serial measurements of their creatinine clearance, proteinuria, and blood pressure (mean+/-SD) with a follow-up of 6.1+/-4.7 yr. The genotype frequencies for each gene were consistent with Hardy-Weinberg equilibrium, and were similar to those of 100 Caucasian control subjects. We examined two primary outcomes: (a) the rate of deterioration of Ccr, and (b) the maximal level of proteinuria. We found that patients with the AGT MT (n = 79) and TT (n = 29) genotypes had a faster rate of deterioration of Ccr than those with the MM (n = 60) genotype (i.e., median values, -6.6 and -6.2 vs. -3. 0 ml/min/yr, respectively; P = 0.01 by Kruskal-Wallis test). Similarly, patients with AGT MT and TT genotypes had higher maximal values of proteinuria than those with the MM genotype (i.e., median values, 2.5 and 3.5 vs. 2.0 g/d, respectively; P < 0.02 by Kruskal-Wallis test). Neither the ACE insertion/deletion nor angiotensin II type I A1166--> C gene polymorphism was associated with disease progression or proteinuria in univariate analysis. Multivariant analysis, however, detected an interaction between the AGT and ACE gene polymorphisms with the presence of ACE/DD polymorphism adversely affecting disease progression only in patients with the AGT/MM genotype (P = 0.008). Neither of these gene polymorphisms was associated with systemic hypertension. Our results suggest that polymorphisms at the AGT and ACE gene loci are important markers for predicting progression to chronic renal failure in Caucasian patients with IgA nephropathy.
PMCID: PMC508253  PMID: 9259580
23.  Polymorphisms in the Renin-Angiotensin System and Migraine in Women 
Headache  2008;49(2):292-299.
Recent findings suggest an association between the renin-angiotensin system and migraine. However, genetic studies are scarce and controversial.
To investigate the association between the AGTR1 1166A>C and AGT Met235Thr polymorphisms with migraine and migraine aura status.
We performed an association study among 25,000 Caucasian U.S. women, participating in the Women's Health Study, with information on the AGTR1 1166A>C and AGT Met235Thr polymorphisms. Migraine and migraine aura status were self-reported. We distinguished between any history of migraine, active migraine with aura, active migraine without aura, and prior migraine (history of migraine, but not in the year prior to baseline). We used logistic regression to investigate the genotype-migraine association.
At baseline, 4,577 (18.3%) women reported any history of migraine; 39.5% of the 3,226 women with active migraine indicated aura. The polymorphisms were not associated with migraine or migraine specific subgroups. We also did not find a significant interaction between the polymorphisms.
Data from this large cohort of Caucasian women do not suggest an association of polymorphisms in the renin-angiotensin system with migraine or aura status. Future studies should focus on haplotype analyses and additional gene-gene as well as gene-environment interactions.
PMCID: PMC2644741  PMID: 19178574
migraine; renin-angiotensin system; polymorphism; women
24.  Association of renin-angiotensin and endothelial nitric oxide synthase gene polymorphisms with blood pressure progression and incident hypertension: prospective cohort study 
Journal of hypertension  2008;26(9):1780-1786.
The renin-angiotensin system and endothelial function have both been associated with hypertension. The aim of the present study was to assess the relationship of six previously characterized gene variants in the renin-angiotensin system and the NOS3 gene with blood pressure progression and incident hypertension.
We analyzed data from 18436 Caucasian women who participated in a prospective cohort study and were free of hypertension at baseline. Six previously characterized single nucleotide polymorphisms (NOS3 rs1800779, NOS3 rs3918226, NOS3 rs1799983, ACE rs1799752, AGT rs699, and AGTR1 rs5186) were genotyped. Blood pressure progression at 48 months and incident hypertension during the entire follow-up according to the different genotypes and inferred haplotypes were assessed by logistic regression and Cox proportional-hazards models, respectively.
At 48 months, 47.4% of the women had blood pressure progression. The odds ratios (95% confidence intervals (CI)) for blood pressure progression associated with NOS3 rs1800779, NOS3 rs3918226, NOS3 rs1799983, ACE rs1799752, AGT rs699, and AGTR1 rs5186 were 1.00 (0.96–1.05), 1.00 (0.92–1.09), 0.99 (0.94–1.04), 0.96 (0.92–1.01), 1.04 (0.99–1.08), and 1.03 (0.98–1.08). During 9.8 years of follow-up, 29.6% of women developed incident hypertension. The hazard ratios (95% CI) for the six polymorphisms were 1.01 (0.97–1.06), 1.06 (0.99–1.14), 1.05 (1.01–1.09), 0.99 (0.95–1.02), 1.01 (0.97–1.05) and 0.99 (0.95–1.04). NOS3-haplotypes were not significantly associated with blood pressure progression (p=0.91) or incident hypertension (p=0.10).
Blood pressure progression and incident hypertension are not consistently associated with six well-characterized genetic polymorphisms of the renin-angiotensin system and the NOS3 gene in a large cohort of Caucasian women.
PMCID: PMC2654571  PMID: 18698212
Blood pressure; Hypertension; Gene polymorphism; Nitric oxide synthase; Angiotensin-converting enzyme; Renin-angiotensin System
25.  Association of the angiotensinogen gene polymorphism with atherosclerosis and its risk traits in the Saudi population 
Angiotensinogen (AGT) constitutes a central component of the renin-angiotensin system that controls the systemic blood pressure and several other cardiovascular functions and may play an important role in atherosclerosis pathways. In this study, we employed TaqMan genotyping assays to evaluate the role of 8 AGT variants in primary hypertension (HTN), type 2 diabetes mellitus (T2DM), and obesity as a possible trigger of coronary artery disease (CAD) in a population of 4615 angiographed native Saudi individuals.
Linkage analysis was done by using the Affymetrix Gene Chip array, sequencing by using the MegaBACE DNA analysis system and genotyping accomplished by TaqMan chemistry using the Applied Biosystem real-time Prism 7900HT Sequence Detection System.
Six variants, rs2067853 GG [Odds ratio(95% Confidence Interval) = 1.44(1.17-1.78); p = 0.001], rs7079 [1.49(1.20-1.85); p < 0.0001], rs699 G [1.19(1.08-1.13); p < 0.0001], rs3789679 A [1.51(1.14-1.99); p = 0.004], rs2148582 GG [1.31(1.11-1.55); p = 0.002] and rs5051 TC + CC [1.32(1.13-1.60); p = 0.001] conferred risk for HTN (3521 cases versus 1094 controls). The rs2067853 (p = 0.042), rs699G (p = 0.007) and rs5051 (p = 0.051) also conferred risk for myocardial infarction (MI; 2982 vs 1633), while rs3789679 A (p < 0.0001) and GA + AA (p < 0.0001) as well as rs4762G (p = 0.019) were associated with obesity (1576 vs 2458). However, while these variants appeared to be also associated with CAD (2323 vs 2292), only the rs7079G (p = 0.035) retained its significant relationship. Interestingly, among the haplotypes constructed from these SNPs, the baseline 8-mer haplotype, GGTGGGGT (χ2 = 7.02; p = 0.0081) and another GGCGGAGT (χ2 = 5.10; p = 0.024), together with several of their derivatives were associated with HTN. T2DM was associated with two 8-mer haplotypes, GGTAGGAC (χ2 = 5.66; p = 0.017) and ATTGAGAC (χ2 = 5.93; p = 0.015), obesity with GGCGGAGT (χ2 = 9.49; p = 0.0021) and MI was linked to ATTGGGAC (χ2 = 6.68; p = 0.010) and GGTGGGAT (χ2 = 4.25; p = 0.039). Furthermore, several causative haplotypes were also shared among the risk traits as well as with CAD.
These results point to AGT as independently conferring risk for various cardiovascular traits, and possibly interacting with these traits in events leading to atherosclerosis.
PMCID: PMC3605175  PMID: 23497386
Angiotensinogen polymorphism; Primary hypertension; Type 2 diabetes mellitus; Obesity; Coronary artery disease; Gene-disease interactions; Pleiotropy

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