Angiotensinogen Gene Haplotype Research Articles

Angiotensinogen gene haplotype is associated with the prevalence of Japanese non‐alcoholic steatohepatitis

Non-alcoholic steatohepatitis (NASH) patients frequently have hypertension, which is considered to be an important predictive factor for the subsequent development of hepatic fibrosis. The renin-angiotensin system is also known to contribute to the progression of NASH. Various types of functional single-nucleotide polymorphisms (SNPs) involved in the development of NASH have been proposed. Angiotensinogen (AGT) gene SNPs related to cardiovascular diseases have been reported. We aimed to evaluate the involvement of the AGT gene haplotype in Japanese NASH patients. Previously described genotypes of SNPs of the AGT gene, rs4762 C/T polymorphism (T207M), rs699 C/T polymorphism (T268M), and rs7079 C/A polymorphism (C11537A), were determined in 124 Japanese biopsy-proven NASH patients and 150 healthy volunteers (controls). The allele and genotype frequencies in rs4762 and rs699 SNPs in NASH patients were similar to those in controls, while the frequency of the A allele and A/- genotype in rs7079 SNPs were much higher in NASH patients than in controls. In addition, the 3-SNP haplotype CTA was significantly over-represented in NASH patients compared with controls. Regarding clinical features of NASH patients, diastolic blood pressures in patients with the CTA/- genotype were much higher than in patients with other genotypes. We found a 3-SNP haplotype of the AGT gene that is involved in the development of NASH and influences hypertension in NASH patients. These results provide new insight into the therapy of NASH patients with the CTA haplotype using ACE inhibitors or angiotensin II type 1 receptor blockers.

Polygenetic regression model of renin-angiotensin system genes and the risk of coronary artery disease in a large angiographic population

Background Polygenetic effect has rarely been addressed in the genetic studies of coronary artery disease (CAD). We used the largest and ethnically homogeneous angiographic cohort to analyze multilocus data in renin-angiotensin system genes, and provide an explicit demonstration of gene–gene interactions. Methods A total of 1254 consecutive patients who underwent cardiac catheterization (735 with coronary artery disease and 519 without) were recruited. Angiotensin converting enzyme(ACE) gene I/D polymorphism; T174M, M235T, G-6A, A-20C, G-152A, and G-217A polymorphisms of the angiotensinogen (AGT) gene; and A1166C polymorphism of the angiotensin II type I receptor (AT1R) gene were genotyped. We used a regression approach based on a generalized linear model to evaluate haplotype effects, adjust non-genetic confounding effects and detect gene–gene interaction between ACE and AT1R genes. Results We found significant differences in global AGT gene haplotype profile and individual haplotypes between cases and controls. Significant two-way and three-way gene–gene interactions between ACE I/D, AT1R A1166C polymorphisms and AGT gene haplotypes were detected. However, subjects carrying both D allele and GGCATC haplotype had an increased risk of CAD (odds ratio = 1.63 [1.16–2.29]; P = 0.004). We also used haplotype counting to directly estimate the odds ratio of each specific AGT gene haplotype, and found that the effects of haplotypes were markedly different in subgroups with different ACE or AT1R gene genotype. Conclusions The regression-based haplotype analyses permits simultaneous dectection of multi-locus and multi-gene effects in determining the risk of CAD. We provide the paradigm for genetic studies of complex-trait diseases using candidate genes based on biological pathways.

Differential effect of two haplotypes of the human angiotensinogen gene on blood pressure in transgenic mice

Angiotensinogen (AGT) gene locus is associated with human essential hypertension and over‐expression of the AGT gene increases blood pressure in transgenic mice. Human AGT gene has A/G polymorphic sites at ‐6 and ‐217 positions in its promoter. The frequency of AA haplotype of the human AGT gene containing ‐6A:‐217A is significantly increased in African‐American hypertensive patients as compared to the AG haplotype‐6A:‐217G. Reporter constructs containing AA haplotype of the AGT gene promoter have increased promoter activity on transient transfection in human liver cells as compared to the AG haplotype. In order to understand the role of AA and AG haplotypes on hAGT expression in an in vivo situation, we have generated double transgenic mice containing either haplotype AA or AG of the hAGT gene (using knock‐in strategy at the HPRT locus) and human renin gene. Our studies show that transgenic mice containing AA haplotype have 1.6 fold increase in the AGT mRNA level in the liver as compared to the transgenic mice containing AG haplotype. In addition, Western blot and immunohistochemistry shows that liver and kidney of transgenic mice containing AA haplotype have increased hAGT protein level as compared to AG haplotype. In addition, blood pressure of three months old male transgenic mice containing AA haplotype is increased by about 8‐10 mmHg as compared to the transgenic mice containing AG haplotype. Supported by NHLBI.

Interaction of gender, hypertension, and the angiotensinogen gene haplotypes on the risk of coronary artery disease in a large angiographic cohort

There is increasing evidence suggesting the importance of evaluating gene–environment interactions in the genetic study of coronary artery disease (CAD). We investigated the association of multiple single nucleotide polymorphisms in the angiotensinogen (AGT) gene with CAD, considering the interaction between the genetic and non-genetic factors, using a larger and ethnically homogeneous angiographic cohort. A total of 1254 consecutive patients who underwent cardiac catheterization (735 with CAD and 519 without) were recruited. T174M (rs4762), M235T (rs699), G-6A, A-20C, G-152A, and G-217A polymorphisms of the AGT gene were genotyped. We used a regression approach based on a generalized linear model to evaluate haplotype effects defined by the multilocus data and detection of gene–environment interaction by incorporating interaction terms in the model. We found significant differences in global AGT gene haplotype profile between patients with and without CAD (the global score statistic=25.411, P=0.008). Significant interactions between AGT gene haplotypes, gender and hypertension were detected. We also used haplotype counting to directly estimate the odds ratio of each AGT gene haplotype, and found that the effects of haplotypes were markedly different in subgroups defined by gender and hypertension, providing strong evidence of gene–environment interaction. Female gender synergistically enhances (or male gender reverses) the effects of AGT gene haplotypes on the risk of CAD in the presence of hypertension. In conclusion, the effect of AGT gene haplotypes on the risk of CAD was significantly increased in women with hypertension, which highlights the importance of evaluating gene–environment interactions in the genetic study of CAD.

Renin-Angiotensin System Gene Polymorphisms and Atrial Fibrillation: A Regression Approach for the Detection of Gene-Gene Interactions in a Large Hospitalized Population

Objectives: To test the association between renin-angiotensin system gene variants and atrial fibrillation (AF) using a regression approach. Methods: A total of 1,236 consecutive patients (227 with AF and 1,009 with normal sinus rhythm as controls) were recruited. Angiotensin-converting enzyme (ACE) gene I/D polymorphism; T174M, M235T, G–6A, A–20C, G–152A and G–217A polymorphisms of the angiotensinogen (AGT) gene, and A1166C polymorphism of the angiotensin II type I receptor (AT1R) gene were genotyped. We used a regression approach based on a generalized linear model to evaluate haplotype effects and to detect gene-gene interactions by incorporating interaction terms in the model. Results: In single-locus analyses, no locus was associated with AF. After adjustment for AF risk factors, we found significant differences in the global AGT gene haplotype profile (the global score statistic = 30.364, p = 0.001) and individual haplotype frequencies between AF patients and controls. Furthermore, significant 2-way gene-gene interactions between ACE I/D polymorphism and AGT gene haplotypes and between AT1R A1166C polymorphism and AGT gene haplotypes, and 3-way interaction between ACE I/D, AT1R A1166C and AGT gene haplotypes were detected. Conclusions: These results are compatible with the concept of multilocus and multigene effects in determining the risk of complex diseases such as AF, which would be missed with conventional single-locus approaches.

Renin–angiotensin system gene polymorphisms and coronary artery disease in a large angiographic cohort: Detection of high order gene–gene interaction

There have been many reports regarding the association between renin–angiotensin system (RAS) gene polymorphisms and coronary artery disease (CAD) or acute myocardial infarction (AMI), but the results are inconsistent. In the present study, we used several new approaches with multilocus data to reappraise this issue in a large and relatively homogeneous Taiwanese population. A total of 1254 consecutive patients who underwent cardiac catheterization (735 with documented coronary artery disease and 519 without) between 1996 and 2003 were recruited. Angiotensin-converting enzyme gene insertion/deletion (I/D) polymorphism; T174M, M235T, G-6A, A-20C, G-152A and G-217A polymorphisms of the angiotensinogen gene; and A1166C polymorphism of the angiotensin II type I receptor gene were genotyped. In single-locus analyses, no locus was associated with CAD, history of AMI and three-vessel CAD, either with or without adjustment for conventional CAD risk factors. For multilocus analyses, we recreated a balanced population, with the controls individually matched to the cases regarding the conventional CAD risk factors. We found that the angiotensinogen gene haplotype profile was significantly different between the cases and controls ( χ 2 = 31.6, P = 0.030) in haplotype analyses. Furthermore, significant three-locus (G-217A, M235T and I/D) gene–gene interactions were detected by multifactor-dimensionality reduction method (highest cross-validation consistency 10.0, lowest prediction error 40.56%, P = 0.017) and many even higher order gene–gene interactions by multilocus genotype disequilibrium tests (16 genotype disequilibria exclusively found in the controls, all of which included at least two genes among AGT, ACE and AT1R genes). Our study is the first to demonstrate epistatic, high-order, gene–gene interactions between RAS gene polymorphisms and CAD. These results are compatible with the concept of multilocus and multi-gene effects in complex diseases that would be missed with conventional approaches.

A haplotype of angiotensinogen gene that is associated with essential hypertension increases its promoter activity in adipocytes

Obesity is associated with hypertension and other cardiovascular diseases especially in the African-American population. Human angiotensinogen ( AGT) gene has seven single nucleotide polymorphisms (SNPs) in 1.2 kb region of its promoter. Recent studies have shown that variant − 217A is associated with hypertension in African-American and Chinese population. Nucleotide sequence of the hAGT gene has shown that variant − 217A almost always occurs with variants − 532T, − 793A and − 1074T (forming haplotype AAT) and variant − 217G almost always occurs with variants − 532C, − 793G and − 1074G (forming haplotype GGG). Since hAGT gene is expressed in the adipose tissue and its expression in this tissue may play a role in hypertension, we have analyzed the role of haplotypes AAT and GGG on the expression of this gene in adipocytes. We show here that a reporter construct with haplotype AAT of the hAGT gene has increased promoter activity on transient transfection in pre-adipocytes and differentiated adipocytes as compared to the reporter construct containing GCGG haplotype. Increased expression of the AGT gene containing haplotype AAT in the liver and adipocytes may be a contributing factor for hypertension.

Renin-angiotensin system gene polymorphisms and atrial fibrillation.

The activated local atrial renin-angiotensin system (RAS) has been reported to play an important role in the pathogenesis of atrial fibrillation (AF). We hypothesized that RAS genes might be among the susceptibility genes of nonfamilial structural AF and conducted a genetic case-control study to demonstrate this. A total of 250 patients with documented nonfamilial structural AF and 250 controls were selected. The controls were matched to cases on a 1-to-1 basis with regard to age, gender, presence of left ventricular dysfunction, and presence of significant valvular heart disease. The ACE gene insertion/deletion polymorphism, the T174M, M235T, G-6A, A-20C, G-152A, and G-217A polymorphisms of the angiotensinogen gene, and the A1166C polymorphism of the angiotensin II type I receptor gene were genotyped. In multilocus haplotype analysis, the angiotensinogen gene haplotype profile was significantly different between cases and controls (chi2=62.5, P=0.0002). In single-locus analysis, M235T, G-6A, and G-217A were significantly associated with AF. Frequencies of the M235, G-6, and G-217 alleles were significantly higher in cases than in controls (P=0.000, 0.005, and 0.002, respectively). The odds ratios for AF were 2.5 (95% CI 1.7 to 3.3) with M235/M235 plus M235/T235 genotype, 3.3 (95% CI 1.3 to 10.0) with G-6/G-6 genotype, and 2.0 (95% CI 1.3 to 2.5) with G-217/G-217 genotype. Furthermore, significant gene-gene interactions were detected by the multifactor-dimensionality reduction method and multilocus linkage disequilibrium tests. This study demonstrates the association of RAS gene polymorphisms with nonfamilial structural AF and may provide the rationale for clinical trials to investigate the use of ACE inhibitor or angiotensin II antagonist in the treatment of structural AF.

Angiotensinogen gene haplotype and hypertension: interaction with ACE gene I allele.

There are many reports demonstrating the association of renin-angiotensin system gene polymorphisms with hypertension in different populations. In the present study, we used haplotype analyses of the angiotensinogen gene with a new permutation-based hypothesis testing method to determine the association between multilocus angiotensinogen gene polymorphisms and hypertension in a relatively homogeneous Taiwanese population. We also genotyped angiotensin-converting enzyme gene insertion/deletion polymorphism and angiotensin II type 1-receptor gene A1166C polymorphism to detect epistatic gene-gene interactions. There were 408 patients with hypertension (hypertensives) and 286 controls. The angiotensinogen gene haplotype frequencies were significantly different between hypertensives and controls, and this finding was only present in subjects with angiotensin-converting enzyme gene II genotypes when the analysis was stratified by genotype of this polymorphism. In addition, the angiotensinogen gene haplotype structure of hypertensives was more heterogeneous than that of controls. Our results showed that angiotensinogen gene haplotypes were associated with hypertension and might act synergistically with I allele of the angiotensin-converting enzyme gene.