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Angiotensinogen gene polymorphisms: relationship to blood pressure response to antihypertensive treatment. Results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs Atenolol (SILVHIA) trial
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Akut- och internmedicin)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Osteoporos)
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2004 (English)In: American Journal of Hypertension, ISSN 0895-7061, Vol. 17, no 1, 8-13 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The renin-angiotensin-aldosterone system (RAAS) is important for the development of hypertension, and several antihypertensive drugs target this system. Our aim was to determine whether specific single nucleotide polymorphisms (SNPs) in RAAS genes were related to the blood pressure (BP) lowering effect of antihypertensive treatment. METHODS: Patients with mild to moderate primary hypertension and left ventricular hypertrophy were randomized in a double-blind fashion to treatment with either the angiotensin II type 1 receptor antagonist irbesartan (n = 48) or the beta(1)-adrenergic receptor blocker atenolol (n = 49) as monotherapy. A microarray-based minisequencing system was used to genotype 30 SNPs in seven genes in the RAAS. These polymorphisms were related to the antihypertensive response after 12 weeks treatment. RESULTS: The BP reductions were similar in the atenolol and the irbesartan groups. Presence of the angiotensinogen (AGT) -6A allele or the AGT 235T allele were both associated with the most pronounced systolic BP response to atenolol treatment (P =.001 when -6 AA+AG was compared with GG and P =.008 for presence of the 235T variant compared with 235 MM). CONCLUSIONS: We found that SNPs in the angiotensinogen gene were associated with the BP lowering response to atenolol. This study is limited by a relatively small sample size, and the results should therefore be viewed as preliminary. Despite this limitation, these results illustrate the potential of using SNP genotyping as a pharmacogenetic tool in antihypertensive treatment.

Place, publisher, year, edition, pages
2004. Vol. 17, no 1, 8-13 p.
Keyword [en]
Angiotensin II Type 1 Receptor Blockers, Angiotensinogen/*genetics, Antihypertensive Agents/*therapeutic use, Atenolol/*therapeutic use, Biphenyl Compounds/*therapeutic use, Blood Pressure, Double-Blind Method, Female, Genotype, Humans, Hypertension/complications/drug therapy/*genetics, Hypertrophy; Left Ventricular/etiology, Male, Middle Aged, Polymorphism; Single Nucleotide, Renin-Angiotensin System/*genetics, Research Support; Non-U.S. Gov't, Tetrazoles/*therapeutic use, Treatment Outcome
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-73304DOI: 10.1016/j.amjhyper.2003.09.009PubMedID: 14700505OAI: oai:DiVA.org:uu-73304DiVA: diva2:101214
Available from: 2005-09-07 Created: 2005-09-07 Last updated: 2016-08-11Bibliographically approved
In thesis
1. Microarray Technology for Genotyping in Pharmacogenetics
Open this publication in new window or tab >>Microarray Technology for Genotyping in Pharmacogenetics
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The studies in this thesis describe the development of a microarray based minisequencing system and its application to highly parallel genotyping of single nucleotide polymorphisms. The technical developments included identification of a three-dimensional microarray surface coating with high binding capacity for oligonucleotides modified with amino groups as the most optimal one for the system. The system was also established for multiplexed, reproducible quantitative analysis of SNP alleles both on the level of DNA and RNA. The sensitivity of the system to distinguish SNP alleles present as a minority in a mixed sample was found to be 1-6%.

The microarray based minisequencing system was applied in a pharmacogenetic study on antihypertensive drug response. A panel of 74 SNPs located in candidate genes related to blood pressure regulation were genotyped in DNA samples from hypertensive patients that had been treated with the antihypertensive drugs irbesartan or atenolol. Multiple regression analysis of the genotype data against the reduction in blood pressure identified genotype combinations of four to five SNPs that explain 44-56% of the reduction in blood pressure in the two treatment groups. The genotypes of two individual SNPs in the angiotensinogen (AGT) gene and a SNP in the low density lipoprotein receptor (LDLR) gene appeared to be associated to reduced blood pressure after treatment with atenolol, while a SNP in the apolipoprotein B (APOB) gene was associated to blood pressure reduction after irbesartan treatment. The genotype of one SNP in the adrenergic alpha-2A-receptor gene (ADRA2A) was related to the reduction in left ventricular mass following atenolol treatment while the genotypes of two SNPs, one in the APOB gene and one in the AGT gene were related to the reduction in left ventricular mass in the patients treated with irbesartan.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2004. 69 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1342
Molecular medicine, microarray, genotyping, pharmacogenetics, molecular medicine, single nucleotide polymorphism, hypertension, Molekylärmedicin
National Category
Medical Genetics
urn:nbn:se:uu:diva-4222 (URN)91-554-5937-4 (ISBN)
Public defence
2004-05-13, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15
Available from: 2004-04-20 Created: 2004-04-20 Last updated: 2016-08-11Bibliographically approved

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Liljedahl, UlrikaMelhus, HåkanSyvänen, Ann-Christine
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