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Single nucleotide polymorphisms predict the change in left ventricular mass in response to antihypertensive treatment
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (molekylär medicin)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Osteoporos)
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2004 (English)In: Journal of Hypertension, ISSN 0263-6352, Vol. 22, no 12, 2321-8 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Our aim was to determine whether the change in left ventricular (LV) mass in response to antihypertensive treatment could be predicted by multivariate analysis of single nucleotide polymorphisms (SNPs) in candidate genes reflecting pathways likely to be involved in blood pressure control. METHODS: Patients with mild to moderate primary hypertension and LV hypertrophy were randomized in a double-blind fashion to treatment with either the angiotensin II type 1 receptor antagonist irbesartan (n = 48) or the beta1 adrenoreceptor blocker atenolol (n = 49). A microarray-based minisequencing system was used for genotyping 74 SNPs in 25 genes. These genotypes were related to the change in LV mass index by echocardiography, after 12 weeks treatment as monotherapy, using stepwise multiple regression analysis. RESULTS: The blood pressure reductions were similar and significant in both treatment groups. Two SNPs in two separate genes (the angiotensinogen T1198C polymorphism, corresponding to the M235T variant and the apolipoprotein B G10108A polymorphism) for those treated with irbesartan, and the adrenoreceptor alpha2A A1817G for those treated with atenolol, significantly predicted the change in LV mass. The predictive power of these SNPs was independent of the degree of blood pressure reduction. CONCLUSION: SNPs in the angiotensinogen, apolipoprotein B, and the alpha2 adrenoreceptor gene predicted the change in LV mass during antihypertensive therapy. These results illustrate the potential of using microarray-based technology for SNP genotyping in predicting individual drug responses.

Place, publisher, year, edition, pages
2004. Vol. 22, no 12, 2321-8 p.
Keyword [en]
Adrenergic beta-Antagonists/therapeutic use, Angiotensin II Type 1 Receptor Blockers/therapeutic use, Angiotensinogen/genetics, Antihypertensive Agents/*therapeutic use, Apolipoproteins B/genetics, Atenolol/therapeutic use, Biphenyl Compounds/therapeutic use, Blood Pressure/*genetics, Double-Blind Method, Echocardiography, Female, Genotype, Humans, Hypertension/complications/*drug therapy/*genetics, Hypertrophy; Left Ventricular/etiology/*ultrasonography, Male, Middle Aged, Multivariate Analysis, Oligonucleotide Array Sequence Analysis, Pharmacogenetics, Polymorphism; Single Nucleotide, Predictive Value of Tests, Receptors; Adrenergic; beta-2/genetics, Research Support; Non-U.S. Gov't, Tetrazoles/therapeutic use
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-70033PubMedID: 15614026OAI: oai:DiVA.org:uu-70033DiVA: diva2:97944
Available from: 2005-09-08 Created: 2005-09-08 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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