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Single nucleotide polymorphisms in the apolipoprotein B and low density lipoprotein receptor genes affect response to antihypertensive treatment
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. (Akut- och internmedicin)
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2004 (English)In: BMC Cardiovascular Disorders, ISSN 1471-2261, E-ISSN 1471-2261, Vol. 4, no 1, 16- p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Dyslipidemia has been associated with hypertension. The present study explored if polymorphisms in genes encoding proteins in lipid metabolism could be used as predictors for the individual response to antihypertensive treatment. METHODS: Ten single nucleotide polymorphisms (SNP) in genes related to lipid metabolism were analysed by a microarray based minisequencing system in DNA samples from ninety-seven hypertensive subjects randomised to treatment with either 150 mg of the angiotensin II type 1 receptor blocker irbesartan or 50 mg of the beta1-adrenergic receptor blocker atenolol for twelve weeks. RESULTS: The reduction in blood pressure was similar in both treatment groups. The SNP C711T in the apolipoprotein B gene was associated with the blood pressure response to irbesartan with an average reduction of 19 mmHg in the individuals carrying the C-allele, but not to atenolol. The C16730T polymorphism in the low density lipoprotein receptor gene predicted the change in systolic blood pressure in the atenolol group with an average reduction of 14 mmHg in the individuals carrying the C-allele. CONCLUSIONS: Polymorphisms in genes encoding proteins in the lipid metabolism are associated with the response to antihypertensive treatment in a drug specific pattern. These results highlight the potential use of pharmacogenetics as a guide for individualised antihypertensive treatment, and also the role of lipids in blood pressure control.

Place, publisher, year, edition, pages
2004. Vol. 4, no 1, 16- p.
Keyword [en]
Antihypertensive treatment, pharmacogenetics, lipids, minisequencing, genotyping
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-73315DOI: 10.1186/1471-2261-4-16PubMedID: 15453913OAI: oai:DiVA.org:uu-73315DiVA: diva2:101225
Available from: 2005-06-02 Created: 2005-06-02 Last updated: 2017-12-14Bibliographically 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.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1342
Keyword
Molecular medicine, microarray, genotyping, pharmacogenetics, molecular medicine, single nucleotide polymorphism, hypertension, Molekylärmedicin
National Category
Medical Genetics
Identifiers
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
Opponent
Supervisors
Available from: 2004-04-20 Created: 2004-04-20 Last updated: 2016-08-11Bibliographically approved

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Liljedahl, UlrikaLind, LarsKurland, LisaBerglund, LarsSyvänen, Ann-Christine

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