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A microarray minisequencing system for pharmacogenetic profiling of antihypertensive drug response

Liljedahl, Ulrikaa; Karlsson, Juliaa; Melhus, Håkana; Kurland, Lisaa; Lindersson, Mariea; Kahan, Thomasc; Nyström, Fredrikd; Lind, Larsa,b; Syvänen, Ann-Christinea

Original Articles
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We aimed to develop a microarray genotyping system for multiplex analysis of a panel of single nucleotide polymorphisms (SNPs) in genes encoding proteins involved in blood pressure regulation, and to apply this system in a pilot study demonstrating its feasibility in the pharmacogenetics of hypertension. A panel of 74 SNPs in 25 genes involved in blood pressure regulation was selected from the SNP databases, and genotyped in DNA samples of 97 hypertensive patients. The patients had been randomized to double-blind treatment with either the angiotensin II type 1 receptor blocker irbesartan or the β1-adrenergic receptor blocker atenolol. Genotyping was performed using a microarray based DNA polymerase assisted ‘minisequencing’ single nucleotide primer extension assay with fluorescence detection. The observed genotypes were related to the blood pressure reduction using stepwise multiple regression analysis. The allele frequencies of the selected SNPs were determined in the Swedish population. The established microarray-based genotyping system was validated and allowed unequivocal multiplex genotyping of the panel of 74 SNPs in every patient. Almost 7200 SNP genotypes were generated in the study. Profiles of four or five SNP-genotypes that may be useful as predictors of blood pressure reduction after antihypertensive treatment were identified. Our results highlight the potential of microarray-based technology for SNP genotyping in pharmacogenetics.

aDepartment of Medical Sciences, Uppsala University, Uppsala, bAstra Zeneca R&D, Mölndal, cDivision of Internal Medicine, Karolinska Institute, Danderyd Hospital, Stockholm and dDepartment of Medicosurgical Gastroenterology, Endocrinology and Metabolism, University Hospital of Linköping, Linköping, Sweden.

Correspondence to Ann-Christine Syvänen, Department of Medical Sciences, Molecular Medicine, Uppsala University Hospital, Entrance 70, Third Floor, Research Department 2, S-751 85 Uppsala, Sweden. Tel: +46 18 611 29 59; fax: +46 18 611 25 19; e-mail: ann-christine.syvanen@medsci.uu.se

Received 1 July 2002 Accepted 24 October 2002

© 2003 Lippincott Williams & Wilkins, Inc.