title: A microarray minisequencing system for pharmacogenetic profiling of antihypertensive drug response.
abstract: 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 beta 1-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.
authors.affiliation: Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Ulrika
authors.initials: U
authors.lastname: Liljedahl
authors.forename: Julia
authors.initials: J
authors.lastname: Karlsson
authors.forename: Håkan
authors.initials: H
authors.lastname: Melhus
authors.forename: Lisa
authors.initials: L
authors.lastname: Kurland
authors.forename: Marie
authors.initials: M
authors.lastname: Lindersson
authors.forename: Thomas
authors.initials: T
authors.lastname: Kahan
authors.forename: Fredrik
authors.initials: F
authors.lastname: Nyström
authors.forename: Lars
authors.initials: L
authors.lastname: Lind
authors.forename: Ann-Christine
authors.initials: AC
authors.lastname: Syvänen
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D017931:DNA Primers / Q000235:genetics; D030541:Databases, Genetic; D004311:Double-Blind Method; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D005787:Gene Frequency / Q000187:drug effects*; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D010597:Pharmacogenetics / Q000379:methods*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011897:Random Allocation; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000378:metabolism
chemical_list: D000319:Adrenergic beta-Antagonists; D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D017931:DNA Primers; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin