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AIMS: To investigate the effects of two single nucleotide polymorphisms (SNPs) in the human P2X₇ receptor gene (P2RX7)--1068G>A (A348T) and 1513A>C (E496A)--on P2X₇ receptor function, using a specific receptor antagonist (GSK1370319A) and prospective genetic stratification. METHODS: Lipopolysaccharide- and ATP-stimulated interleukin-1β production was determined in the presence or absence of GSK1370319A in blood culture from 32 prospectively genotyped subjects. RESULTS: There was approximately 6.7-fold difference (P < 0.0001) in IC₅₀ for inhibition of ATP-stimulated interleukin-1β release by GSK1370319A between individuals with the homozygous gain--(1068A) and loss-of-function (1513C) genotypes (expressing the 348T, 496E and 348A, 496A alleles, respectively). CONCLUSIONS: Leukocyte P2X₇ receptors had significantly altered pharmacodynamic responses to a specific antagonist (GSK1370319A), directly related to SNP genotype.

Original publication

DOI

10.1111/j.1365-2125.2012.04200.x

Type

Journal article

Journal

Br J Clin Pharmacol

Publication Date

08/2012

Volume

74

Pages

376 - 380

Keywords

Adenosine Triphosphate, Adult, Dose-Response Relationship, Drug, Female, Genotype, Heterozygote, Homozygote, Humans, Interleukin-1beta, Leukocytes, Lipopolysaccharides, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Prospective Studies, Purinergic P2X Receptor Antagonists, Pyrrolidines, Receptors, Purinergic P2X7