Effects of genetic variation in the P2RX7 gene on pharmacodynamics of a P2X7 receptor antagonist: a prospective genotyping approach

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Analysis of allelic variation in large populations has identified numerous single nucleotide polymorphisms (SNPs) in the P2RX7 gene. In vitro transfection has demonstrated SNP-dependent alterations (gain or loss) of P2X7 receptor function, as measured by ATP-induced ethidium uptake and interleukin-1 beta production. WHAT THIS STUDY ADDS We provide definitive evidence of SNP-dependent alteration in P2X7 receptor pharmacodynamics to a specific antagonist (GSK1370319A) in a small sample of prospectively genotyped subjects. These effects on drug response underline the importance of genetic stratification in drug development of P2X7 receptor antagonists. 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-1 beta 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-1 beta 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.