title: Effects of genetic variation in the P2RX7 gene on pharmacodynamics of a P2X(7)  receptor antagonist: a prospective genotyping approach.
abstract: OBJECTIVE
  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.
authors.affiliation: GSK Clinical Unit Cambridge-CUC, Addenbrooke's Hospital, Box 128, Hills Road, Cambridge CB2 0GG, UK. simon.m.mchugh@gsk.com
authors.forename: Simon M
authors.initials: SM
authors.lastname: McHugh
authors.forename: Shilina
authors.initials: S
authors.lastname: Roman
authors.forename: Bill
authors.initials: B
authors.lastname: Davis
authors.forename: Annelize
authors.initials: A
authors.lastname: Koch
authors.forename: Alison M
authors.initials: AM
authors.lastname: Pickett
authors.forename: Jill C
authors.initials: JC
authors.lastname: Richardson
authors.forename: Sam R
authors.initials: SR
authors.lastname: Miller
authors.forename: Sally
authors.initials: S
authors.lastname: Wetten
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Cox
authors.forename: Fredrik
authors.initials: F
authors.lastname: Karpe
authors.forename: John A
authors.initials: JA
authors.lastname: Todd
authors.forename: Edward T
authors.initials: ET
authors.lastname: Bullmore
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D007962:Leukocytes / Q000187:drug effects* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D058486:Receptors, Purinergic P2X7 / Q000187:drug effects* / Q000235:genetics*
chemical_list: C574198:GSK 1370319A; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; C546468:P2RX7 protein, human; D058920:Purinergic P2X Receptor Antagonists; D011759:Pyrrolidines; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate