Effects of genetic variation in the P2RX7 gene on pharmacodynamics of a P2X7 receptor antagonist: a prospective genotyping approach
Effects of genetic variation in the P2RX7 gene on pharmacodynamics of a P2X7 receptor antagonist: a prospective genotyping approach
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DOI：
10.1111/j.1365-2125.2012.04200.x
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发表时间：
2012-08-01
影响因子：
3.4
通讯作者：
Bullmore, Edward T.
中科院分区：
文献类型：
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作者：
McHugh, Simon M.;Roman, Shilina;Bullmore, Edward T.
对大规模人群中等位基因变异的分析已经在P2 RX 7基因中鉴定出许多单核苷酸多态性（SNP）。体外转染已经证明了P2 X7受体功能的SNP依赖性改变（获得或丧失），如通过ATP诱导的乙锭摄取和白细胞介素-1 β产生所测量的。我们提供了一个明确的证据，在一个小样本的前瞻性基因分型的受试者中，P2 X7受体药效学对特异性拮抗剂（GSK 1370319 A）的SNP依赖性改变。这些对药物反应的影响强调了遗传分层在P2 X7受体拮抗剂药物开发中的重要性。目的应用特异性受体拮抗剂（GSK 1370319 A）和前瞻性遗传分层方法，研究P2 X7受体基因（P2 RX 7）1068 G>A（A348 T）和1513 A>C（E496 A）两个单核苷酸多态性（SNP）对P2 X7受体功能的影响。方法在32例前瞻性基因分型受试者的血培养中，在存在或不存在GSK 1370319 A的情况下，测定脂多糖和ATP刺激的白细胞介素-1 β的产生。结果在具有纯合获得型（1068 A）和功能缺失型（1513 C）基因型（分别表达348 T，496 E和348 A，496 A等位基因）的个体之间，GSK 1370319 A抑制ATP刺激的白细胞介素-1 β释放的IC 50约有6.7倍的差异（P < 0.0001）。结论白细胞P2 X7受体对特异性拮抗剂（GSK 1370319 A）的药效学反应显著改变，与SNP基因型直接相关。
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.