Rahmioglu Nilufer, Heaton James, Clement Gail, Gill Raj, Surdulescu Gabriela, Zlobecka Karolina, Hodgkiss Dylan, Smith Norman W, Ahmadi Kourosh R
Department of Twin Research and Genetic Epidemiology, St. Thomas' Hospital, King's College London, Lambeth Palace Rd, London, SE1 7EH, UK.
Eur J Drug Metab Pharmacokinet. 2013 Mar;38(1):63-7. doi: 10.1007/s13318-012-0103-z. Epub 2012 Sep 4.
Atypical cytochrome P450 3A4 (CYP3A4) enzyme activity-induced and inhibited-is thought to be the driver of numerous poor or adverse therapeutic responses to up to 50 % of all commonly prescribed drugs. We carried out a genome-wide association study to identify common genetic variants associated with variation in induced CYP3A4 activity. A total of 310 twins were included in this study. Each participant had already completed a 14 days course of St John's Wort to induce CYP3A4, which was quantified through the metabolic ratio of exogenous 3-hydroxyquinine to quinine. We failed to detect any genome-wide significant associations (P < 1 × 10(-8)) with variation in induced CYP3A4 activity although several genomic regions were highlighted which may play minor roles. We report the first GWAS of variation in induced CYP3A4 activity and our preliminary results indicate a complex genetic architecture underpinning induced CYP3A4 enzyme activity.
非典型细胞色素P450 3A4（CYP3A4）酶活性的诱导和抑制——被认为是导致多达50%的常用处方药出现诸多不良或负面治疗反应的原因。我们开展了一项全基因组关联研究，以识别与诱导型CYP3A4活性变异相关的常见基因变体。本研究共纳入310对双胞胎。每位参与者都已完成一个为期14天的圣约翰草疗程以诱导CYP3A4，通过外源性3 - 羟基奎宁与奎宁的代谢比进行量化。尽管突出了几个可能起次要作用的基因组区域，但我们未能检测到与诱导型CYP3A4活性变异存在全基因组显著关联（P < 1×10⁻⁸）。我们报告了诱导型CYP3A4活性变异的首个全基因组关联研究，我们的初步结果表明存在一个支撑诱导型CYP3A4酶活性的复杂遗传结构。
