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首页> 外文期刊>Current pharmacogenomics and personalized medicine >Exome-Wide Pharmacogenomic Analysis of Response to Thiopurines in Inflammatory Bowel Disease Patients
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Exome-Wide Pharmacogenomic Analysis of Response to Thiopurines in Inflammatory Bowel Disease Patients

机译：炎症性肠病患者对硫嘌呤反应的全基因组药物基因组学分析

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Background: The response to thiopurine treatment in inflammatory bowel disease patients differs greatly among individuals and nearly 50% of patients experience no benefit. Several factors have been implicated in determining this response, including individual genetic variation.Methods: Aiming to identify genes involved in the response to thiopurine drugs, a two-stage investigation of 20,000 coding single-nucleotide polymorphisms (cSNPs) in 10,000 genes was performed in a Spanish cohort of 257 individuals, 193 showing steroid free remission versus 64 non responder individuals 12 months after initial dose of the drug. The 20 top cSNPs with lower p-values for the association test identified at the first stage (133 responders / 34 non responders), were replicated in a second cohort (60 responders / 30 non responders).Results: Whereas not statistically significant in all of the two analyzed cohorts, the consistent across samples direction of the observed associations and the allelic joined analysis suggest a significant risk for lack of response related to two genes, PION and ZNF673. With a CMH p-value= 4.26x-06, the associated PION cSNP (rsl7151692) minor A allele increases risk for treatment failure 4.5 times when all data is combined.Conclusion: These findings might help to understand the biological mechanisms behind thiopurine treatment failure and to tailor treatment for individual inflammatory bowel disease patients.
机译：背景：炎症性肠病患者对硫嘌呤治疗的反应因人而异，几乎有50％的患者没有获益。方法：为了确定与硫嘌呤药物反应有关的基因，在10,000个基因中对20,000个编码单核苷酸多态性（cSNPs）进行了两个阶段的研究，旨在确定该反应。西班牙队列257人，初次用药12个月后有193人显示无类固醇释放，而64人无反应。在第二阶段（60个响应者/ 30个非响应者）中复制了第一阶段中鉴定出的20个p值较低的cSNPs（133个响应者/ 34个非响应者）。结果：在这两个分析的队列中，观察到的关联的样本方向一致和等位基因联合分析表明缺乏与两个基因PION和ZNF673相关的应答的显着风险。当CMH p值= 4.26x-06时，结合所有数据后，相关的PION cSNP（rsl7151692）次要A等位基因会增加4.5倍的治疗失败风险。结论：这些发现可能有助于了解硫嘌呤治疗失败的生物学机制。并针对个别炎症性肠病患者量身定制治疗方案。

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