白三烯调节剂在哮喘中的治疗反应的全基因组关联研究
2016/06/20
摘要
对白三烯调节剂(LTMs)不同的治疗反应很可能是由于患者的遗传变异。虽然之前的候选基因研究涉及多个药物基因位点，迄今为止，没有对白三烯调节剂（LTMs）反应的全基因组关联研究（GWAS）报告。在本研究中，对从两个齐留通治疗的安慰剂对照试验（N = 526）获得的DNA和表型信息进行了研究。利用基因环境（G×E）GWAS模型，我们评估了使用LMT治疗，12个星期之后1 秒用力呼气量（FEV1）的变化。排名前50的单核苷酸多态性的关系可以在独立的齐留通治疗队列和另外两个孟鲁司特队列中被复制。综合分析（发现+复制）发现，MRPP3 中的rs12436663在全基因组为显性（P = 6.28×10（-08））；rs12436663纯合子携带者表现出齐留通治疗后平均ΔFEV1显著降低。此外，GLT1D1中的rs517020与孟鲁司特和齐留通（P = 1.25×10（-07））的恶化反应相关。这项研究揭示了之前未被报道的决定LTMs治疗反应的位点。
（苏欣 审校）
Pharmacogenomics J. 2016 Apr;16(2):151-7. doi: 10.1038/tpj.2015.34. Epub 2015 Jun 2.
Genome-wide association study of leukotriene modifier response in asthma.
Dahlin A1, Litonjua A1,2, Irvin CG3, Peters SP4, Lima JJ5, Kubo M6, Tamari M6, Tantisira KG1,2.
Author information
Abstract
Heterogeneous therapeutic responses to leukotriene modifiers (LTMs) are likely due to variation in patient genetics. Although prior candidate gene studies implicated multiple pharmacogenetic loci, to date, no genome-wide association study (GWAS) of LTM response was reported. In this study, DNA and phenotypic information from two placebo-controlled trials (total N=526) of zileuton response were interrogated. Using a gene-environment (G × E) GWAS model, we evaluated 12-week change in forced expiratory volume in 1 second (ΔFEV1) following LTM treatment. The top 50 single-nucleotide polymorphism associations were replicated in an independent zileuton treatment cohort, and two additional cohorts of montelukast response. In a combined analysis (discovery+replication), rs12436663 in MRPP3 achieved genome-wide significance (P=6.28 × 10(-08)); homozygous rs12436663 carriers showed a significant reduction in mean ΔFEV1 following zileuton treatment. In addition, rs517020 in GLT1D1 was associated with worsening responses to both montelukast and zileuton (combined P=1.25 × 10(-07)). These findings implicate previously unreported loci in determining therapeutic responsiveness to LTMs.
Pharmacogenomics J. 2016 Apr;16(2):151-7. doi: 10.1038/tpj.2015.34. Epub 2015 Jun 2.
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很大一部分青少年哮喘患者缺乏气道炎症反应
