Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
J Allergy Clin Immunol. 2012 Aug;130(2):516-22.e4. doi: 10.1016/j.jaci.2012.03.030. Epub 2012 Apr 26.
This is the first large pharmacogenetic investigation of the inflammatory IL-4/IL-13 pathway in patients with moderate-to-severe asthma. We analyzed genomic DNA from participants in a 12-week placebo-controlled efficacy trial of pitrakinra (1, 3, or 10 mg twice daily), a novel IL-4/IL-13 pathway antagonist (Clinicaltrials.govNCT00801853).
The primary hypothesis for this analysis is that amino acid changes in the 3' end of the IL-4 receptor α gene (IL4RA) or closely proximal variants would predict reductions in asthma exacerbations for subjects randomized to pitrakinra therapy.
Nineteen IL4RA single nucleotide polymorphisms (SNPs) were tested in 407 non-Hispanic white subjects for association with the primary clinical end point of asthma exacerbations and changes in secondary end points for asthma symptom scores.
The most consistent pharmacogenetic associations were observed for the correlated tagging SNPs rs8832 and rs1029489 in the IL4RA 3' untranslated and proximal regions, respectively. Subjects homozygous for the rs8832 common G allele randomized to pitrakinra (placebo group nonsignificant) had decreased asthma exacerbations and decreased nocturnal awakenings and activities limited by asthma. There was also a significant pitrakinra dose-response relationship (placebo/1 mg/3 mg/10 mg) for exacerbations in subjects homozygous for the common allele in rs1029489 (P = .005) and rs8832 (P= .009) and the intronic SNPs rs3024585, rs3024622, and rs4787956 (P = .03).
This study demonstrates a significant pharmacogenetic interaction between anti-IL-4 receptor α therapy and IL4RA gene variation, identifying an asthma subgroup that is more responsive to therapy with this antagonist.
这是首次针对中度至重度哮喘患者炎症性 IL-4/IL-13 通路的大型遗传药理学研究。我们分析了参与培拉金拉（1、3 或 10mg，每日两次）为期 12 周安慰剂对照疗效试验的参与者的基因组 DNA，培拉金拉是一种新型的 IL-4/IL-13 通路拮抗剂（Clinicaltrials.govNCT00801853）。
该分析的主要假设是，IL-4 受体 α 基因（IL4RA）3'端的氨基酸变化或紧邻的变体将预测接受培拉金拉治疗的受试者哮喘恶化的减少。
在 407 名非西班牙裔白种人中，测试了 19 个 IL4RA 单核苷酸多态性（SNP）与主要临床终点哮喘恶化以及哮喘症状评分的次要终点变化之间的关联。
在 IL4RA 3'非翻译和近端区域中，分别与 rs8832 和 rs1029489 相关的连锁标签 SNP 观察到最一致的遗传药理学关联。随机分配至培拉金拉（安慰剂组无显著差异）的 rs8832 常见 G 等位基因纯合子受试者哮喘恶化减少，夜间觉醒和哮喘活动受限减少。在 rs1029489（P=.005）和 rs8832（P=.009）以及内含子 SNP rs3024585、rs3024622 和 rs4787956 中常见等位基因纯合子受试者中，也存在显著的培拉金拉剂量反应关系（安慰剂/1mg/3mg/10mg））（P=.03）。
这项研究表明，抗 IL-4 受体 α 治疗与 IL4RA 基因变异之间存在显著的遗传药理学相互作用，确定了对这种拮抗剂治疗反应更强的哮喘亚组。
