IL-4 receptor polymorphisms predict reduction in asthma exacerbations during response to an anti-IL-4 receptor α antagonist.
IL-4 receptor polymorphisms predict reduction in asthma exacerbations during response to an anti-IL-4 receptor α antagonist.
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DOI：
10.1016/j.jaci.2012.03.030
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发表时间：
2012-08
期刊：
影响因子：
--
通讯作者：
Bleecker ER
中科院分区：
文献类型：
--
作者：
Slager RE;Otulana BA;Hawkins GA;Yen YP;Peters SP;Wenzel SE;Meyers DA;Bleecker ER
这是首次对中到重度哮喘患者的炎性IL-4/IL-13途径进行大规模药物遗传学研究。我们分析了一项为期12周的安慰剂对照疗效试验的参与者的基因组DNA，该药是一种新型的IL-4/IL-13途径拮抗剂(ClinicalTrials.gov NCT00801853)。这项分析的主要假设是，IL-4受体α基因(IL4RA)3‘端的氨基酸变化或接近的变异体将预测随机接受龙舌兰治疗的受试者哮喘加重的减少。在407名非西班牙裔白人受试者中检测了19个IL4RA单核苷酸多态(SNPs)，以研究其与哮喘加重的主要临床终点和哮喘症状评分的次要终点的变化之间的关系。相关标签SNPs rs8832和rs1029489分别位于IL4RA3‘未翻译区域和近端区域，观察到最一致的药物遗传学关联。将rs8832常见G等位基因纯合的受试者随机分配到培基松组(安慰剂组没有显着性意义)，可以减少哮喘的加重，减少夜间觉醒和受哮喘限制的活动。在rs1029489(P=.005)和rs8832(P=.009)普通等位基因以及内含子SNPs rs3024585、rs3024622和rs4787956(P=0.03)纯合子的受试者中，还存在显著的龙舌兰剂量-反应关系(安慰剂/1毫克/3毫克/10毫克)。这项研究证明了抗IL-4受体a治疗和IL4RA基因变异之间存在显著的药物遗传学相互作用，确定了对该拮抗剂治疗更敏感的哮喘亚组。
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.gov NCT00801853). 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 a therapy and IL4RA gene variation, identifying an asthma subgroup that is more responsive to therapy with this antagonist.
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影响因子：
158.5
作者：
Corren, Jonathan;Lemanske, Robert F., Jr.;Matthews, John G.
通讯作者：
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影响因子：
24.3
作者：
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120.7
作者：
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影响因子：
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作者：
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通讯作者：
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DOI：
10.1164/rccm.200701-085oc
发表时间：
2007-12-01
影响因子：
24.7
作者：
Flood-Page, Patrick;Swenson, Cheri;Barnes, Neil C.
通讯作者：
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