综合方法确定不同哮喘患者的皮质类固醇反应变异
2018/11/14
摘要
背景：虽然吸入皮质类固醇（ICS）药物被认为是持续性哮喘患者的基石治疗，但很少有ICS药物基因组学研究涉及非白种人群。本文旨在确定多个哮喘人群中ICS反应的遗传预测因子。
方法：该发现组包括来自哮喘表型研究和种族间药物基因组学相互作用的非洲裔美国参与者（SAPPHIRE），他们接受了6周的ICS治疗监测（n = 244）。进行全基因组扫描以鉴定联合相关的单核苷酸多态性（SNP）变体（即SNP和SNP×ICS治疗相互作用的组合效应）与哮喘控制的变化。通过评估另外三组-非洲裔美国人（n=803和n=563）和拉丁美洲人（n=1,461）与哮喘急性加重的联合关联来验证最佳关联。来自408个哮喘病例和405个对照的RNA-seq数据用于检查基因型是否与基因表达相关。
结果：一个变体rs3827907与发现组中ICS介导的哮喘控制变化显著相关（P=7.79x10-8），并且与三个验证队列中的哮喘急性发作共同相关（P=0.023，P=0.029和P=0.041）。RNA-seq分析发现rs3827907 C等位基因与较低的RNASE2表达相关（P=6.10×10-4）。 RNASE2编码嗜酸性粒细胞衍生的神经毒素（EDN），并且rs3827907C-等位基因在嗜酸性粒细胞炎症（即高治疗前EDN水平或血液嗜酸性粒细胞计数）的存在下似乎特别影响ICS治疗反应。
结论：我们鉴定了一种变体rs3827907，它似乎影响多个人群中对ICS治疗的反应，并可能通过嗜酸性粒细胞介导其作用。非洲裔美国人和拉美裔人群受哮喘及其并发症的影响是不一样的。在这里，我们确定了一种药物基因组学变体，它可以帮助识别这些对ICS治疗有反应的人群。
Integrative approach identifies corticosteroid response variant in diverse populations with asthma.
Levin AM, Gui H, Hernandez-Pacheco N, Yang M, Xiao S, Yang JJ, Hochstadt S, Barczak AJ, Eckalbar WL, Rynkowski D, Samedy LA, Kwok PY, Pino-Yanes M, Erle DJ, Lanfear DE, Burchard EG, Williams LK.
Abstract
BACKGROUND:Although inhaled corticosteroid (ICS) medication is considered the cornerstone treatment for patients with persistent asthma, few ICS pharmacogenomic studies have involved non-white populations. To identify genetic predictors of ICS response in multiple population groups with asthma.
METHODS:The discovery group comprised African American participants from the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE) who underwent 6 weeks of monitored ICS therapy (n=244). A genome-wide scan was performed to identify single nucleotide polymorphism (SNP) variants jointly associated (i.e., the combined effect of the SNP and SNP x ICS treatment interaction) with changes in asthma control. Top associations were validated by assessing the joint association with asthma exacerbations in three additional groups - African Americans (n=803 and n=563) and Latinos (n=1,461). RNA-seq data from 408 asthma cases and 405 controls were used to examine whether genotype was associated with gene expression.
RESULTS:One variant, rs3827907, was significantly associated with ICS-mediated changes in asthma control in the discovery set (P=7.79x10-8) and was jointly associated with asthma exacerbations in three validation cohorts (P=0.023, P=0.029, and P=0.041). RNA-seq analysis found the rs3827907 C-allele to be associated with lower RNASE2 expression (P=6.10x10-4). RNASE2 encodes eosinophil-derived neurotoxin (EDN), and the rs3827907 C-allele appeared to particularly influence ICS treatment response in the presence of eosinophilic inflammation (i.e., high pre-treatment EDN levels or blood eosinophil counts).
CONCLUSIONS:We identified a variant, rs3827907, which appears to influence response to ICS treatment in multiple population groups, and likely mediates its effect through eosinophils. African Americans and Latinos are disproportionately affected by asthma and its complications. Here we identify a pharmacogenomic variant that may assist in identifying individuals from these groups who will respond to ICS treatment.
背景：虽然吸入皮质类固醇（ICS）药物被认为是持续性哮喘患者的基石治疗，但很少有ICS药物基因组学研究涉及非白种人群。本文旨在确定多个哮喘人群中ICS反应的遗传预测因子。
方法：该发现组包括来自哮喘表型研究和种族间药物基因组学相互作用的非洲裔美国参与者（SAPPHIRE），他们接受了6周的ICS治疗监测（n = 244）。进行全基因组扫描以鉴定联合相关的单核苷酸多态性（SNP）变体（即SNP和SNP×ICS治疗相互作用的组合效应）与哮喘控制的变化。通过评估另外三组-非洲裔美国人（n=803和n=563）和拉丁美洲人（n=1,461）与哮喘急性加重的联合关联来验证最佳关联。来自408个哮喘病例和405个对照的RNA-seq数据用于检查基因型是否与基因表达相关。
结果：一个变体rs3827907与发现组中ICS介导的哮喘控制变化显著相关（P=7.79x10-8），并且与三个验证队列中的哮喘急性发作共同相关（P=0.023，P=0.029和P=0.041）。RNA-seq分析发现rs3827907 C等位基因与较低的RNASE2表达相关（P=6.10×10-4）。 RNASE2编码嗜酸性粒细胞衍生的神经毒素（EDN），并且rs3827907C-等位基因在嗜酸性粒细胞炎症（即高治疗前EDN水平或血液嗜酸性粒细胞计数）的存在下似乎特别影响ICS治疗反应。
结论：我们鉴定了一种变体rs3827907，它似乎影响多个人群中对ICS治疗的反应，并可能通过嗜酸性粒细胞介导其作用。非洲裔美国人和拉美裔人群受哮喘及其并发症的影响是不一样的。在这里，我们确定了一种药物基因组学变体，它可以帮助识别这些对ICS治疗有反应的人群。
(中日友好医院呼吸与危重症医学科 王瑞茵 摘译 林江涛 审校)
(J Allergy Clin Immunol. 2018 Oct 24. pii: S0091-6749(18)31486-6. doi: 10.1016/j.jaci.2018.09.034. [Epub ahead of print])
(J Allergy Clin Immunol. 2018 Oct 24. pii: S0091-6749(18)31486-6. doi: 10.1016/j.jaci.2018.09.034. [Epub ahead of print])
Integrative approach identifies corticosteroid response variant in diverse populations with asthma.
Levin AM, Gui H, Hernandez-Pacheco N, Yang M, Xiao S, Yang JJ, Hochstadt S, Barczak AJ, Eckalbar WL, Rynkowski D, Samedy LA, Kwok PY, Pino-Yanes M, Erle DJ, Lanfear DE, Burchard EG, Williams LK.
Abstract
BACKGROUND:Although inhaled corticosteroid (ICS) medication is considered the cornerstone treatment for patients with persistent asthma, few ICS pharmacogenomic studies have involved non-white populations. To identify genetic predictors of ICS response in multiple population groups with asthma.
METHODS:The discovery group comprised African American participants from the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE) who underwent 6 weeks of monitored ICS therapy (n=244). A genome-wide scan was performed to identify single nucleotide polymorphism (SNP) variants jointly associated (i.e., the combined effect of the SNP and SNP x ICS treatment interaction) with changes in asthma control. Top associations were validated by assessing the joint association with asthma exacerbations in three additional groups - African Americans (n=803 and n=563) and Latinos (n=1,461). RNA-seq data from 408 asthma cases and 405 controls were used to examine whether genotype was associated with gene expression.
RESULTS:One variant, rs3827907, was significantly associated with ICS-mediated changes in asthma control in the discovery set (P=7.79x10-8) and was jointly associated with asthma exacerbations in three validation cohorts (P=0.023, P=0.029, and P=0.041). RNA-seq analysis found the rs3827907 C-allele to be associated with lower RNASE2 expression (P=6.10x10-4). RNASE2 encodes eosinophil-derived neurotoxin (EDN), and the rs3827907 C-allele appeared to particularly influence ICS treatment response in the presence of eosinophilic inflammation (i.e., high pre-treatment EDN levels or blood eosinophil counts).
CONCLUSIONS:We identified a variant, rs3827907, which appears to influence response to ICS treatment in multiple population groups, and likely mediates its effect through eosinophils. African Americans and Latinos are disproportionately affected by asthma and its complications. Here we identify a pharmacogenomic variant that may assist in identifying individuals from these groups who will respond to ICS treatment.
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重症哮喘的随机对照试验：表型或定型选择
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变应原免疫治疗用于桦树花粉相关变应性鼻炎及哮喘的真实世界获益
