Department of Public Health Sciences, Henry Ford Health System, Detroit, Mich.
Center for Individualized and Genomic Medicine Research (CIGMA), Henry Ford Health System, Detroit, Mich.
J Allergy Clin Immunol. 2019 May;143(5):1791-1802. doi: 10.1016/j.jaci.2018.09.034. Epub 2018 Oct 24.
Although inhaled corticosteroid (ICS) medication is considered the cornerstone treatment for patients with persistent asthma, few ICS pharmacogenomic studies have involved nonwhite populations.
We sought to identify genetic predictors of ICS response in multiple population groups with asthma.
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 (ie, the combined effect of the SNP and SNP × ICS treatment interaction) with changes in asthma control. Top associations were validated by assessing the joint association with asthma exacerbations in 3 additional groups: African Americans (n = 803 and n = 563) and Latinos (n = 1461). RNA sequencing data from 408 asthmatic patients and 405 control subjects were used to examine whether genotype was associated with gene expression.
One variant, rs3827907, was significantly associated with ICS-mediated changes in asthma control in the discovery set (P = 7.79 × 10) and was jointly associated with asthma exacerbations in 3 validation cohorts (P = .023, P = .029, and P = .041). RNA sequencing analysis found the rs3827907 C-allele to be associated with lower RNASE2 expression (P = 6.10 × 10). RNASE2 encodes eosinophil-derived neurotoxin, and the rs3827907 C-allele appeared to particularly influence ICS treatment response in the presence of eosinophilic inflammation (ie, high pretreatment eosinophil-derived neurotoxin levels or blood eosinophil counts).
We identified a variant, rs3827907, that appears to influence response to ICS treatment in multiple population groups and likely mediates its effect through eosinophils.
尽管吸入性皮质类固醇（ICS）药物被认为是持续性哮喘患者的基础治疗方法，但很少有 ICS 药物基因组学研究涉及非白人群体。
我们旨在确定哮喘多种人群中 ICS 反应的遗传预测因子。
发现组包括参与种族-民族哮喘表型和药物基因组相互作用研究（SAPPHIRE）的非裔美国参与者，他们接受了 6 周的监测 ICS 治疗（n=244）。进行全基因组扫描以鉴定与哮喘控制变化联合相关的单核苷酸多态性（SNP）变体（即 SNP 和 SNP×ICS 治疗相互作用的综合效应）。通过在另外 3 个群体（非裔美国人[n=803 和 n=563]和拉丁裔[n=1461]）中评估与哮喘加重的联合相关性，验证了顶级关联。对 408 名哮喘患者和 405 名对照者的 RNA 测序数据进行了检查，以确定基因型是否与基因表达相关。
一个变体 rs3827907 在发现组中与 ICS 介导的哮喘控制变化显著相关（P=7.79×10），并在 3 个验证队列中与哮喘加重联合相关（P=.023、P=.029 和 P=.041）。RNA 测序分析发现 rs3827907 C 等位基因与 RNASE2 表达降低相关（P=6.10×10）。RNASE2 编码嗜酸性粒细胞衍生的神经毒素，rs3827907 C 等位基因似乎特别影响嗜酸性粒细胞炎症（即高预处理嗜酸性粒细胞衍生的神经毒素水平或血液嗜酸性粒细胞计数）存在时的 ICS 治疗反应。
我们确定了一个变体 rs3827907，它似乎影响多种人群对 ICS 治疗的反应，并且可能通过嗜酸性粒细胞介导其作用。
