Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
PRecisiOn Medicine Translational Research (PROMoTeR) Center, Department of Population Medicine, Harvard Pilgrim Health Care Institute and Harvard Medical School, 401 Park Drive, Suite 401, Boston, MA, 02215-5301, USA.
Respir Res. 2020 Jan 28;21(1):31. doi: 10.1186/s12931-020-1295-4.
Global gene expression levels are known to be highly dependent upon gross demographic features including age, yet identification of age-related genomic indicators has yet to be comprehensively undertaken in a disease and treatment-specific context.
We used gene expression data from CD4+ lymphocytes in the Asthma BioRepository for Integrative Genomic Exploration (Asthma BRIDGE), an open-access collection of subjects participating in genetic studies of asthma with available gene expression data. Replication population participants were Puerto Rico islanders recruited as part of the ongoing Genes environments & Admixture in Latino Americans (GALA II), who provided nasal brushings for transcript sequencing. The main outcome measure was chronic asthma control as derived by questionnaires. Genomic associations were performed using regression of chronic asthma control score on gene expression with age in years as a covariate, including a multiplicative interaction term for gene expression times age.
The SMARCD1 gene (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1) interacted with age to influence chronic asthma control on inhaled corticosteroids, with a doubling of expression leading to an increase of 1.3 units of chronic asthma control per year (95% CI [0.86, 1.74], p = 6 × 10), suggesting worsening asthma control with increasing age. This result replicated in GALA II (p = 3.8 × 10). Cellular assays confirmed the role of SMARCD1 in glucocorticoid response in airway epithelial cells.
Focusing on age-dependent factors may help identify novel indicators of asthma medication response. Age appears to modulate the effect of SMARCD1 on asthma control with inhaled corticosteroids.
众所周知，全球基因表达水平高度依赖于年龄等总体人口特征，但在疾病和治疗特异性背景下，尚未全面确定与年龄相关的基因组指标。
我们使用了来自 CD4+ 淋巴细胞的基因表达数据，这些数据来自于哮喘生物资源库的综合基因组探索（Asthma BRIDGE），这是一个开放获取的数据集，其中包含了参与哮喘遗传研究的参与者，并且有可用的基因表达数据。复制人群参与者是波多黎各岛民，他们是正在进行的拉丁裔美国人的基因、环境和混合（GALA II）遗传研究的一部分，他们提供了鼻腔刷样进行转录测序。主要的观察指标是通过问卷得出的慢性哮喘控制情况。使用回归分析慢性哮喘控制评分与基因表达的关系，以年龄（年）为协变量，并包括基因表达与年龄的乘法交互项。
SMARCD1 基因（SWI/SNF 相关基质相关肌动蛋白依赖性染色质调节子亚家族 D 成员 1）与年龄相互作用，影响吸入皮质激素治疗的慢性哮喘控制，表达增加一倍导致慢性哮喘控制每年增加 1.3 个单位（95%置信区间[0.86, 1.74]，p=6×10），提示随着年龄的增长，哮喘控制恶化。这一结果在 GALA II 中得到了复制（p=3.8×10）。细胞实验证实了 SMARCD1 在气道上皮细胞的糖皮质激素反应中的作用。
关注年龄相关因素可能有助于识别哮喘药物反应的新指标。年龄似乎调节了 SMARCD1 对吸入皮质激素治疗哮喘控制的影响。
