Introduction Older adults have the greatest burden of asthma and poorest outcomes. The pharmacogenetics of inhaled corticosteroid (ICS) treatment response is not well studied in older adults. Methods A genome-wide association study of ICS response was performed in asthmatics of European ancestry in Genetic Epidemiology Research on Adult Health and Aging (GERA) by fitting Cox proportional hazards regression models, followed by validation in the Mass General Brigham (MGB) Biobank and Rotterdam Study. ICS response was measured using two definitions in asthmatics on ICS treatment: (1) absence of oral corticosteroid (OCS) bursts using prescription records and (2) absence of asthma-related exacerbations using diagnosis codes. A fixed-effect meta-analysis was performed for each outcome. The validated single-nucleotide polymorphisms (SNPs) were functionally annotated to standard databases. Results In 5710 subjects in GERA, 676 subjects in MGB Biobank, and 465 subjects in the Rotterdam Study, four novel SNPs on chromosome six near PTCHD4 validated across all cohorts and met genome-wide significance on meta-analysis for the OCS burst outcome. In 4541 subjects in GERA and 505 subjects in MGB Biobank, 152 SNPs with p<5 × 10−5 were validated across these two cohorts for the asthma-related exacerbation outcome. The validated SNPs included methylation and expression quantitative trait loci for CPED1 , CRADD and DST for the OCS burst outcome and GM2A , SNW1 , CACNA1C , DPH1 , and RPS10 for the asthma-related exacerbation outcome. Conclusions Multiple novel SNPs associated with ICS response were identified in older adult asthmatics. Several SNPs annotated to genes previously associated with asthma and other airway or allergic diseases, including PTCHD4 . Data may be obtained from a third party and are not publicly available. Data from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort may be obtained by contacting the the Kaiser Permanente Medical Care Plan, Northern California Region (KPNC), Research Program on Genes, Environment and Health (rpgeh-collab@kp.org). Data from the Mass General Brigham (MGB) Biobank can be obtained by contacting biobank@partners.org. Data from the Rotterdam Study can be obtained by contacting the Department of Epidemiology at Erasmus University Medical Center via telephone 0031 (0)10 704 34 88 or through the contact form on their website.

中文翻译：

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与老年哮喘患者吸入皮质类固醇治疗反应相关的新基因变异

简介 老年人的哮喘负担最大，预后也最差。吸入皮质类固醇 (ICS) 治疗反应的药物遗传学在老年人中尚未得到充分研究。方法 通过拟合 Cox 比例风险回归模型，在成人健康与衰老遗传流行病学研究 (GERA) 中对欧洲血统的哮喘患者进行了 ICS 反应的全基因组关联研究，随后在麻省总医院 (MGB) 生物库和鹿特丹研究。ICS 反应使用 ICS 治疗中哮喘患者的两个定义来测量：(1) 使用处方记录不存在口服皮质类固醇 (OCS) 爆发；(2) 使用诊断代码不存在与哮喘相关的恶化。对每个结果进行固定效应荟萃分析。经过验证的单核苷酸多态性 (SNP) 在标准数据库中进行了功能注释。结果 在 GERA 的 5710 名受试者、MGB 生物库的 676 名受试者和鹿特丹研究的 465 名受试者中，PTCHD4 附近第六号染色体上的 4 个新 SNP 在所有队列中得到验证，并在 OCS 突发结果的荟萃分析中满足全基因组显着性。在 GERA 的 4541 名受试者和 MGB Biobank 的 505 名受试者中，在这两个队列中验证了 152 个 p<5 × 10−5 的 SNP，以确定哮喘相关的恶化结果。经验证的 SNP 包括用于 OCS 爆发结果的 CPED1、CRADD 和 DST 的甲基化和表达数量性状位点，以及用于哮喘相关恶化结果的 GM2A、SNW1、CACNA1C、DPH1 和 RPS10。结论 在老年哮喘患者中发现了多个与 ICS 反应相关的新 SNP。几个 SNP 注释了先前与哮喘和其他气道或过敏性疾病相关的基因，包括 PTCHD4。数据可能从第三方获得，并且不公开。成人健康和衰老遗传流行病学研究 (GERA) 队列的数据可通过联系北加州地区凯撒医疗保健计划 (KPNC) 基因、环境和健康研究计划 (rpgeh-collab@kp.组织）。可通过联系biobank@partners.org 获取来自麻省总医院 (MGB) 生物库的数据。鹿特丹研究的数据可以通过电话 0031 (0)10 704 34 88 或通过其网站上的联系表联系伊拉斯姆斯大学医学中心流行病学系获得。