Voorhies Kirsten, Mohammed Akram, Chinthala Lokesh, Kong Sek Won, Lee In-Hee, Kho Alvin T, McGeachie Michael, Mandl Kenneth D, Raby Benjamin, Hayes Melanie, Davis Robert L, Wu Ann Chen, Lutz Sharon M
Department of Population Medicine, Harvard Pilgrim Health Care Institute, Boston, MA 02215, USA.
Center in Biomedical Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Genes (Basel). 2024 Mar 28;15(4):420. doi: 10.3390/genes15040420.
Inhaled corticosteroids (ICS) are efficacious in the treatment of asthma, which affects more than 300 million people in the world. While genome-wide association studies have identified genes involved in differential treatment responses to ICS in asthma, few studies have evaluated the effects of combined rare and common variants on ICS response among children with asthma. Among children with asthma treated with ICS with whole exome sequencing (WES) data in the PrecisionLink Biobank (91 White and 20 Black children), we examined the effect and contribution of rare and common variants with hospitalizations or emergency department visits. For 12 regions previously associated with asthma and ICS response (, , , , , , , , , , ), we used the combined sum test for the sequence kernel association test (SKAT) adjusting for age, sex, and BMI and stratified by race. Validation was conducted in the Biorepository and Integrative Genomics (BIG) Initiative (83 White and 134 Black children). Using a Bonferroni threshold for the 12 regions tested (i.e., 0.05/12 = 0.004), was significantly associated with ICS response for the combined effect of rare and common variants (-value = 0.003) among White children in the PrecisionLink Biobank and replicated in the BIG Initiative (-value = 0.02). Using WES data, the combined effect of rare and common variants for was associated with ICS response among asthmatic children in the PrecisionLink Biobank and replicated in the BIG Initiative. This proof-of-concept study demonstrates the power of biobanks of pediatric real-life populations in asthma genomic investigations.
吸入性糖皮质激素（ICS）对哮喘治疗有效，全球有超过3亿人受哮喘影响。虽然全基因组关联研究已确定了与哮喘患者对ICS不同治疗反应相关的基因，但很少有研究评估罕见变异和常见变异组合对哮喘儿童ICS反应的影响。在精准链接生物样本库中接受ICS治疗且有全外显子测序（WES）数据的哮喘儿童（91名白人儿童和20名黑人儿童）中，我们研究了罕见变异和常见变异对住院或急诊就诊的影响及贡献。对于先前与哮喘和ICS反应相关的12个区域（，，，，，，，，，，），我们使用序列核关联检验（SKAT）的联合和检验，并对年龄、性别和体重指数进行调整，按种族分层。在生物样本库与整合基因组学（BIG）计划（83名白人儿童和134名黑人儿童）中进行了验证。使用针对12个测试区域的Bonferroni阈值（即0.05/12 = 0.004），在精准链接生物样本库的白人儿童中，罕见变异和常见变异的联合效应与ICS反应显著相关（P值 = 0.003），并在BIG计划中得到重复验证（P值 = 0.02）。利用WES数据，在精准链接生物样本库的哮喘儿童中，罕见变异和常见变异对的联合效应与ICS反应相关，并在BIG计划中得到重复验证。这项概念验证研究证明了儿科真实人群生物样本库在哮喘基因组研究中的作用。
