哮喘混合人群吸入皮质激素反应的全基因组关联研究。
Genome-wide association study of inhaled corticosteroid response in admixed children with asthma.
机构信息
Research Unit, Hospital Universitario N.S. de Candelaria, Universidad de La Laguna, San Cristóbal de La Laguna, Spain.
Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna, San Cristóbal de La Laguna, Santa Cruz de Tenerife, Spain.
出版信息
Clin Exp Allergy. 2019 Jun;49(6):789-798. doi: 10.1111/cea.13354. Epub 2019 Feb 15.
BACKGROUND
Inhaled corticosteroids (ICS) are the most widely prescribed and effective medication to control asthma symptoms and exacerbations. However, many children still have asthma exacerbations despite treatment, particularly in admixed populations, such as Puerto Ricans and African Americans. A few genome-wide association studies (GWAS) have been performed in European and Asian populations, and they have demonstrated the importance of the genetic component in ICS response.
OBJECTIVE
We aimed to identify genetic variants associated with asthma exacerbations in admixed children treated with ICS and to validate previous GWAS findings.
METHODS
A meta-analysis of two GWAS of asthma exacerbations was performed in 1347 admixed children treated with ICS (Hispanics/Latinos and African Americans), analysing 8.7 million genetic variants. Those with P ≤ 5 × 10 were followed up for replication in 1697 asthmatic patients from six European studies. Associations of ICS response described in published GWAS were followed up for replication in the admixed populations.
RESULTS
A total of 15 independent variants were suggestively associated with asthma exacerbations in admixed populations (P ≤ 5 × 10 ). One of them, located in the intergenic region of APOBEC3B and APOBEC3C, showed evidence of replication in Europeans (rs5995653, P = 7.52 × 10 ) and was also associated with change in lung function after treatment with ICS (P = 4.91 × 10 ). Additionally, the reported association of the L3MBTL4-ARHGAP28 genomic region was confirmed in admixed populations, although a different variant was identified.
CONCLUSIONS AND CLINICAL RELEVANCE
This study revealed the novel association of APOBEC3B and APOBEC3C with asthma exacerbations in children treated with ICS and replicated previously identified genomic regions. This contributes to the current knowledge about the multiple genetic markers determining responsiveness to ICS which could lead in the future the clinical identification of those asthma patients who are not able to respond to such treatment.
背景
吸入性皮质类固醇（ICS）是控制哮喘症状和加重的最广泛使用和有效的药物。然而，许多儿童尽管接受了治疗，仍会出现哮喘加重，尤其是在混合人群中，如波多黎各人（Hispanics/Latinos）和非裔美国人（African Americans）。已经在欧洲和亚洲人群中进行了少数全基因组关联研究（GWAS），它们证明了遗传因素在 ICS 反应中的重要性。
目的
我们旨在确定接受 ICS 治疗的混合儿童哮喘加重的遗传变异，并验证先前的 GWAS 发现。
方法
对接受 ICS 治疗的 1347 名混合儿童（西班牙裔/拉丁裔和非裔美国人）的两项哮喘加重 GWAS 进行荟萃分析，分析了 870 万个遗传变异。对 P 值≤5×10 的变异进行了随访，以在来自六个欧洲研究的 1697 名哮喘患者中进行复制。对已发表的 GWAS 中描述的 ICS 反应相关性进行了随访，以在混合人群中进行复制。
结果
共有 15 个独立的变异在混合人群中与哮喘加重呈提示性相关（P 值≤5×10）。其中一个位于 APOBEC3B 和 APOBEC3C 基因间区域的变异在欧洲人群中显示出复制的证据（rs5995653，P 值=7.52×10），并且与 ICS 治疗后肺功能的变化相关（P 值=4.91×10）。此外，报告的 L3MBTL4-ARHGAP28 基因组区域的相关性在混合人群中得到了证实，尽管鉴定出了不同的变异。
结论和临床意义
这项研究揭示了 APOBEC3B 和 APOBEC3C 与接受 ICS 治疗的儿童哮喘加重的新关联，并复制了先前确定的基因组区域。这有助于当前关于确定对 ICS 反应的多种遗传标记的认识，这可能导致未来能够临床识别那些不能对这种治疗产生反应的哮喘患者。
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