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Genome‐wide association study of inhaled corticosteroid response in admixed children with asthma

机译：哮喘混合儿童吸入皮质类固醇反应的基因组

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Summary 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 ?6 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 ?6 ). One of them, located in the intergenic region of APOBEC3B and APOBEC3C , showed evidence of replication in Europeans (rs5995653, P? = ? 7.52?×?10 ?3 ) and was also associated with change in lung function after treatment with ICS ( P? = ? 4.91?×?10 ?3 ). 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.
机译：发明内容背景吸入的皮质类固醇（IC）是控制哮喘症状和加剧的最广泛规定和有效的药物。然而，尽管治疗，许多孩子仍然具有哮喘恶化，特别是在混合的人口，例如波多黎各人和非洲裔美国人。少数基因组 - 宽协会研究（GWAs）已经在欧洲和亚洲群体中进行，他们已经证明了遗传成分在ICS反应中的重要性。目的我们旨在鉴定与IC治疗的混合儿童哮喘加剧相关的遗传变异，并验证以前的GWAS发现。方法采用IC（西班牙裔/拉丁美洲和非洲裔美国人）的1347名混合儿童进行两种哮喘加剧的META分析，分析了870万个遗传变异。那些有p？ ≤？ 5？×10？6在1697名欧洲研究中随访697名哮喘患者进行复制。公布的GWA中描述的ICS反应的关联随访，以便在混合群体中复制。结果总共15种独立变体与混合群体中的哮喘加剧相关（P？≤α5？×10？6）。其中之一，位于Apobec3b和apobec3c的基因因地区，显示出欧洲人复制的证据（Rs5995653，p？= 7.52？×10？3），并且在用IC处理后也与肺功能的变化有关（p ？=？4.91？×10？3）。另外，在混合群体中证实了L3MBT14 - arhGap28基因组区域的报告的缔合，尽管鉴定了不同的变体。结论和临床关联本研究揭示了APOBEC3B和APOBEC3C与IC和复制先前鉴定的基因组区域治疗儿童哮喘发恶作的新型哮喘。这有助于目前关于确定对IC的响应性的多种遗传标记的知识，这可能导致未来的临床鉴定，这些哮喘患者无法应对这种治疗的哮喘患者。

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    Hernandez‐Pacheco Natalia; Farzan Niloufar; Francis Ben; Karimi Leila; Repnik Katja; Vijverberg Susanne J.; Soares Patricia; Schieck Maximilian; Gorenjak Mario; Forno Erick; Eng Celeste; Oh Sam S.; Pérez‐Méndez Lina; Berce Vojko; Tavendale Roger; Samedy Lesly‐Anne; Hunstman Scott; Hu Donglei; Meade Kelley; Farber Harold J.; Avila Pedro C.; Serebrisky Denise; Thyne Shannon M.; Brigino‐Buenaventura Emerita; Rodriguez‐Cintron William; Sen Saunak; Kumar Rajesh; Lenoir Michael; Rodriguez‐Santana Jose R.; Celedón Juan C.; Mukhopadhyay Somnath; Poto?nik Uro?; Pirmohamed Munir; Verhamme Katia M.; Kabesch Michael; Palmer Colin N. A.; Hawcutt Daniel B.; Flores Carlos; Maitland‐van der Zee Anke H.; Burchard Esteban G.; Pino‐Yanes Maria;

  • 作者单位

    Research UnitUniversidad de La LagunaSan Cristóbal de La Laguna Spain;

    Department of Respiratory MedicineUniversity of AmsterdamAmsterdam Netherlands;

    Department of Women's and Children's HealthUniversity of LiverpoolLiverpool UK;

    Department of Medical InformaticsErasmus University Medical CenterRotterdam Netherlands;

    Center for Human Molecular Genetics and PharmacogenomicsUniversity of MariborMaribor Slovenia;

    Department of Respiratory MedicineUniversity of AmsterdamAmsterdam Netherlands;

    Academic Department of PaediatricsRoyal Alexandra Children's HospitalBrighton UK;

    Department of Pediatric Pneumology and AllergyUniversity Children's Hospital Regensburg (KUNO;

    Center for Human Molecular Genetics and PharmacogenomicsUniversity of MariborMaribor Slovenia;

    Division of Pediatric Pulmonary MedicineUniversity of PittsburghPittsburgh Pennsylvania;

    Department of MedicineUniversity of CaliforniaSan Francisco California;

    Department of MedicineUniversity of CaliforniaSan Francisco California;

    Department of Clinic Epidemiology and BiostatisticsHospital Universitario N.S. de CandelariaSanta;

    Center for Human Molecular Genetics and PharmacogenomicsUniversity of MariborMaribor Slovenia;

    Population Pharmacogenetics GroupUniversity of DundeeDundee UK;

    Department of MedicineUniversity of CaliforniaSan Francisco California;

    Department of MedicineUniversity of CaliforniaSan Francisco California;

    Department of MedicineUniversity of CaliforniaSan Francisco California;

    Children's Hospital and Research Center OaklandOakland California;

    Department of PediatricsBaylor College of Medicine and Texas Children's HospitalHouston Texas;

    Department of MedicineNorthwestern UniversityChicago Illinois;

    Pediatric Pulmonary DivisionNew York NY;

    Department of PediatricsUniversity of CaliforniaSan Francisco California;

    Department of Allergy and ImmunologyVallejo California;

    Veterans Caribbean Health Care SystemSan Juan Puerto Rico;

    University of Tennessee Health Science CenterMemphis Tennessee;

    Feinberg School of Medicine's Division of Allergy and ImmunologyNorthwestern UniversityChicago;

    Bay Area PediatricsOakland California;

    Centro de Neumología PediátricaSan Juan Puerto Rico;

    Division of Pediatric Pulmonary MedicineUniversity of PittsburghPittsburgh Pennsylvania;

    Academic Department of PaediatricsRoyal Alexandra Children's HospitalBrighton UK;

    Center for Human Molecular Genetics and PharmacogenomicsUniversity of MariborMaribor Slovenia;

    Department of Molecular and Clinical PharmacologyUniversity of LiverpoolLiverpool UK;

    Department of Medical InformaticsErasmus University Medical CenterRotterdam Netherlands;

    Department of Pediatric Pneumology and AllergyUniversity Children's Hospital Regensburg (KUNO;

    Population Pharmacogenetics GroupUniversity of DundeeDundee UK;

    Department of Women's and Children's HealthUniversity of LiverpoolLiverpool UK;

    Research UnitUniversidad de La LagunaSan Cristóbal de La Laguna Spain;

    Department of Respiratory MedicineUniversity of AmsterdamAmsterdam Netherlands;

    Department of MedicineUniversity of CaliforniaSan Francisco California;

    Research UnitUniversidad de La LagunaSan Cristóbal de La Laguna Spain;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 医学免疫学;
  • 关键词

    African American; childhood asthma; exacerbations; Latino; pharmacogenomics;

    机译：非洲裔美国人;儿童哮喘;加剧;拉丁裔;药物替补科学;

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