Pharmacogenetic studies of long-acting beta agonist and inhaled corticosteroid responsiveness in randomised controlled trials of individuals of African descent with asthma,The Lancet Child & Adolescent Health

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Pharmacogenetic studies of long-acting beta agonist and inhaled corticosteroid responsiveness in randomised controlled trials of individuals of African descent with asthma
The Lancet Child & Adolescent Health ( IF 19.9 ) Pub Date : 2021-11-09 , DOI: 10.1016/s2352-4642(21)00268-6
Victor E Ortega ₁ , Michelle Daya ₂ , Stanley J Szefler ₃ , Eugene R Bleecker ₄ , Vernon M Chinchilli ₅ , Wanda Phipatanakul ₆ , Dave Mauger ₅ , Fernando D Martinez ₇ , Esther Herrera-Luis ₈ , Maria Pino-Yanes ₉ , Gregory A Hawkins ₁₀ , Elizabeth J Ampleford ₁ , Susan J Kunselman ₅ , Corey Cox ₂ , Leonard B Bacharier ₁₁ , Michael D Cabana ₁₂ , Juan Carlos Cardet ₁₃ , Mario Castro ₁₄ , Loren C Denlinger ₁₅ , Celeste Eng ₁₆ , Anne M Fitzpatrick ₁₇ , Fernando Holguin ₂ , Donglei Hu ₁₆ , Daniel J Jackson ₁₈ , Nizar Jarjour ₁₅ , Monica Kraft ₄ , Jerry A Krishnan ₁₉ , Stephen C Lazarus ₁₆ , Robert F Lemanske ₁₈ , John J Lima ₂₀ , Njira Lugogo ₂₁ , Angel Mak ₁₆ , Wendy C Moore ₁ , Edward T Naureckas ₂₂ , Stephen P Peters ₁ , Jacqueline A Pongracic ₂₃ , Satria P Sajuthi ₂₄ , Max A Seibold ₂₅ , Lewis J Smith ₂₆ , Julian Solway ₂₂ , Christine A Sorkness ₁₅ , Sally Wenzel ₂₇ , Steven R White ₂₂ , Esteban G Burchard ₁₆ , Kathleen Barnes ₂ , Deborah A Meyers ₄ , Elliot Israel ₂₈ , Michael E Wechsler ₂₉ ,

Affiliation

Department of Internal Medicine, Section for Pulmonary, Critical Care, Allergy, and Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Department of Medicine, University of Colorado Anschutz Medical Campus, Denver, CO, USA.
Department of Pediatrics, University of Colorado Anschutz Medical Campus, Denver, CO, USA.
Department of Internal Medicine, Division of Genetics, Genomics, and Precision Medicine, University of Arizona College of Medicine, Tucson, AZ, USA.
Department of Public Health Sciences, Pennsylvania State University College of Medicine, Hershey, PA, USA.
Division of Pediatric Allergy and Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Asthma and Airway Disease Research Center, University of Arizona Health Sciences, Tucson, AZ, USA.
Department of Biochemistry, La Laguna, Tenerife, Spain; Microbiology, Cell Biology, and Genetics, La Laguna, Tenerife, Spain; Genomics and Health Group, La Laguna, Tenerife, Spain; Universidad de La Laguna, La Laguna, Tenerife, Spain.
Department of Biochemistry, La Laguna, Tenerife, Spain; Microbiology, Cell Biology, and Genetics, La Laguna, Tenerife, Spain; Genomics and Health Group, La Laguna, Tenerife, Spain; Universidad de La Laguna, La Laguna, Tenerife, Spain; CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.
Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA.
Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
Department of Internal Medicine, Division of Allergy and Immunology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin-Madison, Madison, WI, USA.
Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
Department of Pediatrics, Emory University, Atlanta, GA, USA.
Department of Pediatrics, University of Wisconsin-Madison, Madison, WI, USA.
Breathe Chicago Center, Division of Pulmonary, Critical Care, Sleep, and Allergy, University of Illinois, Chicago, IL, USA.
Center for Pharmacogenomics and Translational Research, Nemours Children's Health System, Jacksonville, FL, USA.
Department of Medicine, Division of Pulmonary and Critical Care, University of Michigan, Ann Arbor, MI, USA.
Department of Medicine, University of Chicago, Chicago, IL, USA.
Department of Pediatrics, Ann & Robert H Lurie Children's Hospital of Chicago, Chicago, IL, USA.
Center for Genes, Environment, and Health, Department of Pediatrics, National Jewish Health, Denver, CO, USA.
Department of Medicine, University of Colorado Anschutz Medical Campus, Denver, CO, USA; Center for Genes, Environment, and Health, Department of Pediatrics, National Jewish Health, Denver, CO, USA.
Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Pulmonary and Critical Care Medicine and Allergy and Immunology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Department of Medicine, National Jewish Health, Denver, CO, USA.

Background

Pharmacogenetic studies in asthma cohorts, primarily made up of White people of European descent, have identified loci associated with response to inhaled beta agonists and corticosteroids (ICSs). Differences exist in how individuals from different ancestral backgrounds respond to long-acting beta agonist (LABA) and ICSs. Therefore, we sought to understand the pharmacogenetic mechanisms regulating therapeutic responsiveness in individuals of African descent.

Methods

We did ancestry-based pharmacogenetic studies of children (aged 5–11 years) and adolescents and adults (aged 12–69 years) from the Best African Response to Drug (BARD) trials, in which participants with asthma uncontrolled with low-dose ICS (fluticasone propionate 50 μg in children, 100 μg in adolescents and adults) received different step-up combination therapies. The hierarchal composite outcome of pairwise superior responsiveness in BARD was based on asthma exacerbations, a 31-day difference in annualised asthma-control days, or a 5% difference in percentage predicted FEV₁. We did whole-genome admixture mapping of 15 159 ancestral segments within 312 independent regions, stratified by the two age groups. The two co-primary outcome comparisons were the step up from low-dose ICS to the quintuple dose of ICS (5 × ICS: 250 μg twice daily in children and 500 μg twice daily in adolescents and adults) versus double dose (2–2·5 × ICS: 100 μg twice daily in children, 250 μg twice daily in adolescents and adults), and 5 × ICS versus 100 μg fluticasone plus a LABA (salmeterol 50 μg twice daily). We used a genome-wide significance threshold of p<1·6 × 10⁻⁴, and tested for replication using independent cohorts of individuals of African descent with asthma.

Findings

We included 249 unrelated children and 267 unrelated adolescents and adults in the BARD pharmacogenetic analysis. In children, we identified a significant admixture mapping peak for superior responsiveness to 5 × ICS versus 100 μg fluticasone plus salmeterol on chromosome 12 (odds ratio [OR_{local African}] 3·95, 95% CI 2·02–7·72, p=6·1 × 10⁻⁵) fine mapped to a locus adjacent to RNFT2 and NOS1 (rs73399224, OR_{allele dose} 0·17, 95% CI 0·07–0·42, p=8·4 × 10⁻⁵). In adolescents and adults, we identified a peak for superior responsiveness to 5 × ICS versus 2·5 × ICS on chromosome 22 (OR_{local African} 3·35, 1·98–5·67, p=6·8 × 10⁻⁶) containing a locus adjacent to TPST2 (rs5752429, OR_{allele dose} 0·21, 0·09–0·52, p=5·7 × 10⁻⁴). We replicated rs5752429 and nominally replicated rs73399224 in independent African American cohorts.

Interpretation

BARD is the first genome-wide pharmacogenetic study of LABA and ICS response in clinical trials of individuals of African descent to detect and replicate genome-wide significant loci. Admixture mapping of the composite BARD trial outcome enabled the identification of novel pharmacogenetic variation accounting for differential therapeutic responses in people of African descent with asthma.

Funding

National Institutes of Health, National Heart, Lung, and Blood Institute.

中文翻译：

在非洲裔哮喘患者的随机对照试验中进行长效 β 受体激动剂和吸入皮质类固醇反应性的药物遗传学研究

背景

主要由欧洲血统的白人组成的哮喘队列的药物遗传学研究已经确定了与吸入β受体激动剂和皮质类固醇（ICS）反应相关的位点。来自不同祖先背景的个体对长效β受体激动剂（LABA）和ICS的反应存在差异。因此，我们试图了解调节非洲人后裔治疗反应的药物遗传学机制。

方法

我们对最佳非洲药物反应 (BARD) 试验中的儿童（5-11 岁）以及青少年和成人（12-69 岁）进行了基于血统的药物遗传学研究，其中哮喘患者使用低剂量 ICS 未得到控制（丙酸氟替卡松儿童 50 μg，青少年和成人 100 μg）接受不同的阶梯式联合治疗。 BARD 中成对优越反应性的分层复合结果基于哮喘加重、年度哮喘控制天数的 31 天差异或预测 FEV ₁百分比的 5% 差异。我们对 312 个独立区域内的 15 159 个祖先片段进行了全基因组混合作图，并按两个年龄组进行分层。两项共同主要结果比较是从低剂量 ICS 到五倍剂量 ICS（5 × ICS：儿童 250 μg 每天两次，青少年和成人 500 μg 每天两次）与双剂量（2-2 ·5×ICS：儿童100μg每天两次，青少年和成人250μg每天两次），以及5×ICS与100μg氟替卡松加LABA（沙美特罗50μg每天两次）。我们使用了 p<1·6 × 10 ^-4的全基因组显着性阈值，并使用非洲裔哮喘患者的独立队列进行了复制测试。

发现

我们在 BARD 药物遗传学分析中纳入了 249 名无关儿童和 267 名无关青少年和成人。在儿童中，我们在 12 号染色体上发现了对 5 × ICS 与 100 μg 氟替卡松加沙美特罗的卓越反应性的显着混合图峰（比值比 [OR_当地非洲] 3·95，95% CI 2·02–7·72，p =6·1 × 10 ^-5 ) 精细定位到RNFT2和NOS1附近的基因座（rs73399224，OR_{等位基因剂量}0·17，95% CI 0·07–0·42，p=8·4 × 10 ^-5 ）。在青少年和成人中，我们在 22 号染色体上发现了对 5 × ICS 与 2·5 × ICS 的优异反应性峰值（或_非洲当地3·35、1·98–5·67，p=6·8 × 10 ⁻⁶ ）包含与TPST2相邻的基因座（rs5752429，OR_{等位基因剂量}0·21、0·09–0·52，p=5·7 × 10 ^-4 ）。我们在独立的非裔美国人队列中复制了 rs5752429 并名义上复制了 rs73399224。