Pharmacogenetic studies of long-acting beta agonist and inhaled corticosteroid responsiveness in randomised controlled trials of individuals of African descent with asthma.
Pharmacogenetic studies of long-acting beta agonist and inhaled corticosteroid responsiveness in randomised controlled trials of individuals of African descent with asthma.
复制标题
DOI：
10.1016/s2352-4642(21)00268-6
复制
发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
NHLBI AsthmaNet
中科院分区：
文献类型：
--
作者：
Ortega VE;Daya M;Szefler SJ;Bleecker ER;Chinchilli VM;Phipatanakul W;Mauger D;Martinez FD;Herrera-Luis E;Pino-Yanes M;Hawkins GA;Ampleford EJ;Kunselman SJ;Cox C;Bacharier LB;Cabana MD;Cardet JC;Castro M;Denlinger LC;Eng C;Fitzpatrick AM;Holguin F;Hu D;Jackson DJ;Jarjour N;Kraft M;Krishnan JA;Lazarus SC;Lemanske RF Jr;Lima JJ;Lugogo N;Mak A;Moore WC;Naureckas ET;Peters SP;Pongracic JA;Sajuthi SP;Seibold MA;Smith LJ;Solway J;Sorkness CA;Wenzel S;White SR;Burchard EG;Barnes K;Meyers DA;Israel E;Wechsler ME;NHLBI AsthmaNet
在哮喘队列（主要是欧洲血统的白人）中进行的药物遗传学研究已经确定了与吸入性β受体激动剂和皮质类固醇（ICS）反应相关的基因座。由于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，因此了解非洲裔少数群体调节治疗反应的药物遗传学机制非常重要。我们在来自非洲最佳药物反应（BARD）试验的249名儿童和267名青少年/成人中进行了全基因组混合物定位，该试验基于复合上级反应结果，比较了从低剂量ICS递增至5倍（5xICS）与加倍ICS（2.5xICS）或5xICS与在氟替卡松100 mcg每日2次（FP100 SAL）基础上添加LABA（沙美特罗）。在儿童中，我们在12号染色体上发现了一个显着的混合物图谱峰，表明对5xICS与FP 100 SAL的反应性更佳（OR当地非洲人= 3.95，95%，CI = 2.02 - 7.72，p = 6.1x10 − 5）精细定位于RNFT 2和NOS 1附近的基因座（rs73399224，OR等位基因剂量= 0.17，95%CI = 0.07 - 0.42，p = 8.4x10 − 5）。在青少年/成人中，我们确定了22号染色体上对5xICS与2.5xICS的上级反应性的峰值（OR非洲当地= 3.35，95%CI = 1.98 - 5.67，p = 6.8x10 − 6），该染色体含有一个邻近TPST 2的位点（rs5752429，OR等位基因剂量= 0.21，95%CI = 0.09 - 0.52，p = 5.7x10 − 4）。我们在独立的非裔美国人队列中复制了rs5752429和名义上复制了rs73399224。BARD是首个在非洲裔少数民族临床试验中对LABA和ICS反应进行的全基因组药物遗传学研究，旨在检测和复制全基因组显著位点。混合物映射的复合BARD试验结果，使新的药物遗传学变异的鉴定解释不同的治疗反应，在非洲裔哮喘患者。
Pharmacogenetic studies in asthma cohorts, primarily whites of European descent, have identified loci associated with response to inhaled beta agonists and corticosteroids (ICS). Because differences exist in how individuals from different ancestral backgrounds respond to long-acting beta agonist (LABA) and ICS, it is important to understand pharmacogenetic mechanisms regulating therapeutic responsiveness in African descent minorities. We performed whole-genome admixture mapping in 249 children and 267 adolescents/adults from the Best African Response to Drug (BARD) trials based on the composite superior response outcome comparing step up from low-dose ICS to quintupling (5xICS) versus doubling ICS (2.5xICS) or 5xICS versus adding LABA (salmeterol) to fluticasone 100mcg twice daily (FP100SAL). In children, we identified a significant admixture mapping peak for superior responsiveness to 5xICS versus FP100SAL on chromosome 12 (ORlocal African=3.95, 95%, CI=2.02–7.72, p=6.1x10−5) fine mapped to a locus adjacent to RNFT2 and NOS1 (rs73399224, ORallele dose=0.17, 95%CI=0.07–0.42, p=8.4x10−5). In adolescents/adults, we identified a peak for superior responsiveness to 5xICS versus 2.5xICS on chromosome 22 (ORlocal African=3.35, 95% CI=1.98–5.67, p=6.8x10−6) containing a locus adjacent to TPST2 (rs5752429, ORallele dose=0.21, 95%CI=0.09–0.52, p=5.7x10−4). We replicated rs5752429 and nominally replicated rs73399224 in independent African American cohorts. BARD is the first genome-wide pharmacogenetic study of LABA and ICS response in clinical trials of African descent minorities 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 African descent asthmatics.