Pharmacogenetic Polygenic Risk Score for Bronchodilator Response in Children and Adolescents with Asthma: Proof-of-Concept.
Pharmacogenetic Polygenic Risk Score for Bronchodilator Response in Children and Adolescents with Asthma: Proof-of-Concept.
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DOI：
10.3390/jpm11040319
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发表时间：
2021-04-20
影响因子：
--
通讯作者：
Wu AC
中科院分区：
文献类型：
--
作者：
Sordillo JE;Lutz SM;McGeachie MJ;Lasky-Su J;Weiss ST;Celedón JC;Wu AC
对哮喘药物反应的全基因组关联研究（GWAS）主要集中在高加索人群，其结果可能无法推广到少数人群。我们推导出一个多基因风险评分（PRS）的反应沙丁胺醇作为衡量支气管扩张剂的反应（BDR），并检查了PRS在一个队列的西班牙裔学龄儿童哮喘。我们利用已发表的BDR的GWAS来识别相关的遗传变异，并根据它们的组合注释依赖消耗（CADD）评分对顶级变异进行排名。CADD评分大于10的变量用于计算PRS。一旦我们得出了PRS，我们在调整的线性回归模型中确定了PRS与西班牙裔哮喘儿童队列中BDR的相关性（哥斯达黎加哮喘遗传学研究（GACRS））。GACRS参与者的平均BDR为5.6%，标准差为10.2%。我们观察到沙丁胺醇治疗后BDR降低0.63%，PRS标准差增加（p = 0.05）。我们还观察到，当PRS增加一个标准差时，BDR应答等于或高于12%阈值的几率降低（OR = 0.80（95% CI 0.67至0.95））。我们的研究结果表明，将药物遗传学GWAS的变体结合到PRS中可能有助于预测哮喘的药物反应。
Genome-wide association studies (GWAS) of response to asthma medications have primarily focused on Caucasian populations, with findings that may not be generalizable to minority populations. We derived a polygenic risk score (PRS) for response to albuterol as measured by bronchodilator response (BDR), and examined the PRS in a cohort of Hispanic school-aged children with asthma. We leveraged a published GWAS of BDR to identify relevant genetic variants, and ranked the top variants according to their Combined Annotation Dependent Depletion (CADD) scores. Variants with CADD scores greater than 10 were used to compute the PRS. Once we derived the PRS, we determined the association of the PRS with BDR in a cohort of Hispanic children with asthma (the Genetics of Asthma in Costa Rica Study (GACRS)) in adjusted linear regression models. Mean BDR in GACRS participants was5.6% with a standard deviation of 10.2%. We observed a 0.63% decrease in BDR in response to albuterol for a standard deviation increase in the PRS (p = 0.05). We also observed decreased odds of a BDR response at or above the 12% threshold for a one standard deviation increase in the PRS (OR = 0.80 (95% CI 0.67 to 0.95)). Our findings show that combining variants from a pharmacogenetic GWAS into a PRS may be useful for predicting medication response in asthma.
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影响因子：
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发表时间：
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