Genetic ancestry modifies pharmacogenetic gene-gene interaction for asthma
Genetic ancestry modifies pharmacogenetic gene-gene interaction for asthma
复制标题
DOI：
10.1097/fpc.0b013e32832c440e
复制
发表时间：
2009-07-01
影响因子：
2.6
通讯作者：
Burchard, Esteban Gonzalez
中科院分区：
文献类型：
--
作者：
Corvol, Harriet;De Giacomo, Anthony;Burchard, Esteban Gonzalez
目的新近的混合基因图谱分析证实白细胞介素6（IL 6）和IL 6受体（IL 6 R）是炎症性疾病的候选基因。在过敏性炎症期间的气道中，IL 6信号传导控制促炎因子和抗炎因子的产生。此外，沙丁胺醇，一种常用的哮喘治疗处方，已被证明会影响IL 6基因表达。因此，我们推断，IL 6和IL 6 R基因之间的相互作用可能与支气管扩张剂药物对哮喘患者沙丁胺醇的反应性相关。方法4个功能性IL 6单核苷酸多态性（SNP）和一个非同义的IL 6 R SNP在700个墨西哥和波多黎各哮喘家族和443个非洲裔美国人哮喘病例和对照中进行基因分型。基于家族的关联检验和线性回归模型均用于评估单个SNP和单倍型与支气管扩张剂反应之间的关联。基因-基因交互作用用多元线性回归分析。结果没有一个单一的SNP是一致的与药物反应在所有三个群体。然而，在基因水平上，我们发现了一致的IL 6和IL 6 R在三个人群中的药物遗传学相互作用。这种药物遗传学基因-基因相互作用是上下文和依赖于祖先（种族背景）。这种相互作用导致拉丁美洲人对沙丁胺醇的药物反应较高，但非洲裔美国人的药物反应较低。在此，我们发现，有一个效果修改的祖先对支气管扩张剂的反应沙丁胺醇。结论在IL 6和IL 6 R基因的遗传变异协同作用，以修改支气管扩张剂的药物反应性哮喘和这种药物遗传学的相互作用是修改的遗传祖先。药物遗传学和基因组学19：489-496（C）2009年威科健康|利平科特威廉姆斯&威尔金斯。
Objective A recent admixture mapping analysis identified interleukin 6 (IL6) and IL6 receptor (IL6R) as candidate genes for inflammatory diseases. In the airways during allergic inflammation, IL6 signaling controls the production of proinflammatory and anti-inflammatory factors. In addition, albuterol, a commonly prescribed asthma therapy, has been shown to influence IL6 gene expression. Therefore, we reasoned that interactions between the IL6 and IL6R genes might be associated with bronchodilator drug responsiveness to albuterol in asthmatic patients.Methods Four functional IL6 single nucleotide polymorphisms (SNPs) and a nonsynonymous IL6R SNP were genotyped in 700 Mexican and Puerto Rican asthma families and in 443 African-American asthma cases and controls. Both family-based association tests and linear regression models were used to assess the association between individual SNPs and haplotypes with bronchodilator response. Gene-gene interactions were tested by using multiple linear regression analyses.Results No single SNP was consistently associated with drug response in all the three populations. However, on the gene level, we found a consistent IL6 and IL6R pharmacogenetic interaction in the three populations. This pharmacogenetic gene-gene interaction was contextual and dependent upon ancestry (racial background). This interaction resulted in higher drug response to albuterol in Latinos, but lower drug response in African-Americans. Herein, we show that there is an effect modification by ancestry on bronchodilator responsiveness to albuterol.Conclusion Genetic variants in the IL6 and IL6R genes act synergistically to modify the bronchodilator drug responsiveness in asthma and this pharmacogenetic interaction is modified by the genetic ancestry. Pharmacogenetics and Genomics 19:489-496 (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins.