Estimating the risk for and severity of respiratory infections attributable to CFTR heterozygosity

项目总结/摘要 1囊性纤维化是美国最常见的常染色体退行性遗传病之一： 大约32名白人中有1名和61名非洲裔美国人中有1名是CF携带者。这其中的一个标志是 3疾病是反复呼吸道感染。然而，囊性纤维化需要两个CFTR拷贝 4突变。传统上，一个未突变的CFTR基因被认为足以维持健康。 5然而，我们小组的一些小型研究和初步工作表明，CF载体可能 6呼吸道感染的风险增加，包括复发性鼻窦炎，肺炎和非典型肺炎。 7分枝杆菌感染，比非CF携带者。鉴于估计有1500万CF携带者， 8美国，如果携带者更容易获得呼吸道感染， 9呼吸道感染和相应的抗菌药物的使用可归因于CF-载体状态， 10个实质性因此，迫切需要进行以人口为基础的调查，以准确确定 11呼吸道感染的CF携带者状态的归因风险。 12我们研究的目的是确定CF携带状态对获得呼吸道疾病风险的作用。 13感染由于CFTR突变基因检测用于遗传咨询的频率较高， 14以在一些现有的基于人口的数据集中识别CF携带者。我们的团队最近展示了 CF携带者患呼吸道感染的风险明显高于年龄和性别匹配的 16个对照组。然而，还需要做更多的工作来考虑其他患者特征以及患者的特征 17种特异性CF突变。此外，还需要确定这些发现的生物学可解释性。因此，在本发明中， 我们将使用行政索赔来确定CF携带者的呼吸道感染自然史 19数据;使用来自以下数据确定基因分型队列中CF携带者呼吸道感染的风险： 20份电子病历，并评估CF携带者与非携带者相比的气道上皮功能。 21这项工作意义重大，因为呼吸道感染是发病和死亡的主要原因; 22种携带者是常见的，可以通过目前的遗传咨询方法进行识别;还有CFTR- 23种调节疗法可能是CF携带者的成本效益高的治疗方法， 24呼吸道感染这项工作是创新的，因为所有以前的工作在这一领域已经完成使用 25个小队列的患者，我们将有机会获得一个大队列的CF携带者和对照。我们亦会 能够使用管理数据中的诊断和程序代码识别CF携带者， 在一个队列中，我们将能够识别特定的CFTR突变。 28鉴于普通人群中CF携带者的数量，我们开发的方法和模型将具有 29对呼吸道感染以外的其他疾病的广泛影响。

Project Summary/Abstract 1 Cystic fibrosis is one of the most common autosomal regressive genetic disorders in the United States: 2 approximately 1 out of 32 Caucasians and 1 out of 61 African Americans is a CF carrier. A hallmark of this 3 disease is recurrent respiratory infections. However, cystic fibrosis requires two copies of the CFTR 4 mutation. Traditionally, one non-mutated CFTR gene was thought to be sufficient for maintaining health. 5 However, a few small studies and preliminary work by our group have demonstrated that CF carriers may 6 be at increased risk for respiratory infections, including recurrent sinusitis, pneumonia, and atypical 7 mycobacterial infections, than non-CF carriers. Given an estimated population of 15 million CF carriers in 8 the United States, if carriers are more likely to acquire respiratory infections, the attributable burden of 9 respiratory infections and corresponding antimicrobial use attributable to the CF-carrier state may be 10 substantial. Thus, there is a critical need for population-based investigations to precisely determine the 11 attributable risk of the CF-carrier state for respiratory infections. 12 The goal of our research is to determine the role of the CF-carrier state on the risk for acquiring respiratory 13 infections. Due to the frequency of genetic testing for CFTR mutations for genetic counseling, it is possible 14 to identify CF carriers in some existing population-based data sets. Our group has recently demonstrated 15 that CF carriers are at significantly greater risk for respiratory infections compared to age and sex matched 16 controls. However, more work is needed that considers other patient characteristics as well as patients' 17 specific CF mutations. In addition, the biological plausibility of these findings needs to be established. Thus, 18 we will determine the natural history of respiratory infections for CF carriers using administrative claims 19 data; determine the risk for respiratory infections among CF carriers in a genotyped cohort using data from 20 electronic medical records, and assess airway epithelial function in CF carriers compared to non-carriers. 21 This work is significant because respiratory infections are a major cause of morbidity and mortality; CF 22 carriers are common and can be identified by current genetic counseling methods; and there are CFTR- 23 modulating therapies available that may be cost-effective treatments for CF carriers with excessive 24 respiratory infections. This work is innovative because all previous work in this area has been done using 25 small cohorts of patients, and we will have access to a large cohort of CF carriers and controls. Also, we will 26 be able to identify the CF carriers using diagnosis and procedure codes in administrative data and the 27 medical record an in one cohort we will be able to identify specific CFTR mutations. 28 Given the number of CF carriers in the general population, the methods and models we develop will have 29 broad implications for other diseases beyond respiratory infections.