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

项目摘要/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： 2大约32名高加索人中有1人和61名非裔美国人中有1人是慢性萎缩性胃炎携带者。这是它的一个标志 3疾病为反复呼吸道感染。然而，囊性纤维化需要两份CFTR 4突变。传统上，一个未突变的CFTR基因被认为足以维持健康。 然而，我们小组的一些小规模研究和初步工作表明，CF承运人可能 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，高于非CF型携带者。考虑到年内估计有1500万慢性肺囊炎携带者 8在美国，如果携带者更有可能感染呼吸道感染，可归因于 9可归因于CF携带者状态的呼吸道感染和相应的抗菌剂使用可为 10%相当可观。因此，迫切需要以人口为基础的调查，以准确确定 11 CF携带者状态对呼吸道感染的归因风险。 12我们研究的目标是确定CF型携带者状态对感染呼吸道疾病风险的作用 13例感染。由于用于遗传咨询的CFTR突变的基因检测的频率，这是可能的 14在一些现有的以人口为基础的数据集中识别CF携带者。我们的团队最近展示了 15与年龄和性别匹配的患者相比，CF携带者患呼吸道感染的风险明显更高 16个对照。然而，需要更多的工作来考虑其他患者的特征以及患者的 17个特定的CF突变。此外，这些发现在生物学上的合理性需要得到证实。因此， 18我们将使用行政索赔来确定CF携带者呼吸道感染的自然病史 19数据；使用以下数据确定基因分型队列中CF携带者的呼吸道感染风险 20份电子病历，并评估CF携带者与非携带者的呼吸道上皮功能。 21这项工作意义重大，因为呼吸道感染是发病率和死亡率的主要原因；cf 22个携带者很常见，可以通过目前的遗传咨询方法来识别；还有CFTR- 23种调节疗法可供选择，这些疗法可能是治疗CF携带者 24例呼吸道感染。这项工作具有创新性，因为这一领域以前的所有工作都是使用 25个小队列患者，我们将有机会接触到大量的CF携带者和对照组。此外，我们还将 26能够使用行政数据中的诊断和程序代码以及 27个病历和一个队列，我们将能够识别特定的CFTR突变。 28考虑到普通人群中的慢性粒细胞白血病携带者的数量，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.