IL-1 Family Gene Polymorphisms and Susceptibility to P. aeruginosa in CF Patients

描述(由申请人提供)：该项目将评估白介素1(IL-1)基因簇(IL-1α、β、IL-1受体和IL-1受体拮抗剂)中的遗传变异，这些变异可能会影响藻酸盐特异性调理抗体的存在和缺乏可检测到的粘液性假单胞菌定植。囊性纤维化(CF)肺部疾病的异质性的一个原因可能是IL-1基因家族的遗传变异，该基因家族在介导对铜绿假单胞菌感染的先天免疫中发挥作用，并可能影响调理抗体的水平。总体而言，该项目将测试IL-1基因簇中特定基因的多态是否代表潜在的修饰因素，通过检测携带？F508基因的CF患者中是否存在调理抗体和粘液型铜绿假单胞菌定植来解释表型异质性。病例对照遗传关联研究设计将用于测试IL-1基因簇变异与是否存在调理抗体和粘液性假单胞菌的关联。然后将对另外两个以家庭为基础的CF队列中的遗传关联的重复性进行评估。我们独特的多中心合作，将CF患者纳入威斯康星州新生儿筛查计划，将确保对年轻患者进行必要的纵向跟踪，以确认当前的发现并确定复杂的关联。由此产生的数据将确定在早期粘液性铜绿假单胞菌感染的CF肺中的光学抗体的表达，以及宿主反应对临床结果的贡献。该项目对识别新分子靶点的功能遗传变异以及开发新的临床诊断和预后工具具有重要意义。 公共卫生相关性：囊性纤维化(CF)肺部疾病以铜绿假单胞菌慢性感染为特征，是囊性纤维化患者发病和死亡的主要原因。由此产生的数据将确定在早期粘液性铜绿假单胞菌感染的CF肺中的光学抗体的表达，以及宿主反应对临床结果的贡献。该项目对识别新分子靶点的功能遗传变异以及开发新的临床诊断和预后工具具有重要意义。

DESCRIPTION (provided by applicant): This project will evaluate genetic variants within the interleukin 1 (IL-1) gene cluster (IL-1 alpha, beta, IL-1 receptor and IL-1 receptor antagonist) that may impact the presence of alginate-specific opsonic antibody and lack of detectable mucoid Pseudomonas colonization. One factor accounting for heterogeneity in cystic fibrosis (CF) pulmonary disease is suspected to be genetic variation in the IL-1 gene family, which plays a role in mediating innate immunity to P. aeruginosa infection and potentially influences levels of opsonic antibody. Overall, the project will test whether polymorphisms within specific genes in the IL-1 gene cluster represent potential modifying factors that account for phenotypic heterogeneity as measured by the presence or absence of both opsonic antibodies and mucoid P. aeruginosa colonization in CF patients with the ?F508 genotype. A case-control genetic association study design will be used to test for association of variation in the IL-1 gene cluster with the presence or absence of opsonic antibodies and mucoid Pseudomonas. An assessment will then be made on the reproducibility of the genetic associations in two additional family-based CF cohorts. Our unique multicenter collaboration, incorporating CF patients enrolled in the Wisconsin Newborn Screening Program, will ensure needed longitudinal follow-up of young patients necessary to confirm current findings and define complex associations. The resulting data will define the expression of opsonic antibodies in early infections of the CF lung by mucoid P. aeruginosa and the contribution of host response to clinical outcome. This project has several important implications for identification of functional genetic variation in novel molecular targets and development of novel clinical diagnostic and prognostic tools. PUBLIC HEALTH RELEVANCE: Cystic Fibrosis (CF) lung disease is characterized by chronic infection by Pseudomonas aeruginosa and is the major cause of morbidity and mortality in CF patients. The resulting data will define the expression of opsonic antibodies in early infections of the CF lung by mucoid P. aeruginosa and the contribution of host response to clinical outcome. This project has several important implications for identification of functional genetic variation in novel molecular targets and development of novel clinical diagnostic and prognostic tools.