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

描述（由申请人提供）：该项目将评估白细胞介素1 （IL-1）基因簇（IL-1 α, β， IL-1受体和IL-1受体拮抗剂）内的遗传变异，这些变异可能影响海藻酸盐特异性opsonic抗体的存在和缺乏可检测的粘液假单胞菌定植。囊性纤维化（CF）肺部疾病异质性的一个因素被怀疑是IL-1基因家族的遗传变异，IL-1基因家族在介导对铜绿假单胞菌感染的先天免疫中起作用，并可能影响opsonic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性是否代表了解释表型异质性的潜在修饰因素，这是通过在CF患者中存在或不存在opsonic抗体和粘液样铜绿假单胞菌定植来测量的。F508基因型。病例对照遗传关联研究设计将用于测试IL-1基因簇变异与偶声抗体和粘液样假单胞菌存在或不存在的关联。然后将在另外两个基于家庭的CF队列中对遗传关联的可重复性进行评估。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随访，以确认当前的发现并确定复杂的关联。所得到的数据将定义由粘液样铜绿假单胞菌引起的CF肺早期感染中偶声抗体的表达，以及宿主反应对临床结果的贡献。该项目对鉴定新的分子靶点的功能遗传变异和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.