FAMILY BASED ASSOCIATION ANALYSIS OF MODIFIERS OF CYSTIC FIBROSIS LUNG DISEASE

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。囊性纤维化（CF）患者表现出一系列的疾病严重程度。个体CF患者的肺部疾病差异很大，导致这种异质性的原因尚不清楚。其中一些可变性可归因于囊性纤维化跨膜传导调节基因（CFTR）的突变和其他非遗传因素，如患者的年龄、胰腺功能不全、治疗方案、营养状况和假单胞菌或洋葱伯克霍尔德菌的定植。本研究将确定CF肺病的修饰基因。我们建议对CF人群进行广泛的表型和基因分型分析，纳入500多个家庭，其中至少有一名CF患者，并在波士顿儿童医院和马萨诸塞州总医院进行随访。我们提出，影响CF病程的修饰基因可以通过在基于家族的关联研究中使用单核苷酸多态性（snp）对候选位点进行基于关联的分析来识别。单核苷酸多态性是变异的目录，作为遗传标记的共同遗传差异，在至少1%的普通人群中观察到。如果观察频率高于一般人群，它们可能代表功能变化。我们假设CF群体内的表型差异可以通过修饰基因来解释，并且将与相同CF基因型患者的不同程度的肺功能相关。我们相信，CF中影响肺部疾病程度的遗传因素将改善诊断并确定新的治疗靶点。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Patients with cystic fibrosis (CF) display a range of disease severity. Lung disease in individual CF patients varies widely and what account for this heterogeneity is unclear. Some of this variability can be attributed to mutations within the cystic fibrosis transmembrane conductance regulator gene (CFTR) and by other non-genetic factors such as patient's age, pancreatic insufficiency, treatment regimen, nutritional status and colonization with strains of Pseudomonas or Burkholderia cepacia. This study will identify genes that are modifiers of CF lung disease. We propose an extensive phenotype and genotyping analysis in our CF population enrolling over 500 families with at least one individual with CF who is followed at Children's Hospital, Boston and Massachussetts General Hospital. We propose that modifier genes that impact the course of CF can be identified by performing an association based analysis of candidate loci using single nubleotide polymorphisms (SNPs) in a family based association study. Single nucleotide polymorphisms are a catalog of variatios, common genetic differences that function as genetic markers and are observed in at least 1% of the general population. They may represent a functional change if observed at a greater frequency than the general population. We hypothesize that the phenotypic differences within the CF population can be accounted for by modifier genes and will correlate to varying degress of lung function in patients with the same CF genotype. We believe the genetic factors that contribute to the degree of pulmonary disease in CF wil improve diagnosis and define new theraputic targets.