FAMILY BASED ASSOCIATION ANALYSIS OF MODIFIERS OF CYSTIC FIBROSIS LUNG DISEASE

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 囊性纤维化（CF）患者表现出一系列疾病严重程度。 个体CF患者的肺部疾病差异很大，这种异质性的原因尚不清楚。 这种变异性中的一些可归因于囊性纤维化跨膜传导调节基因（CFTR）内的突变以及其他非遗传因素，例如患者的年龄、胰腺功能不全、治疗方案、营养状态以及假单胞菌或洋葱伯克霍尔德菌菌株的定植。 这项研究将确定CF肺病的修饰基因。 我们建议在我们的CF人群中进行广泛的表型和基因分型分析，该人群招募了500多个家庭，其中至少有一名CF患者在波士顿儿童医院和马萨诸塞州总医院接受随访。 我们建议，修饰基因的影响CF的过程中，可以通过执行基于关联的分析候选基因座使用单核苷酸多态性（SNP）在一个家庭为基础的关联研究。 单核苷酸多态性是一系列变异，作为遗传标记的常见遗传差异，在至少1%的一般人群中观察到。 如果观察到的频率高于一般人群，则可能代表功能变化。 我们假设CF人群中的表型差异可以由修饰基因解释，并与具有相同CF基因型的患者的不同程度的肺功能相关。 我们相信，导致CF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 Massachusetts 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 nucleotide polymorphisms (SNPs) in a family based association study. Single nucleotide polymorphisms are a catalog of variations, 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 degrees 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 will improve diagnosis and define new therapeutic targets.