FAMILY BASED ASSOCIATION ANALYSIS OF MODIFIERS OF CYSTIC FIBROSIS LUNG DISEASE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 囊性纤维化(CF)患者表现出一系列疾病严重程度。肺病患者的个体差异很大，这种异质性的原因尚不清楚。其中一些变异可以归因于囊性纤维化跨膜传导调节基因(CFTR)的突变以及其他非遗传因素，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。这项研究将确定与慢性肺病相关的基因。 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，招募了500多个家庭，其中至少有一个人患有CF，并在儿童医院、波士顿和马萨诸塞州综合医院进行了跟踪调查。我们建议，在一项基于家族的关联研究中，可以通过对候选基因进行基于关联的分析，使用单核苷酸多态(SNPs)来识别影响CF过程的修饰基因。单核苷酸多态是一组变异，即作为遗传标记的常见遗传差异，在至少1%的普通人群中观察到。如果观察频率高于普通人群，它们可能代表着一种功能变化。 我们假设，CF人群中的表型差异可以由修饰基因解释，并将与相同CF型患者的不同程度的肺功能相关。我们相信，影响CF肺部疾病程度的遗传因素将提高诊断水平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.