Family Based Analysis of Modifiers of CF Lung Disease

描述(申请人提供)：囊性纤维化(CF)是一种遗传性的多系统疾病，其特征是肺功能进行性恶化和胰腺功能不全，归因于编码囊性纤维跨膜传导调节因子(CFTR)的单个基因的功能障碍。尽管CF被认为是一种单基因疾病，但即使在具有相同CFTR突变的患者中，其表型表达也相当不同。最常见的突变是Delta508，也就是CFTR508位苯丙氨酸的缺失，患者的临床病程往往截然不同；一些患者的肺部疾病侵袭性较小，并能活到50多岁，而另一些患者的肺功能急剧下降，并在20岁出头死于呼吸衰竭。这种表型异质性的原因尚不清楚。这项建议的目标是确定可能影响CF肺部疾病严重程度并解释表型异质性的非CFTR候选基因。任何已发现的修饰基因都将对明确慢性肺病的病理生理学、对患者进行分层以及确定新的治疗靶点具有重要意义。为了初步验证我们的假设，我们建议评估免疫相关和非CFTR基因的候选基因。我们的策略将使用基于家族的关联分析来测试候选基因与肺部疾病严重程度的关联。我们建议结合新的基因分型技术、动力良好的样本和基于单倍型的方法来全面和明确地确定最有希望的CF肺部疾病候选基因的变异。这项研究的一个独特贡献将是在亲子三人组中检查CF中的遗传修饰物，以评估可能影响表型从而影响CF肺部疾病的基因的多态。有待检验的总体假设是，与明确表型相关的基因的多态代表了修饰因素，这些因素解释了在Delta 508基因型患者中，通过肺功能、一秒用力呼气量(FEV1)衡量的CF肺部疾病表达的可变性。为了验证这一全球假设，我们建立了三个具体目标：1)建立和表征一个CF数据库，并定义我们的CF表型的数量和质量成分的关键特征；将表型与疾病严重程度的变化联系起来，这是根据年龄和性别调整的FEV1水平来定义的，在携带Delta F508 CFTR等位基因的CF患者中，FEV1基因纯合。2)从5个有希望的基因(基于Aim 1、PGA、微阵列分析和文献中的数据)中发现与肺功能相关的5个基因的单核苷酸多态标记(SNPs)，并识别常见的单倍型和标记这些单倍型的htSNP。3)对AIM-2中发现的这些hTSNP进行基因分型，并对F_(508)纯合子及其父母进行基于家系的关联分析。

DESCRIPTION (provided by applicant): Cystic fibrosis (CF) is an inherited multisystem disease characterized by progressive deterioration in lung function and pancreatic insufficiency attributed to dysfunction of a single gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). Although CF is considered a monogenic disorder, phenotype expression is considerably diverse even in patients with the same CFTR mutation. Patients with the most common mutation, delta 508 a deletion of a phenylalanine at position 508 of CFTR, often have markedly different clinical courses; some, have less aggressive lung disease and survive into their 50s, while others have a precipitous decline in lung function and die of respiratory failure in their early 20s. What accounts for this phenotypic heterogeneity is unclear. The goal of this proposal is to identify non-CFTR candidate genes that may impact the severity of CF lung disease and account for phenotypic heterogeneity. Any modifier gene identified will have important implications for defining the pathophysiology of CF lung disease, stratifying patients, and identifying new targets for therapy. To initially test our hypothesis, we propose to evaluate candidate genes that are immune-related and non-CFTR genes. Our strategy will use a family based association analysis to test for association of candidate genes to severity of pulmonary disease. We propose to combine new genotyping technology, well-powered samples, and a haplotype-based approach to comprehensively and definitively determine variation in the most promising candidate genes modifying CF lung disease. A unique contribution of this research will be the examination of genetic modifiers in CF in parent child-trios to evaluate polymorphisms in genes that may impact phenotype and hence CF lung disease. The overall hypothesis to be tested is that polymorphisms in genes associated with a well-defined phenotype represent modifying factors that account for the variability in expression of CF lung disease as measured by lung function, forced expiratory volume in one second (FEV1), in patients with the delta 508 genotype. To test this global hypothesis, we have established three specific aims: 1) Establish and characterize a CF database and define key features of the quantitative and qualitative components of our CF phenotype; relate phenotype to variation in disease severity as defined by levels of FEV1 adjusted for age and gender in CF patients homozygous for delta F508 CFTR allele. 2) Genotype single nucleotide polymorphic markers (SNPs) from five promising genes (selected based on data from Aim 1, the PGA, microarray analysis, and the literature) found to be associated with lung function in a sample of 100 individuals homozygous for delta 508 and identify common haplotypes and htSNPs that tag these haplotypes for these genes. 3) Genotype these htSNPs identified in AIM 2 in a sample of homozygous delta F508 individuals and their parents, and perform family based association analysis for CF phenotype and pulmonary function.