Family Based Analysis of Modifiers of CF Lung Disease

描述（由申请人提供）：囊性纤维化（CF）是一种遗传性多系统疾病，其特征为肺功能进行性恶化和胰腺功能不全，这归因于编码囊性纤维化跨膜传导调节因子（CFTR）的单个基因功能障碍。虽然CF被认为是一种单基因疾病，表型表达是相当不同的，即使在相同的CFTR突变的患者。最常见的突变是CFTR的508位缺失一个苯丙氨酸的delta 508突变，患者的临床病程往往有明显的不同;有些患者的肺部疾病侵袭性较低，存活到50多岁，而另一些患者的肺功能急剧下降，在20多岁时死于呼吸衰竭。这种表型异质性的原因尚不清楚。该提案的目标是确定可能影响CF肺病严重程度并解释表型异质性的非CFTR候选基因。任何修饰基因的确定将有重要的意义，定义CF肺疾病的病理生理，分层患者，并确定新的治疗目标。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。我们建议结合联合收割机新的基因分型技术，良好的动力样本，和单倍型为基础的方法，以全面和明确地确定最有前途的候选基因修饰CF肺疾病的变化。这项研究的一个独特贡献将是检查父母子女三人组中CF的遗传修饰因子，以评估可能影响表型和CF肺病的基因多态性。待检验的总体假设是，与明确定义的表型相关的基因多态性代表修饰因子，其解释了具有δ 508基因型的患者中CF肺病表达的变异性，如通过肺功能，一秒用力呼气量（FEV 1）测量的。为了检验这一总体假设，我们已经建立了三个具体目标：1）建立和表征CF数据库，并定义我们的CF表型的定量和定性组分的关键特征;将表型与疾病严重程度的变化相关联，所述疾病严重程度的变化由Δ F508 CFTR等位基因纯合子的CF患者中的年龄和性别调整的FEV 1水平定义。2)来自五个有希望的基因（基于来自Aim 1、PGA、微阵列分析和文献的数据选择）的基因型单核苷酸多态性标记（SNP）发现与100个δ 508纯合个体的样本中的肺功能相关，并鉴定常见的单倍型和标记这些基因的单倍型的htSNP。3)在纯合Δ F508个体及其父母的样品中对AIM 2中鉴定的这些htSNP进行基因分型，并对CF表型和肺功能进行基于家族的关联分析。

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.