Family Based Analysis of Modifiers of CF Lung Disease

囊性纤维化是一种以肺部进行性恶化为特征的遗传性多系统疾病。 编码囊性纤维化的单个基因功能障碍和胰腺功能不全 跨膜电导调节器(CFTR)。尽管CF被认为是一种单基因疾病， 即使在具有相同CFTR突变的患者中，表型表达也是相当不同的。患有疾病的患者 最常见的突变，德尔塔508，CFTR508位苯丙氨酸的缺失，通常有 明显不同的临床病程；有些人肺部疾病侵袭性较小，并能活到50多岁，而 其他人的肺功能急剧下降，并在20岁出头时死于呼吸衰竭。什么 这种表型异质性的原因尚不清楚。该提案的目标是确定非CFTR 可能影响肺纤维化严重程度并解释表型异质性的候选基因。 任何已发现的修饰基因都将对明确肺纤维化的病理生理机制具有重要意义 疾病，对患者进行分层，并确定新的治疗目标。为了初步检验我们的假设，我们 建议评估与免疫相关和非CFTR基因的候选基因。我们的战略将使用 基于家系的关联分析检测候选基因与肺疾病严重程度的关联性 疾病。我们建议将新的基因分型技术、动力良好的样本和单倍型- 一种全面确定最有希望的候选者变异的方法 改变慢性肺病的基因。这项研究的独特贡献将是对基因的检测 父子三人组中CF中的修饰物评估可能影响表型和 因此，慢性阻塞性肺疾病。需要检验的总体假设是，基因的多态与 明确的表型代表修饰因子，这些修饰因子解释了CF肺表达的变异性 疾病通过肺功能、一秒用力呼气容积(FEV1)来衡量，在患有 德尔塔508基因。为了检验这一全球假说，我们确立了三个具体目标：1)建立和 确定CF数据库的特征，并定义我们的CF的定量和定性组件的关键特征 表型；根据年龄调整后的FEV1水平，将表型与疾病严重程度的变化联系起来 CFTR等位基因Delta F508纯合子携带者的性别分布。2)基因型单核苷酸 来自五个有希望的基因的多态标记(SNPs)(基于来自Aim 1，PGA， 微阵列分析和文献)在100个样本中被发现与肺功能有关 Delta508纯合子的个体，并识别标记这些的常见单倍型和htSNP 这些基因的单倍型。3)纯合子三角洲样本中AIM-2中发现的这些htSNP的基因分型 F508个个体及其父母，并进行基于家族的关联分析 肺功能。

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 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.