Family Based Analysis of Modifiers of CF Lung Disease

CF 肺病修饰因素的家族分析

基本信息

批准号：
7242570
负责人：
HARA LEVY
金额：
$ 12.29万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7242570
关键词：
Accounting Age Alleles Antibodies Antibody Formation Burkholderia cepacia C-reactive protein Candidate Disease Gene Cell physiology Child Clinical Count Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Data Databases Defect Delta F508 mutation Deterioration Diagnosis Disease Exocrine pancreatic insufficiency Family Forced expiratory volume function Functional disorder Gender Gene-Modified Genes Genetic Genetic Polymorphism Genomics Genotype Goals Haplotypes Heterogeneity Host Defense Human Immune Immunoglobulin G Individual Infection Inflammation Inflammatory Inherited Laboratories Literature Lung Lung diseases Lymphocyte Measures Microarray Analysis Microbiology Mucins Mutation Natural Immunity Nucleotides Numbers Outcome Parents Pathology Patients Phenotype Phenylalanine Play Polymorphic Microsatellite Marker Positioning Attribute Principal Investigator Process Prostaglandins A Pseudomonas Pseudomonas aeruginosa Pulmonary Cystic Fibrosis Pulmonary Function Test/Forced Expiratory Volume 1 Research Respiratory Failure Respiratory physiology Role Sampling Severities Severity of illness Testing Transmembrane Transport Treatment Protocols Variant White Blood Cell Count procedure base capsule clinical phenotype cystic fibrosis patients diet and exercise eosinophil genotyping technology macrophage monocyte mucoid neutrophil programs pulmonary function respiratory

项目摘要

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.

囊性纤维化（CF）是一种遗传性多系统疾病，其特征是肺部进行性恶化编码囊性纤维化的单个基因功能障碍导致的功能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，表型表达也相当不同。患者患有最常见的突变 delta 508 是 CFTR 508 位苯丙氨酸的缺失，通常具有明显不同的临床过程；有些人患有不太严重的肺部疾病并能活到 50 多岁，而另一些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解释尚不清楚。该提案的目标是识别非 CFTR 可能影响 CF 肺病严重程度并解释表型异质性的候选基因。任何鉴定出的修饰基因都将对定义 CF 肺的病理生理学产生重要影响疾病、对患者进行分层并确定新的治疗目标。为了最初检验我们的假设，我们建议评估免疫相关基因和非 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，测试候选基因与肺部疾病严重程度的关联疾病。我们建议将新的基因分型技术、强大的样本和单倍型结合起来基于方法来全面、明确地确定最有希望的候选者的变异改变 CF 肺部疾病的基因。这项研究的一个独特贡献是检查遗传亲子三人组中 CF 的修饰符，用于评估可能影响表型和基因的多态性因此CF肺病。要测试的总体假设是与相关的基因多态性明确的表型代表了解释 CF 肺表达变异性的修饰因素通过肺功能、一秒用力呼气量 (FEV1) 来测量患有以下疾病的患者的疾病 Delta 508 基因型。为了检验这一全球假设，我们制定了三个具体目标：1) 建立和表征 CF 数据库并定义 CF 的定量和定性部分的关键特征表型；将表型与疾病严重程度的变化联系起来，疾病严重程度由根据年龄调整的 FEV1 水平定义 δ F508 CFTR 等位基因纯合的 CF 患者的性别和性别。 2) 单核苷酸基因型来自五个有希望的基因的多态性标记（SNP）（根据 Aim 1、PGA、微阵列分析和文献）在 100 个样本中发现与肺功能相关 Delta 508 纯合个体并识别标记这些个体的常见单倍型和 htSNP 这些基因的单倍型。 3) 对纯合 delta 样本中 AIM 2 中鉴定的这些 htSNP 进行基因分型 F508个体及其父母，并对CF表型和基于家族的关联分析肺功能。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Lack of correlation between pulmonary disease and cystic fibrosis transmembrane conductance regulator dysfunction in cystic fibrosis: a case report.

肺部疾病与囊性纤维化跨膜电导调节器功能障碍之间缺乏相关性：病例报告。

DOI：
发表时间：
2010-04-26
期刊：
影响因子：
0
作者：
Levy, Hara;Cannon, Carolynn L;Asher, Daniel;García, Christopher;Cleveland, Robert H;Pier, Gerald B;Knowles, Michael R;Colin, Andrew A
通讯作者：
Colin, Andrew A