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）是一种遗传的多系统疾病，其特征是肺部进行性恶化功能和胰腺功能不全归因于编码囊性纤维化的单个基因功能障碍跨膜电导调节剂（CFTR）。尽管CF被认为是一种单基因障碍，但即使在具有相同CFTR突变的患者中，表型表达也大大不同。患者最常见的突变，Delta 508 A在CFTR位置508处的苯丙氨酸的缺失通常具有明显不同的临床课程；有些人患有侵略性较低的肺部疾病，生存到50年代，而其他人则在20多岁时肺功能急剧下降，死于呼吸道衰竭。什么该表型异质性的解释尚不清楚。该提议的目的是确定非CFTR 可能影响CF肺部疾病严重程度并解释表型异质性的候选基因。确定的任何修饰基因都将对定义CF肺的病理生理具有重要意义疾病，对患者进行分层，并确定治疗的新靶标。最初检验我们的假设，我们建议评估与免疫相关和非CFTR基因的候选基因。我们的策略将使用基于家庭的关联分析，以测试候选基因与肺部严重程度的关联疾病。我们建议结合新的基因分型技术，功能强大的样品和单倍型 - 基于全面和明确确定最有前途的候选人的变化的方法修饰CF肺部疾病的基因。这项研究的独特贡献将检查遗传父母儿童trios中CF的修饰符，以评估可能影响表型和的基因中的多态性因此CF肺部疾病。要检验的总体假设是与基因相关的多态性定义明确的表型表示修改因子，这些因素解释了CF肺表达的变化通过肺功能测量的疾病，在一秒钟内强迫呼气量（FEV1），患有患者 Delta 508基因型。为了检验这一全球假设，我们确定了三个具体目标：1）建立和表征CF数据库并定义我们CF定量和定性组件的关键特征表型；将表型与疾病严重程度的变化相关联，该疾病严重程度由年龄调整的FEV1水平定义 CF患者的性别纯合为Delta F508 CFTR等位基因。 2）基因型单核苷酸来自五个有前途的基因的多态性标记（SNP）（基于AIM 1的数据选择，PGA，PGA，微阵列分析和文献）发现在100样品中与肺功能有关纯合508的个体，并确定标记这些标签的常见单倍型和HTSNP 这些基因的单倍型。 3）基因型这些HTSNP在AIM 2中鉴定的HTSNP在纯合三角洲样本中 F508个人及其父母，并对CF表型进行基于家庭的关联分析和肺功能。

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：
10.1186/1752-1947-4-117
发表时间：
2010
期刊：
Journal of medical case reports
影响因子：
1
作者：
Levy,Hara;Cannon,CarolynnL;Asher,Daniel;García,Christopher;Cleveland,RobertH;Pier,GeraldB;Knowles,MichaelR;Colin,AndrewA
通讯作者：
Colin,AndrewA