Molecular Phenotypes for Cystic Fibrosis Lung Disease

囊性纤维化肺病的分子表型

• 批准号: 8109359
• 负责人: Michael R Knowles
• 金额: $ 71.48万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-24 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8109359
• 关键词: Address; Adopted; Affect; Age; American; Asthma; Biological; Candidate Disease Gene; Cells; Chronic Obstructive Airway Disease; Cis-Trans Tests; Clinical Research; Collection; Culture Techniques; Cultured Cells; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; DNA; Data; Diagnosis; Disease; Dissection; Environment; Epithelial Cells; Family; Gene Expression; Genes; Genetic; Genetic Risk; Genetic Transcription; Genome; Genomics; Genotype; Goals; Hereditary Disease; Heritability; Homozygote; Human; In Vitro; Individual; Joints; Lead; Life; Lung; Lung diseases; Lymphocyte; Maps; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Mutation; Nasal Epithelium; Nature; Neonatal Screening; Organ; Outcome; Outcome Study; Patients; Phenotype; Play; Population; Positioning Attribute; Pulmonary Cystic Fibrosis; RNA; Reporting; Research; Research Activity; Risk; Role; Sample Size; Sampling; Severities; Severity of illness; Structure of respiratory epithelium; Testing; Therapeutic Intervention; Time; Tissue-Specific Gene Expression; Transcript; Twin Multiple Birth; Twin Studies; Validation; Variant; base; biological research; case control; cell type; cystic fibrosis patients; design; genetic variant; genome wide association study; lymphoblastoid cell line; molecular phenotype; mortality; novel; prognostic; small hairpin RNA; trait; validation studies

DESCRIPTION (provided by applicant): Cystic fibrosis (CF) is a monogenic genetic disorder caused by mutations in CFTR, and respiratory disease is the major cause of morbidity and mortality. The median age of survival in CF is only 37 years, but there is a broad range of disease severity in the lung, even among patients with identical CFTR genotypes, including ?F508 homozygotes. Robust twin/sib studies conclude that genetic factors must play a critical role in disease severity. Two transformational studies of twins and sibs assessed environmental versus genetic influences, and both concluded that genetic factors play a major, or even majority, role in lung disease severity, and heritability estimates ranged from 0.54 to 0.89. Early candidate gene studies to identify CF modifiers were limited by small sample size and poorly defined phenotypes. These limitations have been addressed by a North American CF Genetic Consortium, which includes study groups at UNC/CWRU, Johns Hopkins, and Toronto. Genetic Modifier Consortium patients are now being tested in a whole-genome scan (Illumina 610K Quad). This RFA now provides the opportunity to study the role of gene expression variation in CF lung disease, and the integrated analysis of SNPs/CNVs and expression data. This project holds great promise for defining a robust molecular phenotype for CF lung disease, and we will be uniquely positioned to develop an integrated view of molecular mechanisms underlying CF lung disease severity. Since most CF patients are now diagnosed by neonatal screening, each CF patient could have a molecular signature, and associated risk, established early in life. Taken together, expression data and whole genome SNP data in the same CF patients are likely to spawn a variety of biological and clinical research activity in CF (and other) lung diseases, and provide unprecedented opportunities for novel prognostic and therapeutic interventions in CF. The identification of molecular mechanisms relevant to lung disease severity in CF is also likely to be relevant to more common lung diseases, such as asthma and COPD, as has already been shown for variants and differential gene expression in TGF¿1.

描述(申请人提供)：囊性纤维化(CF)是一种单基因遗传病，由CFTR突变引起，呼吸系统疾病是发病率和死亡率的主要原因。CF患者的平均存活年龄只有37岁，但肺部的疾病严重程度范围很广，即使在CFTR基因相同的患者中也是如此，包括？F508纯合子。强有力的双胞胎/同胞研究得出结论，遗传因素在疾病严重程度中肯定起着关键作用。两项针对双胞胎和兄弟姐妹的变革性研究评估了环境和遗传因素的影响，两项研究都得出结论，遗传因素在肺部疾病严重程度中发挥着主要甚至大多数作用，遗传力估计在0.54到0.89之间。早期的候选基因研究因样本量小和表型定义不明确而受到限制。北美CF基因联盟已经解决了这些限制，该联盟包括北卡罗来纳大学/CWRU、约翰·霍普金斯大学和多伦多的研究小组。遗传修饰剂联盟患者现在正在接受全基因组扫描(Illumina 610K Quad)测试。这种RFA为研究基因表达变异在慢性肺疾病中的作用，以及对SNPs/CNV和表达数据的综合分析提供了机会。该项目为确定CF肺疾病的分子表型提供了极大的希望，我们将独一无二地发展一种完整的关于CF肺疾病严重程度的分子机制的观点。由于大多数CF患者现在都是通过新生儿筛查来诊断的，每个CF患者都可能在生命早期就有一个分子标记和相关的风险。综上所述，在同一个CF患者中的表达数据和全基因组SNP数据可能会在CF(和其他)肺部疾病中产生各种生物学和临床研究活动，并为CF的新的预后和治疗干预提供前所未有的机会。与肺疾病严重程度相关的分子机制的鉴定也可能与更常见的肺部疾病相关，如哮喘和COPD，正如已经在转化生长因子1中的变异和差异基因表达中所显示的那样。