Genetic Modifiers of CF: Sibling Study

CF 的遗传修饰：兄弟姐妹研究

• 批准号: 7792331
• 负责人: Garry R Cutting
• 金额: $ 74.14万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7792331
• 关键词: Affect; Age of Onset; Biological; Candidate Disease Gene; Chronic; Clinical; Clinical Data; Collection; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; DNA; Diabetes Mellitus; Disease; Exocrine pancreatic insufficiency; Family; Foundations; Functional disorder; Gene-Modified; Genes; Genetic; Genetic Variation; Genotype; Goals; Growth; Heritability; Heritable Quantitative Trait; Human Genome; Lod Score; Lung diseases; Malnutrition; Measures; Medical Records; Methods; Mutation; Neurofibromin 2; Nutritional status; Obstructive Lung Diseases; Parents; Patients; Phenotype; Principal Investigator; Pulmonary function tests; Recruitment Activity; Registries; Respiratory physiology; Scanning; Severities; Severity of illness; Short Tandem Repeat; Siblings; Single Nucleotide Polymorphism; Testing; Twin Multiple Birth; Variant; airway surface liquid; cystic fibrosis patients; density; genetic linkage analysis; genetic variant; longitudinal analysis; non-genetic; patient registry; prospective; trait; transmission process

DESCRIPTION (provided by applicant): Cystic fibrosis (CF) is a highly variable but inevitably fatal disorder caused by mutations in the CFTR gene. The disease manifests as progressive obstructive lung disease due to abnormalities in airway surface liquid and chronic malnutrition due to exocrine pancreatic insufficiency. Survival of CF patients is highly correlated with the severity of lung disease and degree of malnutrition. Although CFTR genotype is predictive of some aspects of the CF phenotype, we are still trying to understand the underlying causes of variation in traits that have significant effect upon survival. To this end, we initiated the CF Twin and Sibling Study to determine the degree to which genetic factors contribute to trait variability independent of CFTR genotype. Analysis of over 600 families with twins or siblings affected with CF reveal that modifier genes underlie variation in lung disease severity, as measured by pulmonary function testing (heritability estimates 0.6-0.8) and malnutrition, as measured by nutritional status (heritability estimates 0.5-0.9). A 10cM short tandem repeat scan of a subset of families has identified several regions of suggestive linkage (LOD scores >2.0) for these traits. Intriguingly, several of the linkage regions for lung function and nutritional status coincide, consistent with the clinical observation of a close relationship between these two quantitative traits. The overall goal of this application is to identify the genes that modify lung function and nutritional status in CF patients. This goal will be achieved by pursuit of the following aims: Aim 1. To confirm and refine regions of linkage for lung function and nutritional status. Aim 2. To identify genetic variants within linkage peaks that contribute to variance in lung function and/or growth in CF patients. Aim 3. To refine estimates of the contribution of genetic and non-genetic factors to variation in CF phenotypes by prospective longitudinal analysis.

描述（由申请人提供）：囊性纤维化（CF）是一种高度可变但不可避免的致命疾病，由CFTR基因突变引起。这种疾病表现为由于气道表面液体异常和由于胰腺外分泌功能不全引起的慢性营养不良而导致的进行性阻塞性肺病。CF患者的生存率与肺部疾病的严重程度和营养不良程度高度相关。虽然CFTR基因型可以预测CF表型的某些方面，但我们仍在试图了解对生存有显著影响的性状变异的根本原因。为此，我们启动了CF双胞胎和同胞研究，以确定遗传因素在多大程度上有助于独立于CFTR基因型的性状变异。对600多个患有CF的双胞胎或兄弟姐妹家庭的分析表明，修饰基因是肺部疾病严重程度变化的基础，如肺功能测试（遗传力估计为0.6-0.8）和营养不良，如营养状况（遗传力估计为0.5-0.9）。一个10 cM的短串联重复序列扫描的一个子集的家庭已经确定了几个区域的暗示连锁（LOD得分>2.0），这些性状。有趣的是，肺功能和营养状况的几个连锁区域一致，与这两个数量性状之间密切关系的临床观察一致。本申请的总体目标是鉴定改变CF患者的肺功能和营养状态的基因。这一目标将通过追求以下目标来实现：目标1。确认并细化肺功能和营养状况的相关区域。目标2.确定导致CF患者肺功能和/或生长变化的连锁峰内的遗传变异。目标3.通过前瞻性纵向分析，精确估计遗传和非遗传因素对CF表型变异的贡献。