Genetic Modifiers of CF: Sibling Study

CF 的遗传修饰：兄弟姐妹研究

• 批准号: 7261443
• 负责人: Garry R Cutting
• 金额: $ 81.37万
• 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/7261443
• 关键词: Affect; Age of Onset; Biological; Candidate Disease Gene; Chronic; Class; Clinical; Clinical Data; Collection; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; DNA; Diabetes Mellitus; Disease; Disease regression; 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; 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）是由CFTR基因突变引起的高度可变但不可避免的致命疾病。由于胰腺胰腺胰腺不足，由于气道表面液体异常和慢性营养不良，该疾病表现为进行性阻塞性肺部疾病。 CF患者的存活与肺部疾病的严重程度和营养不良程度高度相关。尽管CFTR基因型可以预测CF表型的某些方面，但我们仍在尝试了解对生存具有显着影响的性状变化的根本原因。为此，我们启动了CF双胞胎和同胞研究，以确定与CFTR基因型无关的遗传因素导致性状变异性的程度。分析超过600个受CF影响的双胞胎或兄弟姐妹的家族的分析表明，通过肺功能测试（遗传力估计为0.6-0.8）和营养不良（通过遗传性估计估计0.5-0.9）来衡量的肺部疾病严重程度的变化是肺部疾病严重程度的差异。对一部分家庭的一个短串联重复扫描已确定了这些特征的几个暗示性联系（LOD得分> 2.0）的区域。有趣的是，肺功能和营养状况的几个连锁区是一致的，这与对这两个定量性状之间紧密关系的临床观察一致。该应用的总体目标是确定CF患者改变肺功能和营养状况的基因。追求以下目标将实现此目标：目标1。确认并完善肺功能和营养状况的连锁区域。目的2。确定连锁峰内的遗传变异，这有助于CF患者的肺功能和/或生长。目的3。通过前瞻性纵向分析来完善遗传和非遗传因素对CF表型变异的贡献的估计。