Genetic Modifiers of CF: Sibling Study

CF 的遗传修饰：兄弟姐妹研究

• 批准号: 7589744
• 负责人: Garry R Cutting
• 金额: $ 78.65万
• 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/7589744
• 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性疾病，由 CFTR 基因突变引起。该疾病表现为气道表面液体异常导致的进行性阻塞性肺病和外分泌胰腺功能不全导致的慢性营养不良。 CF患者的生存率与肺部疾病的严重程度和营养不良的程度高度相关。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有重大影响的性状变异的根本原因。为此，我们发起了 CF 双胞胎和兄弟姐妹研究，以确定遗传因素对独立于 CFTR 基因型的性状变异的影响程度。对超过 600 个患有 CF 的双胞胎或兄弟姐妹的家庭进行的分析表明，修饰基因是肺部疾病严重程度（通过肺功能测试测量（遗传力估计为 0.6-0.8））和营养不良（通过营养状况测量（遗传力估计为 0.5-0.9）测量）差异的基础。 ）。对部分家族的 10cM 短串联重复扫描已识别出这些性状的几个暗示性连锁区域（LOD 分数 >2.0）。有趣的是，肺功能和营养状况的几个连锁区域是一致的，这与这两个数量性状之间密切关系的临床观察结果一致。该应用的总体目标是确定改变 CF 患者肺功能和营养状况的基因。这一目标将通过追求以下目标来实现： 目标 1. 确认和细化肺功能和营养状况的联系区域。目标 2. 鉴定连锁峰内导致 CF 患者肺功能和/或生长差异的遗传变异。目标 3. 通过前瞻性纵向分析完善对遗传和非遗传因素对 CF 表型变异的贡献的估计。