Genetic Modifiers of CF: Sibling Study

描述(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。该疾病表现为由于呼吸道表面液体异常引起的进行性阻塞性肺疾病和由于胰腺外分泌功能不全而导致的慢性营养不良。CF患者的生存与肺部疾病的严重程度和营养不良程度密切相关。虽然CFTR型可以预测CF型的某些方面，但我们仍在努力了解对生存有重大影响的性状变异的潜在原因。为此，我们启动了CF双胞胎和兄弟姐妹研究，以确定遗传因素对独立于CFTR型的性状变异的影响程度。对600多个患有CFs的双胞胎或兄弟姐妹家庭的分析表明，通过肺功能测试(遗传率估计为0.6-0.8)和营养不良(遗传率估计为0.5-0.9)衡量的肺部疾病严重程度的差异是由修饰基因造成的。对家系子集进行的10厘米短串联重复扫描已经确定了这些特征的几个暗示连锁的区域(LOD评分和2.0)。有趣的是，肺功能和营养状态的几个连锁区域重合，这与临床观察到的这两个数量性状之间的密切关系一致。这项应用的总体目标是确定改变CF患者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.确认和完善与肺功能和营养状况相关的区域。目的2.确定连锁高峰内的遗传变异对CF患者肺功能和/或生长的影响。目的3.通过前瞻性纵向分析，完善遗传因素和非遗传因素对CF表型变异的贡献估计。

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.