Molecular Phenotypes for Cystic Fibrosis Lung Disease

描述（申请人提供）：囊性纤维化（CF）是由CFTR突变引起的单基因遗传性疾病，呼吸系统疾病是发病和死亡的主要原因。CF的中位生存年龄仅为37岁，但即使在具有相同CFTR基因型的患者中，肺部疾病的严重程度也有很大范围，包括？F508纯合子。强有力的双胞胎/同胞研究得出结论，遗传因素必须在疾病严重程度中发挥关键作用。两项关于双胞胎和同胞的转化研究评估了环境与遗传的影响，两项研究都得出结论，遗传因素在肺部疾病的严重程度中起主要作用，甚至是大多数作用，遗传度估计值为0.54至0.89。早期的候选基因的研究，以确定CF修改器是有限的小样本量和定义不明确的表型。这些局限性已经由北美CF遗传联盟解决，该联盟包括在芝加哥/CWRU，约翰霍普金斯和多伦多的研究小组。遗传修饰剂联盟的患者现在正在接受全基因组扫描（Illumina 610 K Quad）的测试。该RFA现在提供了研究基因表达变异在CF肺病中的作用以及SNP/CNV和表达数据的综合分析的机会。该项目为CF肺病定义一个强大的分子表型提供了很大的希望，我们将独特地定位于开发CF肺病严重程度相关分子机制的综合观点。由于大多数CF患者现在都是通过新生儿筛查诊断的，因此每位CF患者都可能在生命早期就确定了分子特征和相关风险。总而言之，同一CF患者的表达数据和全基因组SNP数据可能会引发CF（和其他）肺部疾病的各种生物学和临床研究活动，并为CF的新型预后和治疗干预提供前所未有的机会。与CF中肺部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，例如哮喘和COPD，如已经显示的TGF β 1的变体和差异基因表达。

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.