Genetic and Epigenetic Changes in MUC5B and Fibrosing Interstitial Lung Disease

描述（由申请人提供）： 总结/摘要：这项研究建立在我们最近的观察基础上，即MUC 5 B启动子和香烟烟雾中的一种常见多态性与家族性间质性肺炎（FIP）和特发性肺纤维化（IPF）的发生密切相关。我们以前已经发现，在E2例IIP的家庭中，FIP的发展受到吸烟的强烈影响。最近，利用连锁、精细定位和关联，我们发现了MUC 5 B启动子区的一个共同多态性（rs35705950）与家族性间质性肺炎（FIP）（P=1.2x10-15）和特发性肺纤维化（IPF）（P= 2.5 × 10 ~（-37））;该SNP的稀有等位基因杂合子和纯合子受试者的疾病优势比为6.8（95% CI 3.9-12.0）和20.8（95% CI 3.8-113.7），IPF为9.0（95% CI 6.2-13.1）和21.8（95% CI 5.1-93.5）。此外，肺中MUC 5 B基因表达在IPF受累受试者中比未受累受试者高14.1倍（P=0.0001），MUC 5 B的变体启动子等位基因与肺MUC 5 B基因表达在未受累（但未受累）受试者中的上调相关（37.4倍; P=0.0003），并且MUC 5 B蛋白在IPF的病理性病变中表达。 在这项提案中，我们计划将重点放在MUC 5 B的遗传和表观遗传变异，香烟烟雾和几种类型的纤维化间质性肺病（fILD），以确定为什么只有一些具有MUC 5 B启动子多态性的个体发生肺纤维化。尽管相当一部分患有FIP或IPF的受试者携带MUC 5 B启动子SNP的罕见等位基因（59%的FIP和60-67%的IPF），但大约1/3患有FIP或IPF的受试者是MUC 5 B启动子SNP的野生型。此外，一般人群中具有这种常见SNP的大多数个体（存在于19-20%的对照中）不会发生肺纤维化。我们还发现，无论MUC 5 B启动子SNP如何，受IPF影响的受试者的肺中MUC 5 B基因表达均升高，表明MUC 5 B过表达是IPF发病机制中的常见机制。由于其他人已经报道了MUC 5 B的表达受到MUC 5 B启动子甲基化的强烈影响，因此推测MUC 5 B启动子甲基化的缺失可能会增强MUC 5 B表达并影响那些不携带MUC 5 B启动子SNP的罕见等位基因甲基化的肺纤维化受试者中MUC 5 B MUC 5 B肺纤维化的发展是合乎逻辑的。或者，超甲基化变异标志物可以保护那些具有MUC 5 B启动子SNP的人免于发展IPF。推动拟议研究的总体概念是，由遗传、表观遗传或环境因素引起的MUC 5 B过表达纤维化增强了ILD和发生纤维化间质性肺病的风险。因此，我们假设ExMpUreCs 5sBion，MUC 5 B中的基因变异（除rs35705950外）、MUC 5 B启动子中的甲基化变化和/或香烟烟雾暴露影响MUC 5 B的表达，并与纤维化间质性肺病（fILD）的香烟发展相关。右边的烟雾暴露图说明了我们研究这一假设的方法。目标1目标2目标3目标3目标3

DESCRIPTION (provided by applicant): Summary/Abstract: The proposed research builds on our recent observations that a common polymorphism in the promoter of MUC5B and cigarette smoke are strongly associated with the development of both familial interstitial pneumonia (FIP) and idiopathic pulmonary fibrosis (IPF). We have previously found that within families with e 2 cases of IIP, the development of FIP is strongly influenced by cigarette smoking. More recently, using linkage, fine mapping, and association, we have discovered a common polymorphism in the promoter region of MUC5B (rs35705950) that is associated with both familial interstitial pneumonia (FIP) (P=1.2x10-15) and idiopathic pulmonary fibrosis (IPF) (P=2.5x10-37); odds ratios of disease for subjects heterozygous and homozygous for the rarer allele of this SNP were 6.8 (95% CI 3.9-12.0) and 20.8 (95% CI 3.8-113.7) for FIP, and 9.0 (95% CI 6.2-13.1) and 21.8 (95% CI 5.1-93.5) for IPF. Moreover, MUC5B gene expression in the lung was 14.1 fold higher in IPF affected subjects versus unaffected subjects (P=0.0001), the variant promoter allele of MUC5B was associated with upregulation in lung MUC5B gene expression among unaffected (but not affected) subjects (37.4-fold; P=0.0003), and MUC5B protein was expressed in pathologic lesions of IPF. In this proposal, we plan to focus on genetic and epigenetic variants of MUC5B, cigarette smoke, and several types of fibrosing interstitial lung disease (fILD) to determine why only some individuals with the MUC5B promoter polymorphism develop pulmonary fibrosis. Although a substantial portion of subjects with FIP or IPF carry the rare allele of the MUC5B promoter SNP (59% of FIP and 60-67% of IPF), approximately 1/3 of subjects with either FIP or IPF are wild type for the MUC5B promoter SNP. Moreover, most individuals in the general population with this common SNP (present in 19-20% of controls) do not develop pulmonary fibrosis. We have also found that MUC5B gene expression in the lung of IPF affected subjects was elevated irrespective of the MUC5B promoter SNP, suggesting MUC5B overexpression is a common mechanism in the pathogenesis of IPF. Since others have reported that expression of MUC5B is strongly influenced by methylation of the MUC5B promoter, it is logical to speculate that loss of methylation in the MUC5B promoter may enhance MUC5B expression and influence the development of MUC5B MUC5B pulmonary fibrosis in those subjects with pulmonary fibrosis that do not carry Gene Methylation the rare allele of the MUC5B promoter SNP. Alternatively, hypermethylation Variants Marks may protect those with the MUC5B promoter SNP from developing IPF. The overall concept driving the proposed research is that MUC5B overexpression Fibrosing caused by either genetic, epigenetic, or environment factors enhances the ILD and risk of developing fibrosing interstitial lung disease. Thus, we hypothesize ExMpUreCs5sBion that gene variants in MUC5B (in addition to rs35705950), methylation changes in the promoter of MUC5B, and/or cigarette smoke exposure affect the expression of MUC5B and are associated with the Cigarette development of fibrosing interstitial lung disease (fILD). The figure on Smoke Exposure the right illustrates our approach to study this hypothesis. Aim 1 Aim 2 Aim 3 Aim 3 Aim 3