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
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 and idiopathic pulmonary fibrosis - two common types of fibrosing interstitial lung disease (fILD). While substantial progress has been made in understanding the clinical, radiological, and pathological manifestations of fILD, it remains difficult for the cliniian to predict the clinical course or the response to therapy for the subtypes of fILD, particularly from individual to individual with the same diagnosis. The goal of this proposal is to focus on genetic and epigenetic variants of MUC5B, cigarette smoke, and several types of fILD to determine why only some individuals with the MUC5B promoter polymorphism develop pulmonary fibrosis. Once established, this new knowledge should enhance early detection, predict outcome, develop biomarkers, and design personalized therapeutic strategies.
| Monte, Andrew A; Sun, Hao; Rapp-Olsson, Anna Malin et al. (2018) The Plasma Concentration of MUC5B Is Associated with Clinical Outcomes in Paraquat-poisoned Patients. Am J Respir Crit Care Med 197:663-665 |
| Putman, Rachel K; Gudmundsson, Gunnar; Araki, Tetsuro et al. (2017) The MUC5B promoter polymorphism is associated with specific interstitial lung abnormality subtypes. Eur Respir J 50: |
| Manichaikul, Ani; Sun, Li; Borczuk, Alain C et al. (2017) Plasma Soluble Receptor for Advanced Glycation End Products in Idiopathic Pulmonary Fibrosis. Ann Am Thorac Soc 14:628-635 |
| Mathai, Susan K; Newton, Chad A; Schwartz, David A et al. (2016) Pulmonary fibrosis in the era of stratified medicine. Thorax 71:1154-1160 |
| Chung, Jonathan H; Peljto, Anna L; Chawla, Ashish et al. (2016) CT Imaging Phenotypes of Pulmonary Fibrosis in the MUC5B Promoter Site Polymorphism. Chest 149:1215-22 |
| Araki, Tetsuro; Putman, Rachel K; Hatabu, Hiroto et al. (2016) Development and Progression of Interstitial Lung Abnormalities in the Framingham Heart Study. Am J Respir Crit Care Med 194:1514-1522 |
| Mathai, Susan K; Pedersen, Brent S; Smith, Keith et al. (2016) Desmoplakin Variants Are Associated with Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 193:1151-60 |
| Nakano, Yasushi; Yang, Ivana V; Walts, Avram D et al. (2016) MUC5B Promoter Variant rs35705950 Affects MUC5B Expression in the Distal Airways in Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 193:464-6 |
| Mathai, Susan K; Schwartz, David A (2015) Taking the ""I"" out of IPF. Eur Respir J 45:1539-41 |
| Yang, Ivana V; Pedersen, Brent S; Liu, Andrew et al. (2015) DNA methylation and childhood asthma in the inner city. J Allergy Clin Immunol 136:69-80 |
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