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​​Genetics and Genomics of Pulmonary Fibrosis

Pulmonary fibrosis is a general term used to describe the group of fibrosing interstitial lung diseases that are characterized by progressive scarring of the alveolar interstitium, often leading to hypoxemic respiratory insufficiency. Pulmonary fibrosis can result from environmental exposures, or occur as an isolated, sporadic disease without extrapulmonary involvement (idiopathic interstitial pneumonia or IIP). IIPs are composed of several subtypes of pulmonary diseases that differ in clinical, radiographic, and histopathologic presentation; while some have a constellation of specific features that allows a clear diagnosis to be made, all too frequently the type of IIP can’t be characterized and many of the subtypes of IIP have overlapping clinical and laboratory features indicating that the current definitions remain too broad. There is also emerging evidence that the development of all forms of interstitial lung disease is, at least in part, determined by genetic factors.

Our pulmonary fibrosis research seeks to uncover the genetic and environmental determinants of IIP.Our ongoing effort to establish the etiology of this complex human disease involves a linkage study in 200 families, a GWAS in 2000 individuals with IIP, high-throughput resequencing and genotyping, whole genome sequencing, gene expression and miRNA profiling, and defining the IIP methylome.Our ultimate goal is to identify candidate susceptibility genes, explore relationships between specific environmental exposures and candidate susceptibility genes, and define the unique molecular phenotypes in pulmonary fibrosis.

We have recently discovered a common variant in the promoter region of MUC5B that has a profound effect in the risk of developing either familial or sporadic forms of IIP in two independent cohorts.

Click the image to See Figure 1
Figure 1

We are investigating the role MUC5B plays in the development of pulmonary fibrosis by pursuing several lines of investigation:

  1. Identification of additional genetic (common and rare) and epigenetic variants of MUC5B and the influence of cigarette smoke in several types of fibrosing interstitial lung disease (fILD) to determine why only some individuals with the MUC5B promoter polymorphism develop pulmonary fibrosis.

  2. We are also continuing to perform genetic screens to identify other genetic risk factors for pulmonary fibrosis. We are using next generation sequencing and genotyping to identify polymorphisms in lungs of individuals with pulmonary fibrosis. We are taking several complementary approaches.

Click the image to See Figure 2
Figure 2

Our previous work in genomic signatures of IPF demonstrated that genetics influences gene expression profiles in IIP, and identified a gene expression signature that predicts prognosis in IPF. More recently, we identified a strong molecular signature associated with the expression of cilium genes that separates IPF into two subtypes, one with increased cilium gene expression and one with low expression of cilium genes. The cilium gene expression signature was associated with microscopic honeycombing and was also predictive of survival in an independent cohort of subjects with IPF.

To examine genomic changes in DNA methylation in IPF, we recently used the Comprehensive High-throughput Arrays for Relative Methylation (CHARM) method to collect genomewide methylation profiles on DNA isolated from the lungs of 100 IPF and 79 nondiseased control subjects. This project is a part of the Lung Genomics Research Consortium (

Click the image to See Figure 3
Figure 3
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Figure 4










Selected Pulmonary Fibrosis Publications 

  1. Seibold MA, Wise AL, Speer MC, Steele MP, Brown KK, Loyd JE, Fingerlin TE, Zhang W, Gudmundsson G, Groshong SD, Evans CM, Garantziotis S, Adler KB, Dickey BF, du Bois RM, Yang IV, Herron A, Kervitsky D, Talbert JL, Markin C, Park J, Crews AL, Slifer SH, Auerbach S, Roy MG, Lin J, Hennessy CE, Schwarz MI, and Schwartz DA.A common polymorphism in the putative promoter of MUC5B is associated with familial interstitial pneumonia (FIP) and idiopathic pulmonary fibrosis (IPF). N Engl J Med. 2011; 364:1503-12

  2. Boon K, Bailey NW, Yang, J, Steele MP, Groshong S, Yang J, Kervitsky D, Brown KK, Schwarz MI, Schwartz DA. Molecular phenotypes distinguish patients with relatively stable from progressiveIdiopathic Pulmonary Fibrosis (IPF). PLoS ONE 2009; 4:e5134.

  3. Garantziotis S, Zudaire E, Trempus CE, Hollingsworth JW, Jiang D, Lancaster LH, Richardson E, Zhuo L, Cuttitta F, Brown KK, Noble PW, Kimata K, Schwartz DA.Serum inter-alpha-trypsin inhibitorand matrix hyaluronon promote angiogenesis in fibrotic lung injury. Am J Resp Crit Care Med 2008; 178:939-947.

  4. Yang IV, Burch LH, Steele MP, Savov JD, Hollingsworth JW, McElvaniaTekippe E, Berman KG, Speer MC, Sporn TA, Brown KK, Schwarz MI, Schwartz DA.Gene Expression Profiling of Familial and Sporadic Cases of Interstitial Pneumonia.Am J Resp Crit Care Med 2007; 175:45-54.

  5. Steele MP, Speer MC, Loyd JE, Brown KK, Herron A, Slifer SH, Burch LH, Phillips JA, Sporn TA, McAdams HP, Schwarz MI, Schwartz DA. Clinical and pathologic features of familial interstitial pneumonia (FIP).Am J Resp Crit Care Med 2.005; 172:1146-1152.