title: IDIOPATHIC PULMONARY FIBROSIS IS A COMPLEX GENETIC DISORDER.
abstract: Idiopathic pulmonary fibrosis (IPF) is a complex, heterogeneous genetic disorder that is associated with rare and common sequence variants in many genes (MUC5B,SFTPC,SFTPA2,RTEL1,TERT, andhTR), 11 novel loci, and multiple emerging epigenetic and transcriptional profiles. In the past 5 years, we have found that: 1) genetic risk variants play major and similar roles in the development of both familial and sporadic fibrotic idiopathic interstitial pneumonia, accounting for up to 35% of the risk of idiopathic interstitial pneumonia (a disease that was previously thought to be idiopathic); 2) a promoter variant inMUC5Brs35705950 is the strongest risk factor for the development of IIP and IPF; however, rs35705950 has a low penetrance; and 3) IPF is a complex genetic disease with 11 independent loci contributing to the development of this disease, pronounced changes in DNA methylation, and transcriptional subtypes. In aggregate, these findings suggest that IPF is a heterogeneous disease and that genetic and molecular subtypes of IPF will provide essential clues to disease pathogenesis, prognosis, treatment, and survival, all of which remain major problems in understanding and treating patients with IPF. Although the basic biological mechanisms involved in IPF are emerging, the disease is heterogeneous pathologically and the final common pathways of fibrogenesis are not well understood. These observations lead us to postulate that the etiology and severity/extent of this complex condition will best be understood through an integrated approach that accounts for inherited factors, epigenetic marks, and dynamic changes in the transcriptome.
authors.affiliation: AURORA, COLORADO.
authors.forename: David A
authors.initials: DA
authors.lastname: Schwartz
mesh_terms: D016022:Case-Control Studies; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D055106:Genome-Wide Association Study; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics*; D055257:Mucin-5B / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D059467:Transcriptome
chemical_list: C524578:MUC5B protein, human; D055257:Mucin-5B