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The Genetics of Pulmonary Fibrosis

Mark P. Steele, MD Associate Professor of Medicine Pulmonary, Allergy, and Critical Care Duke University Medical Center. The Genetics of Pulmonary Fibrosis. Idiopathic Pulmonary Fibrosis (IPF). Onset between 50 and 70 years of age Progressive shortness of breath and hypoxemia

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The Genetics of Pulmonary Fibrosis

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  1. Mark P. Steele, MD Associate Professor of Medicine Pulmonary, Allergy, and Critical Care Duke University Medical Center The Genetics of Pulmonary Fibrosis

  2. Idiopathic Pulmonary Fibrosis (IPF) Onset between 50 and 70 years of age Progressive shortness of breath and hypoxemia Median survival is 3-5 years and untreatable Environmental lung disease - cigarette smoke, asbestos, silica, beryllium, tungsten carbide, avian antigens, and molds

  3. Idiopathic Interstitial Pneumonia (IIP) RB-ILD: Respiratory Bronchiolitis Interstitial Lung Disease IPF: Idiopathic Pulmonary Fibrosis (IPF) NSIP: Nonspecific Interstitial Pneumonia AIP: Acute Interstitial Pneumonia DIP: Desquamative Interstitial Pneumonia COP: Cryptogenic Organizing Pneumonia LIP: Lymphocytic Interstitial Pneumonia

  4. 51 49 52 50 53 60 58 60 Genetic Basis of Pulmonary Fibrosis • Familial pulmonary fibrosis appears to be inherited as an autosomal dominant trait with variable penetrance • Pulmonary fibrosis is associated with specific complex genetic disorders and autoimmune diseases • Variable susceptibility to fibrogenic agents is evident among workers and laboratory animals Marshall. Thorax 2000; 55:143 Raghu. Sem Respir Med 1993; 14:323

  5. Search for Genes in Pulmonary Fibrosis • Gene expression studies • Linkage studies

  6. Search for Genes in Pulmonary Fibrosis • Gene expression studies – total genomic response to identify pathogenic genes IN LUNG. • Linkage studies

  7. Gene Expression Profiling of FPF Specimens Yang. A83 Mini-Symposium • Microarray • Whole human genome array (44k probes, 41k genes/ESTs) • 25 genes, 114 EST clusters, and 370 singleton ESTs in the “FPF critical region” on Chromosome 10 • Samples of Lung Tissue • surgical lung biopsy, transplant, or autopsy • 9 normal controls • 16 sporadic IIP (14 UIP and 2 NSIP) • 10 FPF (6 UIP and 4 NSIP) Mark Steele Jordan Savov Ivana Yang

  8. Study Group Histology Normal (n=9) Sporadic IIP (n=16) FPF (n=10) Normal (n=9) UIP (n=20) NSIP (n=6) Disease vs. Normal 135 transcripts 5% FDR (SAM) > 1.8 fold change

  9. Growth factors Cell adhesion Cell prolif/death Chemokines ECM FPF Candidate Genes (n=62) [Genes with FPF/sporadic IIP > 1.8] CXCR4 is the receptor for CXCL12

  10. The Search for Genes in Pulmonary Fibrosis • Gene expression studies • Linkage studies – genomic screen to identify regions of DNA (loci) that contain a gene or genes that predispose individuals to develop pulmonary fibrosis

  11. Linkage Analysis: Segregation Analysis 1 2 2 2 1 2 2 2 12 2 2 22 12 12 12 22 22 22

  12. Linkage Analysis: Strategies for Segregation Analysis • More and Larger Pedigrees • More chromosome markers • N=1000 microsatellite • N= 300,000 SNPs

  13. FPF 10 cM 1 cM Candidate loci Candidate genes + Genome-Wide Markers • STRPs • Gene-based Linkage Analysis • Identified > 350 families over the past 5 years • 114 Familes phenotyped • 83 Families phenotyped and genotyped

  14. Diagnosis of Pulmonary Fibrosis [IPF/UIP, NSIP, COP, RB-ILD, DIP, and AIP] • Possible IIP – suggestive CXR with no additional confirmatory tests • Probable IIP – HRCT scan with reticular or ground glass opacities with either class 2 dyspnea or DLCO < 80% • Definite IIP – surgical lung biopsy or autopsy ATS/ERS. Am J Respir Crit Care Med 2000;161:646 ATS/ERS. Am J Respir Crit Care Med 2002;165:277

  15. 714 Family Members Self-Report 418 Unaffected 296 Affected 28 356 34 Consensus Diagnosis 356 Unaffected 34 Possible 28 Probable/Definite Phenotype of 114 Families

  16. 714 Family Members Self-Report 418 Unaffected 296 Affected Accuracy of Self Report 87% Phenotype of 114 Families 28 3 25 268 356 34 Consensus Diagnosis 359 Unaffected 59 Possible 296 Probable/Definite

  17. Type of Idiopathic Interstitial Pneumonia [IPF/UIP, NSIP, COP, RB-ILD, DIP, and AIP] • 68 (60%) families had uniform IPF/UIP • 46 (40%) families had more than one type of IIP • 82% Idiopathic Pulmonary Fibrosis (UIP) • 6% Non-specific Interstitial Pneuomonia • 2% Cryptogenic Organizing Pneumonia • 1% Respiratory Bronchiolitis-ILD • 9% Unclassifiable ILD

  18. Number of Subjects Age at Onset Risk Factors for FPF [IPF, NSIP, COP, RB-ILD, DIP, and AIP] • Age of onset highly correlated among sibs • Older age (68 years vs 53 years; P<0.001) • Male gender (56% vs 37%; P=0.004) • Cigarette smoking (68% vs 34%; ORadj= 3.6 [1.3-9.8]; P<0. 01) Steele. Am J Resp Crit Care Med 2005; 172:1146

  19. Epidemiology of FPF [IPF, NSIP, COP, RB-ILD, DIP, and AIP] • Autosomal dominant pattern - vertical transmission with male to male inheritance • Cigarette smoking enhances the risk of transmission • Phenotypic heterogeneity of IIP suggests that tobacco smoke (or other exposures) may initiate common pathogenic mechanisms that place individuals at risk for IIPs Steele. Am J Resp Crit Care Med 2005; 172:1146

  20. Histopathology of FIP The most common diagnosis is an unclassifiable chronic fibrosing interstitial pneumonia with septal fibrosis, fibroblast and smooth muscle proliferation and honeycombing that may be diffuse or sub-pleural. ATS 2006: A242

  21. LOD Score cM (recombinant distance) Genomic Screen on 83 Families with FPF [1100 markers  5 cM; 242 affected individuals] Mark Steele Marcy Speer Nell Burch Anastasia Wise Jim Loyd Kevin Brown Marvin Schwarz Hakon Hakonarson

  22. Chr11 Fine Map in 83 Families with FPF Multipoint LOD = 3.5 LOD Score cM (recombinant distance) on Chr 11

  23. Chr11 SNP Map for FPF and IPF [150 FPF, 167 IPF, and 237 Controls]

  24. LOD Score cM (recombinant distance) Genomic Screen on 83 Families with FPF [1100 markers  5 cM] LOD = 2.1 LOD = 3.5 Mark Steele Marcy Speer Nell Burch Anastasia Wise Jim Loyd Kevin Brown Marvin Schwarz Hakon Hakonarson

  25. Influence of Loci on Chr10 and Chr11 Chr10 Chr11 26 Families 17 Both 25 Families • Younger • Smokers • Nonsmokers

  26. 36 Families – 100% affected smoke Influence of Smoking on Chr10 LOD LOD = 3.0 LOD Score cM (recombinant distance)

  27. Future Research Approaches • Determine whether SNPs in Chr11 candidate gene map with disease in families • Identify Chr11 gene variants in founder population and other IIPs • Genotype and sequence all candidates in Chr10 region • Focus on unique phenotypes (rapid progressors and early disease) 3 million base pairs

  28. Search for Genes in Pulmonary Fibrosis: Summary • Gene expression studies • novel genes potentially involved in pathogenesis (CXCR4, CXCL12, tenacin C, osteopontin, MMPs, cathepsin G, etc) • FPF is quite different than sporadic IIP • UIP and NSIP appear somewhat similar • Linkage studies • Chr 11 and Chr10 looks promising • Evidence for gene by environment interaction • Phenotypic heterogeneity suggests common pathogenic mechanisms place individuals at risk for IIPs

  29. Genetic Determinants of Familial Pulmonary Fibrosis David David Schwartz Mark Steele Marcy Speer Aretha Herron Susan Slifer Frank Zhao Jordan Savov Ivana Yang Kevin Brown Marvin Schwarz Jim Loyd Gunner Gudmunson Hakon Hakonarson Nell Burch Tony Church Hadley Hartwell Zareen Kapadia Jason Thacker

  30. A Special Thank You To all the family members Without whom This would not be possible. Genetic Determinants of Familial Pulmonary Fibrosis

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