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Idiopathic Pulmonary Fibrosis

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Idiopathic Pulmonary Fibrosis Department of Pulmonary Medicine, Helsinki University Central Hospital and Department of Medical Genetics, University of Helsinki IDIOPATHIC PULMONARY FIBROSIS - FROM EPIDEMIOLOGY TO GENE MAPPING Ulla Hodgson Academic dissertation To be publicly discussed with the permission of the Faculty of Medicine, University of Helsinki, in Lecture Hall 4, Meilahti Hospital, Helsinki, on the March 3rd 2006, at 12 noon. Helsinki 2006 Supervised by Docent Tarja Laitinen, M.D., Ph.D. Department of Medical Genetics University of Helsinki Professor Pentti Tukiainen, M.D., Ph.D. Department of Pulmonary Diseases Helsinki University Central Hospital Reviewed by Docent Lauri Tammilehto, M.D., Ph.D. Department of Pulmonary Diseases Jorvi Hospital Helsinki University Central Hospital Docent Markus Perola, M.D., Ph.D. Department of Molecular Medicine National Public Health Institute Official Opponent Professor Leif Groop, M.D., Ph.D. Department of Clinical Sciences/Diabetes & Endocrinology Lund University University Hospital Malmö ISBN 952-91-9839-6 (print) ISBN 952-10-2879-3 (PDF) Yliopistopaino Helsinki 2006 As a well spent day bring happy sleep, So life, well used, bring happy death. Time abides long enough, For those who make use of it. - Leonardo da Vinci - CONTENTS LIST OF ORIGINAL PUBLICATIONS.........................................................................................6 ABBREVIATIONS ............................................................................................................................7 ABSTRACT........................................................................................................................................9 INTRODUCTION............................................................................................................................11 REVIEW OF THE LITERATURE................................................................................................13 1. Idiopathic pulmonary fibrosis.................................................................................................13 1.1 From history to novel classification.....................................................................................13 1.2 Epidemiology.......................................................................................................................14 1.3 Etiology................................................................................................................................15 1.4 Pathological findings............................................................................................................16 1.5 Diagnosis of idiopathic pulmonary fibrosis.........................................................................19 1.6 Treatment .............................................................................................................................21 2. Gene mapping of complex diseases ........................................................................................23 2.1 General.................................................................................................................................23 2.2 Linkage analysis...................................................................................................................24 2.3 Association analysis.............................................................................................................27 2.4 Characteristics of the Finnish population.............................................................................28 3. Genetics of idiopathic pulmonary fibrosis.............................................................................31 3.1 Idiopathic pulmonary fibrosis in families ............................................................................31 3.2 Candidate genes ...................................................................................................................32 3.2.1 Immune response genes ................................................................................................32 3.2.2 Genes in biochemical defence.......................................................................................34 3.3 Mouse models ......................................................................................................................36 AIMS OF THE STUDY...................................................................................................................39 MATERIALS AND METHODS ....................................................................................................40 1. Patient selection........................................................................................................................40 1.1 Identifying idiopathic pulmonary fibrosis patients ..............................................................40 1.2 Family selection for the genome-wide scan and for haplotype association analysis...........40 1.3 Replication data set ..............................................................................................................41 1.4 Patients and controls for association studies on the CR1 and ESCOD genes......................41 2. Diagnostic criteria....................................................................................................................42 3. Genome scan and fine mapping markers and genotyping methods....................................42 4. Genotyping of the Pro1827Arg variant in the CR1 gene .....................................................43 5. Genotyping of the Arg213Gly variant in the ECSOD gene .................................................44 6. Sequencing ................................................................................................................................44 7. mRNA expression.....................................................................................................................45 8. In vitro translation...................................................................................................................46 9. In situ hybridization.................................................................................................................47 10. Statistical analyses .................................................................................................................47 10.1 Linkage analysis.................................................................................................................47 10.2 Power estimations for linkage analysis (simulations)........................................................47 10.3 Association analyses ..........................................................................................................48 RESULTS .........................................................................................................................................49 1. Prevalence.................................................................................................................................49 2. Familial idiopathic pulmonary fibrosis..................................................................................50 3. Genome-wide linkage analysis................................................................................................51 4. Haplotype association analysis on chromosomes 3, 4, 9, 12, and 13....................................53 5. Positional candidate genes.......................................................................................................54 6. Sequencing ................................................................................................................................55 7. Association study on the Pro1827Arg variant in the CR1 gene...........................................56 8. Association study on the Arg213Gly variant in the ESCOD gene.......................................56 DISCUSSION ...................................................................................................................................57 1. Prevalence of idiopathic pulmonary fibrosis.........................................................................57 2. Familial idiopathic pulmonary fibrosis..................................................................................58 3. Identifying novel candidate genomic region for idiopathic pulmonary fibrosis by genome-wide scan combined with hierarchial association study ............................................59 4. Characterization of candidate genes ......................................................................................61 5. Association studies on functional candidate genes CR1 and ECSOD.................................63 CONCLUSIONS ..............................................................................................................................66 ACKNOWLEDGEMENTS.............................................................................................................67 REFERENCES.................................................................................................................................69 ORIGINAL COMMUNICATIONS...............................................................................................82 LIST OF ORIGINAL PUBLICATIONS This thesis is based on the following original publications, which are referred to in the text by their Roman numerals. I Hodgson U, Laitinen T, Tukiainen P. Nationwide prevalence of sporadic and familial idiopathic pulmonary fibrosis: evidence of founder effect among multiplex families in Finland. Thorax 2002;57:338-342. II Hodgson U,
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