Idiopathic Pulmonary Fibrosis - from Epidemiology to Gene Mapping

.......................................................................................................................................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