GENETIC STUDIES ON FINNISH LUPUS ERYTHEMATOSUS PATIENTS WITH CUTANEOUS MANIFESTATIONS

14 TIIVISTELMÄ . 16 INTRODUCTION . 18 REVIEW OF THE LITERATURE . 19 1 Structure of the skin . 19 2 Historical aspects of cutaneous lupus erythematosus . 19 3 Classification and nomenclature of lupus erythematosus . 19 3.1 Cutaneous lupus erythematosus . 20 3.2 Systemic lupus erythematosus . 21 3.3 Diagnosis . 22 4 Clinical and histopathological features . 23 4.1 Discoid lupus erythematosus . 23 4.2 Subacute cutaneous lupus erythematosus . 23 4.3 Acute cutaneous and systemic lupus erythematosus . 23 4.4 Characteristic histopathology . 24 5 Laboratory findings. 24 5.1 Haematological features . 24 5.2 Autoantibodies . 24 6 Other clinical manifestations . 26 7 Quality of life . 26 8 Treatment for cutaneous lupus erythematosus . 26 9 Prevalence and incidence . 27 10 Aetiology . 27 10.1 The female gender . 28 10.2 Environmental triggering factors . 28 10.2.1 Smoking . 29 10.3 Ultraviolet light. 29 10.3.1 Photosensitivity . 30 10.4 Apoptosis . 30 11 Pathogenesis . 31 11.1 Pathogenesis of cutaneous lupus erythematosus . 31 11.2 Pathogenesis of systemic lupus erythematosus . 33 11.3 Type 1 interferons . 33 11.3.1 Type 1 interferons in cutaneous lupus erythematosus. 33 12 Genetic mapping in complex diseases . 34 12.1 Association analysis . 35 12.2 The genome-wide association study approach . 36 13 Genetic variation in the human genome . 37 13.1 Single nucleotide polymorphisms. 37 14 Genetics of lupus erythematosus . 39 14.1 Susceptibility genes for cutaneous lupus erythematosus . 39 14.1.1 Insights into CLE susceptibility genes . 40 14.2 Susceptibility genes for systemic lupus erythematosus . 41 14.2.1 Insights into SLE susceptibility genes . 44 14.3 Shared genetic predisposing factors in autoimmune diseases . 45 14.4 Gene-gene and gene-environment interactions . 46 15 Matrix metalloproteinases . 46 15.1 Matrix metalloproteinases in lupus erythematosus. 47 15.2 Matrix metalloproteinases in apoptosis. 48 AIMS OF THE STUDY . 49 MATERIALS AND METHODS . 50 1 Study subjects and tissue samples . 50 1.1 Ethical considerations . 50 1.2 Finnish case-control cohort (Studies I-IV) . 50 1.3 Finnish family cohort (Study III) . 52 1.4 Swedish case-control cohort (Study IV) . 52 1.5 Tissue samples (Studies II and V) . 54 2 Methods . 55 2.1 Data storage and management . 56 2.2 DNA extraction (Studies II-IV) . 57 2.3 Marker selection (Studies II-IV and unpublished data) . 57 2.4 Statistical power analysis (Studies II-IV) . 58 2.5 Genotyping (Studies II-IV and unpublished data) . 58 2.6 Association analyses (Studies II-V and unpublished data) . 59 2.7 Statistical analysis (Studies I-V) . 59 2.8 Immunohistochemistry (Studies II and V) . 62 RESULTS . 64 1 Smoking characterises DLE (Study I) . 64 2 IRF5 and TYK2 confer risk for DLE and SCLE (Study II) . 66 3 IRF5 and TYK2 show evidence of gene-gene interaction (Study III) . 69 4 ITGAM is a novel susceptibility gene with high risk estimate for DLE (Study IV). 71 5 Several of the GWAS-identified SLE susceptibility genes are replicated in lupus erythematosus patients with cutaneous manifestations (unpublished data) . 75 6 ITGAM variants predict skin lesions in SLE (Studies II-IV) . 77 7 Similar MMP expression profile in different subtypes of CLE (Study V) . 77 DISCUSSION . 81 1 Clinical investigation of patients . 81 2 Genetic studies implicate shared predisposing genes for CLE and SLE . 82 2.1 Sjögren’s syndrome and ITGAM (unpublished data) . 84 3 GWAS-identified SLE susceptibility genes implicate possible new pathways in CLE (unpublished data) . 85 4 Gene-gene interaction . 86 5 Smoking as an indicator of possible gene-environment interaction . 86 6 Subphenotype analyses . 87 7 Matrix metalloproteinases as mediators of tissue injury. 88 CONCLUSIONS AND FUTURE PROSPECTS . 90 APPENDIX .