The Hereditary Basis of Rheumatic Diseases (eBook)

Contents 5
List of contributors 7
A. Introduction 10
Genetics of joint inflammation – problems and possibilities 11
B. Genetic studies on rheumatic diseases 15
The epidemiology of rheumatoid arthritis and the use of linkage and association studies to identify disease genes 16
Genes vs. environment 18
Twin and family studies 19
Identification of genes for complex diseases 20
Linkage analysis 20
Association studies 24
The future 28
References 30
Heterogeneity in rheumatoid arthritis based on expression analysis: towards personalised medicine 36
Introduction 36
Protein biomarkers in serum and synovial fluid of patients with RA 37
Gene expression profiling in cells and tissues of patients with RA 40
Concluding remarks 45
References 46
Gene-based large scale LD-mapping of rheumatoid arthritis-associated genes 50
Introduction 50
Gene-based LD mapping with SNPs 50
Identification of RA-associated variants in PADI4 and SLC22A4 52
Summary 60
References 60
Epidemiology of rheumatoid arthritis 16
C. Shared heredity of rheumatic diseases 65
Emerging relationships: rheumatoid arthritis and the PTPN22 associated autoimmune disorders 66
Familial aggregation of autoimmune diseases and phenotypes 67
Genetic studies based on linkage suggest genetic overlap among different autoimmune diseases 68
Genetic studies based on association: from candidate genes to ‘genomewide’ association studies 68
PTPN22: two routes to discovery 69
PTPN22 is a negative regulator of early T-cell signaling events 70
The PTPN22 620W is associated with many autoimmune diseases that are characterized by a prominent humoral component 72
Wide variation in allele frequency of PTPN22 R620W in different populations: evidence for selection? 74
Gene discovery in human autoimmune disease: an engine of hypothesis generation 76
References 77
Shared genes in rheumatic diseases, the role of PD1 and the genes in disease susceptibility 84
Introduction 84
Concluding remarks 88
References 88
The role of B27 and other genes associated with ankylosing spondylitis 94
Introduction 94
HLA-B27 prevalence in ankylosing spondylitis (AS), background prevalence of HLA- B27 in the population, and the risk to develop AS in HLA- B27 positives 94
HLA-B27 subtypes and their association with ankylosing spondylitis 96
HLA-B27 and bacteria in the pathogenesis of AS 96
Models to explain the role of HLA-B27 in the pathogenesis of SpA 97
Other genes associated with ankylosing spondylitis 101
References 103
Introduction 66
D. Tools for analysing complexity 110
Emerging tools for dissecting complex disease 111
A set of DNA ligation-based techniques for molecular analyses 115
References 121
Introduction 122
Expression analysis of rheumatic diseases, prospects and problems 122
Expression analysis in rheumatic diseases 123
Problems 124
Prospects 128
Conclusions 130
References 131
The use of humanized MHC mouse strains for studies of rheumatic diseases 134
Introduction 134
Humanized mice as models for rheumatoid arthritis 134
HLA-B27 transgenic mice as models for spondyloarthropathy 139
Murine models for Lyme arthritis 142
References 144
SKG mice, a monogenic model of autoimmune arthritis due to altered signal transduction in T-cells 150
Introduction 150
Immunopathology of arthritis in SKG mice 151
Thymic production of arthritogenic autoimmune T-cells in SKG mice 152
A point mutation of the ZAP-70 gene as the primary cause of SKG arthritis 152
Altered T-cell development, function, and selection in SKG mice 154
Contribution of environmental factors to the development of SKG arthritis 157
SKG autoimmune arthritis as a model of human RA 158
References 160
A genetic approach to select and validate new targets for treatment of rheumatic diseases 163
Introduction 163
Pharmaceutical treatment of RA 164
Biologic drugs against RA 164
The genetic component in RA 165
Gene expression profiling to identify drug targets 165
Linkage analysis to identify drug targets 166
Genetically segregating crosses and positional cloning in animal models 167
New targets identified by positional cloning in animal models 168
Pharmacogenomics to tailor RA treatment 169
References 172
Emerging tools for dissecting complex disease 111
Introduction 111
Accessing increasing amounts of molecular information 111
Expression analysis of rheumatic diseases, prospects and problems 122
Introduction 122
Expression analysis in rheumatic diseases 123
Problems 124
Prospects 128
Conclusions 130
The use of humanized MHC mouse strains for studies of rheumatic diseases 134
Introduction 134
Humanized mice as models for rheumatoid arthritis 134
HLA-B27 transgenic mice as models for spondyloarthropathy 139
Murine models for Lyme arthritis 142
SKG mice, a monogenic model of autoimmune arthritis due to altered signal transduction in T-cells 150
Introduction 150
Immunopathology of arthritis in SKG mice 151
Thymic production of arthritogenic autoimmune T-cells in SKG mice 152
A point mutation of the ZAP-70 gene as the primary cause of SKG arthritis 152
Altered T-cell development, function, and selection in SKG mice 154
Contribution of environmental factors to the development of SKG arthritis 157
SKG autoimmune arthritis as a model of human RA 158
References 160
A genetic approach to select and validate new targets for treatment of rheumatic diseases 163
Introduction 163
Pharmaceutical treatment of RA 164
Biologic drugs against RA 164
The genetic component in RA 165
Gene expression profiling to identify drug targets 165
Linkage analysis to identify drug targets 166
Genetically segregating crosses and positional cloning in animal models 167
New targets identified by positional cloning in animal models 168
Pharmacogenomics to tailor RA treatment 169
References 172
Index 177