The basis of susceptibility to rheumatoid arthritis (RA) is complex, comprising genetic and environmental susceptibility factors. We have reviewed the available approaches to the investigation of the genetic basis of complex diseases and how these are being applied to RA. Affected-sibling-pair methods for nonparametric linkage analysis, linkage-disequilibrium-based approaches, transmission disequilibrium testing, and disease-association studies are discussed. The pros, cons, and limitations of the approaches are considered and are illustrated by examples from the literature about rheumatoid arthritis.

Genes in the human leukocyte antigen (HLA) region remain the most powerful disease risk genes in rheumatoid arthritis (RA). Several allelic variants of HLA-DRB1 genes have been associated with RA, supporting a role for T-cell receptor-HLA-antigen interactions in the pathologic process. Disease-associated HLA-DRB1 alleles are similar but not identical and certain allelic variants are preferentially enriched in patient populations with defined clinical characteristics. Also, a gene dosing effect of HLA-DRB1 alleles has been suggested by the accumulation of patients with two RA-associated alleles, especially in patient subsets with a severe disease course. Therefore, polymorphisms in HLA genes are being explored as tools to dissect the clinical heterogeneity of the rheumatoid syndrome. Besides HLA polymorphisms, other risk genes will be helpful in defining genotypic profiles correlating with disease phenotypes. One such phenotype is the type of synovial lesion generated by the patient. HLA genes in conjunction with other genetic determinants may predispose patients to a certain pathway of synovial inflammation. Also, patients may or may not develop extraarticular manifestations, which are critical in determining morbidity and mortality. HLA genes, complemented by other RA risk genes, are likely involved in shaping the T-cell repertoire, including the emergence of an unusual T-cell population characterized by the potential of vascular injury, such as seen in extraarticular RA.

The causes of rheumatoid arthritis (RA) are largely unknown. However, RA is most probably a multifactorial disease with contributions from genetic and environmental factors. Searches for genes that influence RA have been conducted in both human and experimental model materials. Both types of study have confirmed the polygenic inheritance of the disease. It has become clear that the features of RA complicate the human genetic studies. Animal models are therefore valuable tools for identifying genes and determining their pathogenic role in the disease. This is probably the fastest route towards unravelling the pathogenesisis of RA and developing new therapies.

Inherited susceptibility to rheumatoid arthritis (RA) is associated with the DRB1 genes encoding the human leukocyte antigen (HLA)-DR4 and HLA-DR1 molecules. Transgenic mice expressing these major histocompatibility complex (MHC) class II molecules have been developed to generate humanized models for RA. The relevance of these models for understanding RA will be discussed.

Results and new hypotheses in animal models often stimulate development of new paradigms in how we view rheumatoid arthritis (RA). The complexity of RA does, however, eventually lead to the rejection of these hypotheses. Here, it is argued that the large number of so-far described animal models, when taken together, also reveals a complex disease. Fortunately, detailed study of each of the animal models will reveal this complexity, and may also be helpful in elucidating the complexity of the human disease. Benoist and Mathis [1] recently contributed a new animal model in which an autoimmune response to a ubiquitous antigen leads to an antibody-mediated inflammatory attack in the joints. It is argued that this new model, as with other animal models, is unlikely to explain RA, but it will add to the tools available to reveal the complexity of RA.

In the present study 55 IgVH genes amplified from three different anatomical regions of a rheumatoid arthritis (RA) patient were analyzed, adding further information on synovial B-cell maturation and recirculation in RA. This analysis demonstrated somatically mutated IgVh genes in all regions studied, with amino acid deletions and mixed IgVh molecules, suggesting the existence of a novel pathway to generate (auto) antibody specificities. Comparison of amino acid sequences of amplified genes that belong to the VH1 family (with predominantly the same germline counterpart) exhibited strong homology, indicating an apparently conserved mutational pattern. This suggests that the number of antigens that activate B cells in different locations is restricted. The most striking result was the finding of clonally related sequences in different anatomical regions, indicating a recirculation of activated B cells between the different affected joints.

The existence of psoriatic arthritis as a distinct clinical entity remains a topic of debate; some authors propose that it is simply the co-occurrence of psoriasis and inflammatory arthritis. However, a distinct entity is likely to have distinct susceptibility factors in addition to those that contribute to psoriasis and inflammatory arthritis alone. These aetiological factors may be genetic and/or environmental, and in this review, the evidence for distinct psoriatic arthritis genetic susceptibility factors is considered.

Systemic lupus erythematosus is the prototype multisystem autoimmune disease. A strong genetic component of susceptibility to the disease is well established. Studies of murine models of systemic lupus erythematosus have shown complex genetic interactions that influence both susceptibility and phenotypic expression. These models strongly suggest that several defects in similar pathways, e.g. clearance of immune complexes and/or apoptotic cell debris, can all result in disease expression. Studies in humans have found linkage to several overlapping regions on chromosome 1q, although the precise susceptibility gene or genes in these regions have yet to be identified. Recent studies of candidate genes, including Fcγ receptors, IL-6, and tumour necrosis factor-α, suggest that in human disease, genetic factors do play a role in disease susceptibility and clinical phenotype. The precise gene or genes involved and the strength of their influence do, however, appear to differ considerably in different populations.

Studies have established the magnitude of the genetic basis of juvenile idiopathic arthritis (JIA). JIA is a complex genetic condition and the genes that influence susceptibility are actively being sought. A candidate gene approach is being used by several groups. MHC-, cytokine- and T-cell-related genes have all been positively associated with JIA. Here we review some of the latest genetic data, and discuss ways in which JIA genetic research might proceed.

Risk of systemic lupus erythematosus (SLE) is high in west Africans compared with Europeans, and risk of rheumatoid arthritis (RA) is high in Native Americans compared with Europeans. These differences are not accounted for by differences in allele or haplotype frequencies in the human leucocyte antigen (HLA) region or any other loci known to influence risk of rheumatic disease. Where there has been admixture between two or more ethnic groups that differ in risk of disease, studies of the relationship of disease risk to proportionate admixture can help to distinguish between genetic and environmental explanations for ethnic differences in disease risk and to map the genes underlying these differences.