Autoimmune disorders (AIDs), which as a group affect approximately 8.5% of individuals worldwide [1
], are responsible for a substantial amount of disability and morbidity. Some AIDs are organ specific (for example, type 1 diabetes (T1D) targets the pancreas, autoimmune thyroid disease (AITD) attacks the thyroid gland), whereas others can affect multiple organs and/or be associated with systemic manifestations. Systemic lupus erythematosus (SLE) is the prototypic systemic AID that can affect multiple organs and can also be associated with significant systemic manifestations, morbidity and early mortality [2
]. Most AIDs, including rheumatoid arthritis (RA), ankylosing spondylitis (AS), inflammatory bowel disease (IBD) and multiple sclerosis (MS) have a predilection for specific organs (for example, the synovial joints in RA and the gastrointestinal tract in IBD) but are also associated with manifestations outside the primary target organ. Reasons for the diverse manifestations exhibited by different AIDs remain unclear, but recent progress in elucidating genetic susceptibility loci for this group of disorders promises to shed light on this important issue.
Although AIDs encompass a broad range of phenotypic manifestations and severity, several features suggest that they share common etiologic factors. For example, most AIDs are characterized by female predominance, and many are associated with the production of autoantibodies (for example, anti-citrullinated-peptide antibodies are observed among 70 to 80% of RA patients). These shared disease features, in conjunction with epidemiologic evidence that demonstrates the clustering of multiple AIDs within individuals and families, strongly implicate shared etiologic factors, including shared genetic loci.
Familial clustering of autoimmune disorders has been long recognized and supports a role for shared genetic predisposition. For example, family studies have documented the clustering of certain autoimmune diseases among the relatives of individuals who have RA, MS, SLE, T1D and other diseases [3
]. One of the earliest autoimmune disease clusters to be described involved RA, T1D and AITD, and this cluster was recently supported by a systematic review of studies describing clustering of RA, T1D, AITD and MS [3
]. Interestingly, that systematic review found evidence of inverse clustering of RA and MS, suggesting that MS and RA might be less closely related than some other AIDs [3
]. This conclusion was reinforced by a recent study comparing the genetic variation profiles of six AIDs [10
]. That study, by Sirota et al
], was based on an analysis of a large number of genetic variants examined in recent genome-wide association studies (GWAS). It found that RA and AS appeared to represent one AID cluster that is distinct from another represented by MS and AITD, with T1D showing similarity to both groups and Crohn's disease to neither.
Early candidate gene studies, particularly those focusing on genes within the human leukocyte antigen (HLA) region [11
], also supported the notion of shared 'autoimmunity' loci. Strong support for genetic loci that are shared across autoimmune disorders and located outside the HLA region has been demonstrated for several loci encoding proteins that have immune-mediating functions, including cytotoxic T-lymphocyte antigen 4 (CTLA4; a member of the immunoglobulin superfamily that is expressed on the surface of helper T cells and transmits an inhibitory signal to T cells), protein tyrosine phosphatase non-receptor type 22 (PTPN22; which is expressed primarily in lymphoid tissue and plays a role in the regulation of T-cell receptor signaling pathways), and tumor necrosis factor (TNF) alpha-induced protein 3 (TNFAIP3; which inhibits NF-kappa B activation as well as TNF-mediated apoptosis) [12
]. Many of the recently identified AID loci involve pathways related to B-cell or T-cell activation and differentiation, innate immunity, and regulation of cytokine signaling [15
]. Certain loci, however, appear to be associated with specific autoimmune diseases. For example, variants in NOD2 (nucleotide-binding oligomerization domain containing 2) and ATG16L1 (ATG16 autophagy-related-16-like 1) have been associated with defective autophagy in dendritic cells from Crohn's disease patients [17
A theme emerging from recent genetic studies of AIDs relates to the surprising degree of overlap between genetic loci for this diverse group of disorders, given the phenotypic diversity. Several recent reviews have summarized emerging work that identifies both genetic loci that are shared across the spectrum of autoimmune disease and the biologic pathways whose involvement is implicated by these shared loci [15
]. For example, Zhernakova et al
] completed a detailed review of 16 genome-wide association (GWA) or non-synonymous SNP scans for 11 immune-related disorders that were published in 2007 or 2008. Their analysis underscores the extensive sharing of genetic risk loci across this spectrum of disorders, and the fact that most of these loci can be mapped to a few shared biologic pathways, including those related to innate immunity, immune signaling, T-cell differentiation, cytokines and chemokines.
The analysis by Zhernakova et al
] also suggests that the degree to which each of these disorders is characterized by shared (rather than unique) susceptibility loci varies substantially, from all loci shared (for RA) to 50% or more shared for celiac disease, psoriasis, MS, SLE, T1D, AS and AITD [18
]. The two types of IBD examined, Crohn's disease and ulcerative colitis (UC), shared substantial numbers of loci between them but relatively few with the other AIDs studied. The extent to which the T-cell differentiation, immune cell signaling, innate immunity and TNF signaling, or other pathways are implicated for each of these disorders varies, but overall the analysis by Zhernakova et al
] suggests that most of these pathways contribute (to a variable degree) to most of these disorders.
In this review we focus on recent studies that have sought to refine genotype-phenotype associations by comparing susceptibility loci between specific AIDs. We concentrate on RA, AS, celiac disease, MS, SLE, T1D and IBD. Table summarizes these AIDs in terms of their prevalence in the population and major phenotypic features. In particular, we focus on comparative studies that use GWA results to distinguish genetic variants that are specific to individual AIDs from those that are shared among multiple AIDs. We also summarize the results of a recently published cross-phenotype meta-analysis that uses genetic association results to highlight four main AID clusters. A detailed understanding of these shared and distinct genetic loci provides insight into fundamental etiologic mechanisms in autoimmune disease. It has the potential to inform the choice of current therapies and the development of novel targeted therapies and other interventions that could improve our ability to manage these complex human disorders.
Prevalence and major phenotypic features of autoimmune diseases