The most extensively studied susceptibility locus for autoimmune disorders is the major histocompatibility complex (MHC) located on chromosome 6p. This region is densely packed with more than 200 genes [28
] and several of these are essential to the immune system, including the human leukocyte antigen (HLA) genes. The genes of the MHC in general, and the HLA genes in particular, are highly polymorphic. Studies have consistently shown associations between HLA and several autoimmune diseases, including both RA and JRA. The HLA region is thought to account for half of familial cases of RA [29
]. HLA associations are distinct for RA and JRA, demonstrating that the immunogenetic factors involved in susceptibility to these two diseases are indeed different. The class II HLA molecule HLA DR4 is associated with RA and is encoded by HLA DRB1*0401
alleles. HLA DRB1*0101
, which encodes HLA DR1, is also associated with susceptibility to RA in Caucasians. Other HLA DR alleles are associated with disease susceptibility in other ethnic groups.
However, the various HLA alleles that are associated with susceptibility to RA have a common determinant in the third hypervariable region of the DRB1 chain, encompassing the amino acid positions 67-74 [30
]. This common region, designated the shared epitope, is thought to play a crucial role in the interaction of the T cells with the peptide HLA complex. Those RF-positive RA patients with severe disease, with erosions and extra-articular features, are more likely to carry two DRB1 susceptibility loci alleles than are patients with milder forms of the disease [31
]. Recently de Vries et al.
studied 167 Caucasian RA patients and 166 controls [32
]. They confirmed the association of susceptibility to RA with alleles encoding the susceptibility sequences of the shared epitope. They also showed that some alleles, including DRB1*07
, showed significant protective effects. Interestingly the protective alleles also shared a third motif in the hypervariable region. Independent homozygosity effects were observed both for susceptibility and for protective alleles. This suggests that amino acid substitutions at position 67-74 of the HLA-DRB1 molecule influences the HLA-associated risk (both susceptibility and protection) of RA.
JRA, like RA, also has associations with HLA. However the different clinical subtypes of JRA themselves differ in their HLA associations. For instance, the class I gene HLA-B27 has consistently been found to contribute risk for pauciarticular JRA, especially among older males. HLA-DR1 and -DR4, class II genes, have been reported to increase the risk for polyarticular JRA. Much as in adults with RA, HLA-DR4 is associated with RF-positive polyarticular disease in older children. Interestingly, this gene might be protective in patients with EOPA. In this subtype, combined class I and II MHC associations are seen. Other MHC-encoded genes such as LMP7 have also been shown to be associated with early-onset JRA [33
]. HLA-A2, HLA-DR5, HLA-DR8 and HLA-DPB1*0201
have all been shown to be associated with JRA by several investigators, and interactions between these alleles yield high odds ratios for EOPA [34
]. It is possible that in this type of JRA, four individual genes (one HLA-A gene, two HLA-DR or DQ genes and an HLA-DP gene) may be involved [24
]. Confirming the associations that have been reported, linkage between pauciarticular JRA and the HLA region has been shown both by using transmission disequilibrium testing in simplex families [40
] and by allele sharing among affected sibling pairs [41
]. Similarly, linkage between polyarticular JRA and the HLA region has also been shown by allele sharing among affected sibling pairs [41
One of the unique features of JRA is that there appears to be a window of susceptibility, during which children with predisposing HLA alleles or combination of alleles are maximally susceptible to the development of JRA, suggesting gene–gene and gene–environment interactions [42
]. In a study of 680 patients with JRA and 254 ethnically matched, unrelated controls, we used survival analysis to calculate the age by which 50% and 80% of children with particular HLA alleles and combinations of alleles develop disease. Certain alleles were strongly associated with early susceptibility to pauciarticular JRA, including HLA-A2, -DR8, -DR5 and -DPB1*0201
. Of the children carrying at least one of these alleles, 50% had disease onset before their third birthday. Among children who carry HLA-A2 and any two HLA-DR alleles (HLA-DR3, -DR5, -DR6, -DR8), the median age at onset of pauciarticular disease was only 2.7 years. Combinations of HLA-A2 and -DPB1*0201
and one DR allele narrowed the window further to a median age at onset of 2.4 years. Gender strongly influenced the age at which many of the alleles have their effect. These results demonstrate the complex interactions between different HLA susceptibility alleles that influence the age of onset of JRA.
Several non-HLA susceptibility loci have been reported in connection with both RA and JRA. For instance, the macrophage-resistance gene NRAMP1 regulates activation of macrophages for enhanced expression of tumor necrosis factor (TNF)-α, IL1-β and MHC class II. This gene has been implicated in susceptibility to RA [43
]. Associations between NRAMP1 and RA have been reported both in Caucasian [44
] and in Korean populations [45
]. Sanjeevi et al.
showed that allele 3 of the NRAMP1 gene increased the susceptibility of Latvian patients to JRA, whereas allele 2 conferred protection [46
]. Polymorphisms of the genes related to the cytokine network have also been implicated in the pathogenesis of both JRA and RA and these findings have been supported by association studies.
The results of genome-wide scans from RA patients and families, in addition to confirming the linkage between RA and the HLA region, suggest the hypothesis that RA susceptibility loci overlap with loci implicated in other autoimmune disorders. Cornelis et al.
reported the first genome scan in RA performed on 114 European RA sibling pairs [19
]. Linkage was significant only for HLA and nominal for 19 markers in 14 other regions. Four of these regions overlapped loci implicated in IDDM. In a further study of a second set of families, linkage to one region (3q13) was extended significantly. This non-MHC locus could account for 16% of the genetic component of RA. In another genome-wide scan for allele sharing in 309 RA-affected sibling pairs collected in the USA, significant sharing was observed both within and outside the HLA region [20
]. This study confirmed the linkage of the HLA locus to RA and revealed a number of non-HLA loci on chromosomes 1, 4, 12, 16 and 17, with the significance of evidence for linkage at P
< 0.005. Not surprisingly, several of the regions positive for linkage were found to overlap with chromosomal locations implicated in other autoimmune disorders, including systemic lupus erythematosus, psoriasis and inflammatory bowel disease. Myerscough et al.
tested for linkage and linkage disequilibrium between IDDM susceptibility loci and RA [47
]. Evidence for linkage disequilibrium was found for a microsatellite marker at IDDM8 and two markers at IDDM5. Another genome-wide scan performed on 252 affected sibling pairs with RA from the UK confirmed the significant linkage to the MHC region [21
]. In addition, 11 non-HLA regions had suggestive or nominal linkage. Six of these regions had been previously identified in the other genome-wide scans [19
]. Genome-wide scans are under way in JRA and have not yet been reported.