A novel juvenile idiopathic arthritis (JIA) susceptibility gene in HLA class I region marked by microsatellite D6S265

Objective

Juvenile idiopathic arthritis (JIA), a chronic inflammatory joint disease, is associated with particular alleles at three different HLA loci: HLA-A, DR-DQ, and DP. We have recently found that a gene in the vicinity of microsatellite (MS) marker D6S265 in the HLA class I region may contribute to a predisposition to JIA. To further evaluate the implicated region containing marker D6S265, we analyzed a denser set of polymorphic markers covering ~1.8 Mb of the HLA region around D6S265.

Methods

We investigated 102 patients with JIA classified according to the ACR criteria. As controls we selected 207 healthy, unrelated individuals. Only patients and controls carrying the DR8-DQ4 haplo-type were included in this study. We used 13 MS markers covering a region ~1 Mb and ~0.8 Mb centromeric and telomeric, respectively, to D6S265. An EM- algorithm was used to estimate haplotypes, and the distribution of MS alleles on the DR8-DQ4 haplotype was compared between patients and controls, in order to exclude associations secondary to linkage disequilibrium (LD) with this high-risk haplotype.

Results

The strongest association with JIA was observed for allele 5 at D6S265 (OR = 3.1; P_c < 10^-4) (~100 kb centromeric to HLA-A). LD and haplotype analyses showed that the D6S265*5 association was not secondary to an association to HLA-A*0201, previously reported to be associated with JIA. Positive associations with JIA showed also: allele 7 at D6S2704 (P_c < 0.05) (~160 kb centromeric to D6S265) and allele 11 at D6S2707 (P_c < 0.005) (~300 kb telomeric to D6S265). This strongly suggests that our initially observed association to D6S265*5 is not a false positive result, but reflects the presence of a true disease-susceptibility gene in this region. Furthermore, the analysis of three-marker rolling haplotypes demonstrated a peak of association close to D6S265.

Conclusion

This hitherto unidentified gene in the HLA class I region, marked by D6S265*5 and distinct from HLA-A2, influences the risk for JIA conferred by the DR8-DQ4 haplotype. The gene in question remains to be identified.