A gene in the telomeric HLA complex distinct from HLA-A is involved in predisposition to juvenile idiopathic arthritis (JIA)

Objective

Juvenile idiopathic arthritis (JIA) is associated with particular alleles at three different Human Leukocyte Antigen (HLA) loci: HLA-A, -DR/DQ and -DP. These associations are independent of each other; i.e. they cannot be explained by the known linkage disequilibrium (LD) between alleles at these loci. The purpose of this study was to look for additional JIA susceptibility genes in the HLA complex.

Methods

We investigated 102 Norwegian JIA patients and 270 healthy individuals, all carrying the DQ4-DR8 haplotype, by scanning ~10 Mb of DNA covering the HLA complex for microsatellite polymorphisms. An expectation-maximization (EM) algorithm was used to estimate haplotype frequencies, and the distribution of microsatellite alleles on the high-risk DQ4-DR8 haplotype was compared between patients and controls, to exclude effects secondary to LD with these susceptibility genes.

Results

Allele 5 at the microsatellite locus D6S265 (D6S265*5), 100 kb centromeric of HLA-A, showed strong positive association with disease (OR = 4.7, Pc < 10–6). Haplotype analysis demonstrated that the D6S265*5 association was not caused by LD to the gene encoding HLA-A*02, which has previously been described also to be associated with JIA. Rather our data suggest that a gene in LD with D6S265*5, but distinct from HLA-A*02, is involved in predisposition to JIA.

Conclusion

We found that D6S265*5 could be a marker for an additional susceptibility gene in JIA which is distinct from A*02, adding to the risk provided by DQ4-DR8.