A gene in the telomeric HLA complex distinct from HLA-A is involved in predisposition to juvenile idiopathic arthritis.
OBJECTIVE
Juvenile idiopathic arthritis (JIA) is associated with particular alleles at 3 different HLA loci: HLA-A, HLA-DR/DQ, and HLA-DP. These associations are independent of each other (i.e., they cannot be explained by the known linkage disequilibrium between alleles at these loci). The purpose of this study was to look for additional JIA susceptibility genes in the HLA complex.


METHODS
One hundred two Norwegian JIA patients and 270 healthy individuals, all carrying the DQ4;DR8 haplotype, were investigated by scanning approximately 10 megabases of DNA covering the HLA complex with microsatellite polymorphisms. An expectation-maximization 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 linkage disequilibrium with these susceptibility genes.


RESULTS
Allele 5 at the microsatellite locus D6S265 (D6S265* 5), 100 kb centromeric of HLA-A, showed a strong positive association with the disease (odds ratio 4.7, corrected P < 10(-6)). Haplotype analysis demonstrated that the D6S265*5 association was not caused by linkage disequilibrium to the gene encoding HLA-A*02, which has previously been reported to be associated with JIA. Instead, our data suggested that a gene in linkage disequilibrium with D6S265*5, but distinct from HLA-A*02, is involved in the predisposition to JIA.


CONCLUSIONS
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 conferred by DQ4;DR8.
Smerdel
Anna
A
Institute of Immunology and Center for Rheumatic Diseases, Rikshospitalet University Hospital, N-0027 Oslo, Norway. anna.smerdel@klinmed.uio.no
Lie
Benedicte A
BA
Ploski
Rafal
R
Koeleman
Bobby P C
BP
Førre
Øystein
Ø
Thorsby
Erik
E
Undlien
Dag E
DE
D000293:Adolescent; D001171:Arthritis, Juvenile / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D015234:HLA-A Antigens / Q000235:genetics*; D006683:HLA-DQ Antigens / Q000235:genetics; D006684:HLA-DR Antigens / Q000235:genetics; D059810:HLA-DR Serological Subtypes; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D018895:Microsatellite Repeats; D010641:Phenotype; D016615:Telomere / Q000235:genetics*
D015234:HLA-A Antigens; D006683:HLA-DQ Antigens; C060029:HLA-DQ4 antigen; D006684:HLA-DR Antigens; D059810:HLA-DR Serological Subtypes; C041559:HLA-DR8 antigen