Polymorphism in the MHC-encoded LMP7 gene: association with JRA without functional significance for immunoproteasome assembly.
OBJECTIVE
To determine if a polymorphism in the immunoproteasome subunit LMP7 was associated with juvenile rheumatoid arthritis (JRA) and had functional significance.


METHODS
The frequency of LMP7QQ+ vs QQ- (QK and KK genotypes) among 207 patients with JRA and 50 controls was determined. JRA subtypes were pauciarticular (53%), polyarticular (33%), and systemic (14%). Onset was before age 6 (early onset) in 60% of patients. The functional significance of the LMP7 polymorphism was determined by comparing incorporation of LMP7Q vs LMP7K into proteasomes.


RESULTS
There was an increased frequency of LMP7QQ in patients vs controls (73 vs 56%; p = 0.016), mainly due to the pauciarticular and systemic JRA subtypes (p = 0.037), and more pronounced in early onset disease (77 vs 56%; p = 0.006). The association persisted with stratification for HLA-DR5(11) and -DPB 1 *0201 (p = 0.002 and 0.013). We found no difference in the relative incorporation of LMP7Q and LMP7K into proteasomes.


CONCLUSIONS
These results support an association between LMP7QQ homozygosity and JRA, particularly early onset disease. The difference persists with stratification, at least for DR5(11) and DPB1*0201, suggesting that this effect is unlikely to be due to linkage disequilibrium with HLA alleles known to be associated with early onset pauciarticular JRA. Importantly, as there does not appear to be functional significance associated with the LMP7 polymorphism, this may be a marker for another as yet unidentified susceptibility locus.
Prahalad
S
S
William S. Rowe Division of Rheumatology, Children's Hospital Medical Center, University of Cincinnati College of Medicine, Ohio 45229-3039, USA.
Kingsbury
D J
DJ
Griffin
T A
TA
Cooper
B L
BL
Glass
D N
DN
Maksymowych
W P
WP
Colbert
R A
RA
D001171:Arthritis, Juvenile / Q000235:genetics* / Q000276:immunology*; D002648:Child; D003546:Cysteine Endopeptidases / Q000235:genetics* / Q000276:immunology; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics; D015805:HLA-DR5 Antigen / Q000235:genetics; D059811:HLA-DRB1 Chains; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics*; D008297:Male; D009097:Multienzyme Complexes / Q000235:genetics* / Q000276:immunology; D011110:Polymorphism, Genetic; D046988:Proteasome Endopeptidase Complex; D011506:Proteins / Q000235:genetics*
D006684:HLA-DR Antigens; D015805:HLA-DR5 Antigen; D059811:HLA-DRB1 Chains; D009097:Multienzyme Complexes; D011506:Proteins; D003546:Cysteine Endopeptidases; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex