Polymorphism in the LMP2 gene influences disease susceptibility and severity in HLA-B27 associated juvenile rheumatoid arthritis.
OBJECTIVE
To determine the potential contribution of the MHC class II region proteasome subunit gene, LMP2, to disease susceptibility, severity, and phenotype in patients with juvenile rheumatoid arthritis (JRA).


METHODS
A CfoI restriction site polymorphism in the coding region of the LMP2 gene was evaluated in 279 patients with JRA and 107 healthy controls of similar ethnicity. Patients were divided into 5 groups on the basis of clinical presentation; 46% had early onset pauciarticular disease, 10% early onset polyarticular, 10% late onset pauciarticular, 20% late onset polyarticular, and 11% systemic onset arthritis. The influence of this LMP2 polymorphism on susceptibility to disease, clinical subtype of disease at onset (age and number of joints involved), progression and severity of joint disease (pauci to polyarticular course and radiographic changes), and occurrence of inflammatory eye disease was evaluated.


RESULTS
Comparison of genotypes revealed a significantly increased prevalence of homozygosity for the LMP2 B allele (LMP2 BB genotype) in patients who were older (> or = 6 years) at onset of disease (65%, p < 0.05), particularly in those with pauciarticular (71%) involvement at presentation (p < 0.05), compared to controls (51%). The BB genotype was also more prevalent in patients with a polyarticular course, either from onset (63%) or those who progressed from pauciarticular disease (69%), compared with controls, (p = 0.05 and < 0.05, respectively). Stratification for HLA-B27 and DR4, the HLA alleles most frequently associated with late onset pauciarticular and late onset polyarticular JRA, respectively, revealed a persistent effect of LMP2 BB homozygosity on disease susceptibility and phenotype that remained statistically significant in HLA-B27 positive children, and was not due to linkage disequilibrium.


CONCLUSIONS
We show that homozygosity of the B allele of the proteasome subunit LMP2 increases susceptibility to certain subgroups of JRA, and influences the phenotype of disease, predisposing to more progressive and severe articular disease.
Pryhuber
K G
KG
William S. Rowe Division of Rheumatology, Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA.
Murray
K J
KJ
Donnelly
P
P
Passo
M H
MH
Maksymowych
W P
WP
Glass
D N
DN
Giannini
E H
EH
Colbert
R A
RA
D000483:Alleles; D001171:Arthritis, Juvenile / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D003546:Cysteine Endopeptidases; D004198:Disease Susceptibility; D005802:Genes, MHC Class II; D005838:Genotype; D015796:HLA-B27 Antigen / Q000235:genetics*; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics; D008969:Molecular Sequence Data; D015345:Oligonucleotide Probes / Q000737:chemistry; D010641:Phenotype; D012150:Polymorphism, Restriction Fragment Length; D011506:Proteins / Q000235:genetics*; D012307:Risk Factors; D012720:Severity of Illness Index
D015796:HLA-B27 Antigen; D015345:Oligonucleotide Probes; D011506:Proteins; C071313:LMP-2 protein; D003546:Cysteine Endopeptidases