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Polymorphism in the LMP2 gene influences disease susceptibility and severity in HLA-B27 associated juvenile
K G Pryhuber1, K J Murray, P Donnelly
1William S. Rowe Division of Rheumatology, Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA.
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.
Conclusion:
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.
Insights
The LMP2 gene's B allele homozygosity increases juvenile rheumatoid arthritis (JRA) susceptibility, particularly in pauciarticular and polyarticular forms. This genetic factor also influences JRA phenotype, leading to more severe joint disease progression.
Area of Science:
- Immunogenetics
- Rheumatology
- Molecular Biology
Background:
- Juvenile rheumatoid arthritis (JRA) is a complex autoimmune disease with genetic and environmental influences.
- The Major Histocompatibility Complex (MHC) class II region contains genes critical for immune regulation, including proteasome subunit genes like LMP2.
- Understanding the genetic contribution of specific genes within the MHC region is crucial for elucidating JRA pathogenesis.
Purpose of the Study:
- To investigate the association between a specific polymorphism in the LMP2 gene and susceptibility to JRA.
- To determine if the LMP2 polymorphism influences disease severity, clinical subtype, and progression in JRA patients.
- To evaluate the impact of the LMP2 polymorphism on the development of inflammatory eye disease in JRA.
Main Methods:
- A CfoI restriction site polymorphism within the LMP2 gene was analyzed in 279 JRA patients and 107 healthy controls.
- JRA patients were categorized into five clinical subtypes based on onset and disease pattern.
- Statistical analyses were performed to assess the association between LMP2 genotypes and JRA susceptibility, clinical features, disease progression, and eye involvement.
Main Results:
- Homozygosity for the LMP2 B allele (LMP2 BB genotype) was significantly more prevalent in JRA patients, especially those with pauciarticular onset (71%) and older age at onset (65%).
- The LMP2 BB genotype was also associated with a polyarticular disease course, both at onset (63%) and in those progressing from pauciarticular disease (69%).
- The association between LMP2 BB homozygosity and JRA susceptibility and phenotype remained significant even after stratification for known HLA risk alleles (HLA-B27 and DR4), indicating an independent effect.
Conclusions:
- Homozygosity for the LMP2 B allele is a risk factor for specific JRA subgroups, increasing susceptibility.
- The LMP2 BB genotype is linked to a more severe and progressive articular phenotype in JRA.
- These findings highlight the role of the LMP2 gene in JRA pathogenesis and disease manifestation.