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A distinct HLA-DRw8 haplotype characterizes patients with juvenile rheumatoid arthritis
C Van Kerckhove1, H Melin-Aldana, M S Elma
1Children's Hospital Medical Center, Cincinnati, OH.
Insights
A specific human leukocyte antigen (HLA) genotype, HLA-DRB1*0801, DQA1*0401, DQB1*0402, significantly increases the risk for early-onset pauciarticular juvenile rheumatoid arthritis (EOPA-JRA). This finding highlights the role of DQ genes in EOPA-JRA pathogenesis.
Area of Science:
- Immunogenetics
- Rheumatology
- Human Leukocyte Antigen (HLA) complex
Background:
- Juvenile rheumatoid arthritis (JRA), specifically the early-onset pauciarticular (EOPA-JRA) subtype, has known associations with HLA genes.
- Previous studies have identified associations between HLA-DRw8 serology and EOPA-JRA, but the specific genetic contributions within the HLA-DR/DQ haplotype were less clear.
Purpose of the Study:
- To investigate the specific HLA-DRB1, HLA-DQA1, and HLA-DQB1 genotypes associated with EOPA-JRA.
- To determine the relative risk conferred by specific HLA genotypes compared to serologically defined HLA-DRw8 in EOPA-JRA patients.
Main Methods:
- Genotyping of HLA-DRB1, HLA-DQA1, and HLA-DQB1 loci using serology, restriction fragment length polymorphism (RFLP), and polymerase chain reaction (PCR) oligotyping.
- Disease association studies comparing HLA genotypes in EOPA-JRA patients and healthy controls.
- Family studies to confirm HLA haplotype associations.
Main Results:
- A specific genotype, HLA-DRB1*0801, DQA1*0401, DQB1*0402, was found in 62 out of 67 HLA-DRw8-positive Caucasians, including all 43 EOPA-JRA patients studied.
- This genotype conferred a significantly higher relative risk (RR=12.8) for EOPA-JRA compared to the presence of serologically defined HLA-DRw8 (RR=8).
- Analysis suggests that DQ genes on HLA-DRw8 haplotypes contribute substantially to EOPA-JRA pathogenesis, potentially as much as DR genes.
Conclusions:
- The HLA-DRB1*0801, DQA1*0401, DQB1*0402 genotype is strongly associated with EOPA-JRA in Caucasian populations.
- The study identifies specific HLA-DQ alleles as key contributors to EOPA-JRA susceptibility.
- This research expands the known HLA-DR/DQ haplotypes associated with HLA-DRw8.
Abstract:
We studied the first domain of the HLA-DRB1, HLA-DQA1, and HLA-DQB1 loci of 67 HLA-DRw8-positive Caucasians including 43 with early-onset pauciarticular juvenile rheumatoid arthritis (EOPA-JRA, alternatively known as early-onset pauciarticular juvenile chronic arthritis). Serology, restriction fragment length polymorphism (RFLP), and polymerase chain reaction (PCR) oligotyping revealed that 62, including all the EOPA-JRA patients, carried the HLA-DRB1*0801, DQA1*0401, DQB1*0402 genotype. Approximately one-fifth of the controls carried atypical HLA-DRB1, HLA-DQA1, and/or HLA-DQB1 loci on their HLA-DRw8 haplotype confirmed by family studies. DNA sequences of HLA-DRB1, DQA1, and DQB1 alleles in patients and controls were identical to those previously reported. Disease association studies in 113 EOPA-JRA patients and 207 controls unselected for HLA-DRw8 revealed that the HLA-DRB1*0801, DQA1*0401, DQB1*0402 genotype was associated with a higher relative risk (RR) for disease (RR = 12.8, chi 2 = 48.8, P less than 10(-4)) than was the serologically defined presence of HLA-DRw8 (RR = 8, chi 2 = 39, P less than 10(-4)). Further analysis suggested that the DQ genes on HLA-DRw8 haplotypes are as likely as the DR genes to contribute to the pathogenesis of EOPA-JRA. This study increases to five the number of HLA-DR/DQ haplotypes identified in HLA-DRw8 Caucasians.