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Dw14(DRB1*0404) is a Dw4-dependent risk factor for rheumatoid arthritis. Rethinking the "shared epitope" hypothesis
J L Nelson1, E Mickelson, S Masewicz
1Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Abstract:
HLA-DR4 has been shown to be associated with risk for developing rheumatoid arthritis (RA) in multiple populations and racial groups. The allelic variants of DR4 share the DR4 serologic specificity but differ by 1 to 3 amino acids in the third hypervariable region (positions 67 to 74) and at positions 57 and 86 of the DR beta 1 chain. We have examined DR4 variants in 61 DR4+ RA cases and 55 DR4+ healthy controls. Dw14 was not associated with RA risk in DR4 heterozygous (DR4,X) cases. Only 15% of DR4,X cases had the Dw14 allele compared with 28% of DR4,X controls. In homozygous (DR4,4) individuals who also expressed Dw4, however, Dw14 was associated with increased RA risk. Moreover, the relative risk for Dw4,Dw14 (16.1, p = 0.001) actually exceeded that of Dw4,Dw4 (2.2, p = ns). Thus Dw14 is not an independent risk factor for RA but is a synergistic risk factor for individuals who also have the Dw4 allele.
Insights
The Dw14 allele does not independently increase rheumatoid arthritis (RA) risk. However, in individuals with the Dw4 allele, Dw14 acts synergistically to significantly elevate RA risk.
Area of Science:
- Immunogenetics
- Rheumatology
- Human Leukocyte Antigen (HLA) complex
Background:
- The Human Leukocyte Antigen (HLA)-DR4 serotype is linked to rheumatoid arthritis (RA) susceptibility across diverse populations.
- Allelic variants of HLA-DR4 share serologic specificity but exhibit minor amino acid differences in the DR beta 1 chain, particularly in hypervariable regions.
Purpose of the Study:
- To investigate the association of specific HLA-DR4 variants, namely Dw4 and Dw14, with rheumatoid arthritis risk.
- To determine if Dw14 is an independent or synergistic risk factor for RA in individuals carrying the HLA-DR4 allele.
Main Methods:
- Genotyping of HLA-DR4 variants (Dw4 and Dw14) in 61 rheumatoid arthritis cases and 55 healthy controls, all positive for HLA-DR4.
- Statistical analysis to compare allele frequencies between cases and controls and calculate relative risks.
Main Results:
- Dw14 was not associated with increased RA risk in HLA-DR4 heterozygous individuals (DR4,X).
- In HLA-DR4 homozygous individuals (DR4,4) who also carried the Dw4 allele, Dw14 was significantly associated with elevated RA risk (relative risk = 16.1, p = 0.001).
- The combined presence of Dw4 and Dw14 conferred a substantially higher RA risk compared to Dw4 alone.
Conclusions:
- Dw14 is not an independent risk factor for rheumatoid arthritis.
- Dw14 acts as a synergistic risk factor, significantly increasing RA susceptibility only in the presence of the Dw4 allele in individuals with HLA-DR4.