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Association of HLA-DRB1*0901-DQB1*0303 haplotype with microscopic polyangiitis in Japanese
N Tsuchiya1, S Kobayashi, H Hashimoto
1Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Hongo, Tokyo, Japan. tsuchiya-tky@umin.ac.jp
Abstract:
Microscopic polyangiitis (MPA) is a rare and severe form of systemic necrotizing vasculitis associated with myeloperoxidase (MPO)-specific antineutrophil cytoplasmic antibody (ANCA). We previously reported significant association of HLA-DRB1*0901 with MPA. To define the susceptibility loci within the HLA region, we determined the genotypes of HLA-DQB1, DPB1, B and C in 50 patients with MPA and 77 unrelated Japanese controls. In addition to HLA-DRB1*0901, significant association of DQB1*0303 (allele carrier frequencies 50% in MPA, 29.9% in controls, odds ratio 2.35, P = 0.017) was detected. These alleles were in strong linkage disequilibrium (D' = 0.95, r2 = 0.82). Increased frequency was also observed for DPB1*0201, B*15111 and Cw*0303, which was at least partly accounted for by linkage disequilibrium with DRB1*0901 and DQB1*0303. These results indicate that DRB1*0901-DQB1*0303 haplotype represents the primary genetic risk for MPA within the HLA region in Japanese, and provides the basis that future functional studies on the role of HLA in MPA should target DR9, DQ9 and DR53 proteins encoded by this haplotype.
Insights
The HLA-DRB1*0901-DQB1*0303 haplotype is strongly associated with microscopic polyangiitis (MPA) in Japanese individuals. This finding identifies a primary genetic risk factor for MPA within the HLA region.
Area of Science:
- Immunogenetics
- Rheumatology
- Genetics
Background:
- Microscopic polyangiitis (MPA) is a severe systemic necrotizing vasculitis.
- MPA is associated with myeloperoxidase (MPO)-specific antineutrophil cytoplasmic antibodies (ANCAs).
- Previous studies identified HLA-DRB1*0901 as associated with MPA.
Purpose of the Study:
- To define specific susceptibility loci within the HLA region for MPA.
- To investigate the genetic basis of MPA in a Japanese population.
Main Methods:
- Genotyping of HLA-DQB1, DPB1, B, and C alleles in 50 MPA patients and 77 controls.
- Analysis of allele frequencies and linkage disequilibrium.
- Statistical analysis to determine significant associations.
Main Results:
- Significant association of HLA-DQB1*0303 with MPA (50% in patients vs. 29.9% in controls, OR 2.35, P=0.017).
- Strong linkage disequilibrium observed between HLA-DRB1*0901 and HLA-DQB1*0303 (D'=0.95, r2=0.82).
- Increased frequencies of DPB1*0201, B*15111, and Cw*0303, partly due to linkage with DRB1*0901 and DQB1*0303.
Conclusions:
- The DRB1*0901-DQB1*0303 haplotype is identified as the primary genetic risk factor for MPA in the Japanese population.
- This haplotype provides a basis for future functional studies on the role of HLA in MPA pathogenesis.
- Targeting DR9, DQ9, and DR53 proteins encoded by this haplotype is recommended for future research.
