Dataset Information

Protective Role of HLA-DRB1*13:02 against Microscopic Polyangiitis and MPO-ANCA-Positive Vasculitides in a Japanese Population: A Case-Control Study.

ABSTRACT: Among antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV), granulomatosis with polyangiitis (GPA) and proteinase 3-ANCA-positive AAV (PR3-AAV) are prevalent in European populations, while microscopic polyangiitis (MPA) and myeloperoxidase-ANCA-positive AAV (MPO-AAV) are predominant in the Japanese. We previously demonstrated association of DRB1*09:01-DQB1*03:03 haplotype, a haplotype common in East Asians but rare in the European populations, with MPA/MPO-AAV, suggesting that a population difference in HLA-class II plays a role in the epidemiology of this disease. To gain further insights, we increased the sample size and performed an extended association study of DRB1 and DPB1 with AAV subsets in 468 Japanese patients with AAV classified according to the European Medicines Agency algorithm (MPA: 285, GPA: 92, eosinophilic GPA [EGPA]: 56, unclassifiable: 35) and 596 healthy controls. Among these patients, 377 were positive for MPO-ANCA and 62 for PR3-ANCA. The significance level was set at ? = 3.3x10-4 by applying Bonferroni correction. The association of DRB1*09:01 with MPO-AAV was confirmed (allele model, P = 2.1x10-4, odds ratio [OR] = 1.57). Protective association of DRB1*13:02 was detected against MPO-AAV (allele model, P = 2.3x10-5, OR = 0.42) and MPA (dominant model, P = 2.7x10-4, OR = 0.43). A trend toward increased frequency of DPB1*04:01, the risk allele for GPA in European populations, was observed among Japanese patients with PR3-AAV when conditioned on DRB1*13:02 (Padjusted = 0.0021, ORadjusted = 3.48). In contrast, the frequency of DPB1*04:01 was decreased among Japanese patients with MPO-AAV, and this effect lost significance when conditioned on DRB1*13:02 (Padjusted = 0.16), suggesting that DRB1*13:02 or other allele(s) in linkage disequilibrium may be responsible for the protection. The differential association of DPB1*04:01 with PR3-AAV and MPO-AAV and difference in DPB1*04:01 allele frequencies between populations supported the hypothesis that the HLA-class II population difference may account in part for these epidemiologic characteristics. Furthermore, taken together with our previous observations, the haplotype carrying DRB1*13:02 was suggested to be a shared protective factor against multiple autoimmune diseases.

SUBMITTER: Kawasaki A

PROVIDER: S-EPMC4868057 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Protective Role of HLA-DRB1*13:02 against Microscopic Polyangiitis and MPO-ANCA-Positive Vasculitides in a Japanese Population: A Case-Control Study.

Kawasaki Aya A Hasebe Narumi N Hidaka Misaki M Hirano Fumio F Sada Ken-Ei KE Kobayashi Shigeto S Yamada Hidehiro H Furukawa Hiroshi H Yamagata Kunihiro K Sumida Takayuki T Miyasaka Nobuyuki N Tohma Shigeto S Ozaki Shoichi S Matsuo Seiichi S Hashimoto Hiroshi H Makino Hirofumi H Arimura Yoshihiro Y Harigai Masayoshi M Tsuchiya Naoyuki N

PloS one 20160511 5

Among antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV), granulomatosis with polyangiitis (GPA) and proteinase 3-ANCA-positive AAV (PR3-AAV) are prevalent in European populations, while microscopic polyangiitis (MPA) and myeloperoxidase-ANCA-positive AAV (MPO-AAV) are predominant in the Japanese. We previously demonstrated association of DRB1*09:01-DQB1*03:03 haplotype, a haplotype common in East Asians but rare in the European populations, with MPA/MPO-AAV, suggesting tha ...[more]

PMID: 27166610

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Project description:BackgroundProteasomes are found in both the cell nucleus and cytoplasm and play a major role in the ubiquitin-dependent and -independent non-lysosomal pathways of intracellular protein degradation. Proteasomes are also involved in the turnover of various regulatory proteins, antigen processing, cell differentiation, and apoptosis. To determine the diagnostic value of serum proteasome in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), we investigated patients with AAV at various stages of the disease.MethodsSerum 20S-proteasome was measured by ELISA in 44 patients with MPO-ANCA-associated microscopic polyangiitis (MPA) and renal involvement. Thirty of the patients provided serum samples before the initial treatment, and 30 provided samples during remission; 16 provided samples at both time points.ResultsThe mean serum 20S-proteasome level was significantly higher in the active-vasculitis patients (3414.6 ± 2738.9 ng/mL; n = 30) compared to the inactive-vasculitis patients (366.4 ± 128.4 ng/mL; n = 30; p < 0.0001) and 40 controls (234.9 ± 90.1 ng/mL; p < 0.0001). There were significant positive correlations between the serum 20S-proteasome level and the Birmingham Vasculitis Activity Score (BVAS) (r = 0.581, p < 0.0001), the ANCA titer (r = 0.384, p < 0.0001), the white blood cell (WBC) count (r = 0.284, p = 0.0042), the platelet count (r = 0.369, p = 0.0002), and the serum C-reactive protein (CRP) level (r = 0.550, p < 0.0001). There were significant negative correlations between the serum 20S-proteasome level and both the hemoglobin concentration (r = - 0.351, p = 0.0003) and the serum albumin level (r = - 0.460, p < 0.0001). In a multiple regression analysis, there was a significant positive correlation between the serum 20S-proteasome level and only the BVAS results (β = 0.851, p = 0.0009). In a receiver operating curve analysis, the area under the curve for the serum 20S-proteasome level was 0.996, which is higher than those of the WBC count (0.738) and the serum CRP level (0.963).ConclusionThe serum level of 20S-proteasome may be a useful marker for disease activity in AAV.

Project description:ObjectivesThe aim of this study is to investigate the clinical significance of myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA) on eosinophilic granulomatosis with polyangiitis (EGPA) from a longitudinal Chinese cohort.MethodsA total of 120 patients with EGPA were consecutively enrolled and followed up. Two patients with PR3 ANCA was excluded and our analysis focused on the 118 patients with EGPA. On the basis of MPO-ANCA status, baseline clinical manifestations, treatment, and outcomes were analyzed. Logistic regression analysis was performed to analyze the independently associated factors for renal involvement.ResultsANCA positivity was observed in 24.2% of patients with EGPA. Patients with MPO-ANCA accounted for 20.8%. Patients with positive MPO-ANCA had higher levels of erythrocyte sedimentation rate (ESR), C-reactive protein, Birmingham Vasculitis Activity Score (BVAS), higher ratios of fever, myalgia, renal involvement, and biopsy-proven vasculitis. Heart manifestations and asthma were more common in patients with negative ANCA. Baseline MPO-ANCA titers positively correlated with ESR, eosinophil count, and BVAS and were higher in patients with methylprednisolone pulse. Among patients with renal involvement, patients with positive MPO-ANCA had higher proportions of female, fever, biopsy-proven vasculitis, and faster ESR; patients with negative ANCA developed more skin and cardiac involvement. MPO-ANCA positivity, male, and ear involvement were the independent factors associated with renal involvement. Intravenous cyclophosphamide and immunoglobulins were prescribed more frequently in patients with positive MPO-ANCA.ConclusionIn this cohort, patients with positive MPO-ANCA and negative ANCA displayed distinct clinical features, suggesting that MPO-ANCA might be a valuable biomarker for EGPA stratification. Baseline MPO-ANCA level correlated positively with disease activity of EGPA. MPO-ANCA was a significant independent factor associated with renal involvement.

Dataset Information

Protective Role of HLA-DRB1*13:02 against Microscopic Polyangiitis and MPO-ANCA-Positive Vasculitides in a Japanese Population: A Case-Control Study.

Publications

Protective Role of HLA-DRB1*13:02 against Microscopic Polyangiitis and MPO-ANCA-Positive Vasculitides in a Japanese Population: A Case-Control Study.

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