Session Type: Poster Session (Tuesday)
Session Time: 9:00AM-11:00AM
Background/Purpose: Clinical and serological features of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) are different across geographical regions and ethnicities, which strongly indicates significant roles of genetic factors in development of AAV. In AAV patients with Asian ethnicity, MHC and non-MHC genes associated with susceptibility or clinical characteristics of AAV were reported using the candidate-gene approach, but genome-wide association study (GWAS) has not been reported. We implemented GWAS to identify single nucleotide variants (SNV) associated with AAV in the Japanese population.
Methods: GWAS was implemented using samples from 374 Japanese patients with AAV comprised of 214 with microscopic polyangiitis (MPA), 75 with granulomatosis with polyangiitis (GPA), and 45 with eosinophilic granulomatosis with polyangiitis (EGPA). Myeloperoxidase (MPO)-ANCA was positive in 300 patients and proteinase 3 (PR3)-ANCA was positive in 47 patients. Data were compared with those of 2,994 healthy Japanese owned by Japan PGx Data Science Consortium. The genotype data were obtained using HumanOmni 2.5-8 BeadChip Kits (Illumina, San Diego, CA, USA). From the genotypes of several SNVs around HLA regions, two alleles of each subject were predicted by HIBAG algorithm using the parameters tuned by Japanese population. The four-digit HLA alleles on six loci (HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1, HLA-DPB1) for ANCA subjects were predicted. For JPDSC data, alleles of HLA-DQB1 were also predicted and other HLA loci were genotyped using the Luminex assay as four digits HLA allele.
Results: GWAS revealed substantially different associations from those reported from populations of European ancestry. SNVs rs2858331 in a region between HLA-DQB1 and HLA-DQA2 was associated with MPO-ANCA (OR=1.649, P=9.504E-09) at the genome-wide significance level, and tended to be associated with the phenotype MPA as well (OR=1.631, P=1.373E-06). HLA association test showed significant association of HLA-B*51:01-C*14:02 haplotype in addition to the previously reported HLA-DRB1*09:01-DQB1*03:03 haplotype with MPA and MPO-ANCA. SNV rs749873 in a region near CXCR4 gene showed a trend toward association with GPA (OR=8.058, P=6.755E-08).
Conclusion: GWAS demonstrated multiple association signals in MHC class I and class II regions, as well as potential associations in the non-MHC regions, not previously reported from European populations.
The authors are the members of Japan Research Committee of the Ministry of Health, Labour, and Welfare for Intractable Vasculitis (JPVAS) and Research Committee of Progressive Renal Disease, Ministry of Health, Labour, and Welfare of Japan. This study was performed in collaboration with Japan PGx Data Science Consortium.
To cite this abstract in AMA style:Harigai M, Kawasaki A, Tsuchiya N, Sada K, Hirano F, Sugihara T, Amano K, Yamagata K, Dobashi H, Nagasaka K, Atsumi T, Khor S, Tokunaga K, Ozaki S, Matsuo S, Arimura Y, Makino H. Genome-wide Association Study in a Japanese Population Revealed Novel Candidate Genes for Antineutrophil Cytoplasmic Antibody-associated Vasculitis [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/genome-wide-association-study-in-a-japanese-population-revealed-novel-candidate-genes-for-antineutrophil-cytoplasmic-antibody-associated-vasculitis/. Accessed April 13, 2021.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/genome-wide-association-study-in-a-japanese-population-revealed-novel-candidate-genes-for-antineutrophil-cytoplasmic-antibody-associated-vasculitis/