Genetic Background of Japanese Patients with Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: Association of HLA-DRB1*0901 with Microscopic Polyangiitis

NAOYUKI TSUCHIYA, SHIGETO KOBAYASHI, AYA KAWASAKI, CHIEKO KYOGOKU, YOSHIHIRO ARIMURA, MASAHARU YOSHIDA, KATSUSHI TOKUNAGA, and HIROSHI HASHIMOTO

ABSTRACT.

Objective. To examine association of 8 candidate genes with susceptibility to antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in Japanese patients. Little is known on the genetic background of AAV in Japanese patients mainly because of the difficulty in collecting a sufficient number of samples for the genetics study.

Methods. Sixty-nine patients, including 50 with microscopic polyangiitis (MPA), were recruited in a multicenter study. Among them, 64 patients were positive for myeloperoxidase (MPO)-ANCA. Associations of HLA-DRB1, tumor necrosis factor-a promoter (TNF), TNF receptor 2 (TNFR2), Fcg receptor IIa (FCGR2A), IIb (FCGR2B), IIIa (FCGR3A), IIIb (FCGR3B), and CTLA-4 (CTLA4) polymorphisms were examined in a case-control analysis.

Results. A significant association of HLA-DRB1*0901 with MPA (p = 0.0037, OR 2.44, 95% CI 1.33–4.46), as well as with MPO-ANCA positivity (p = 0.0014, OR 2.44, 95% CI 1.41–4.22), was detected. There was no difference in the TNF promoter haplotype frequencies between patients with MPA and controls, excluding the possibility that the association of DRB1*0901 was secondarily caused by linkage disequilibrium with TNF. No association was observed for TNFR2, FCGR, or CTLA4 with MPA, nor with the presence of MPO-ANCA, although the combined genotype FCGR2A-131H/H and 3A-176F/F was increased in patients with MPA (p = 0.025).

Conclusion. There was an association of HLA-DRB1*0901 with MPA and MPO-ANCA positive vasculitis in Japanese patients. (J Rheumatol 2003;30:1534-40)

Key Indexing Terms:

ANTINEUTROPHIL CYTOPLASMIC ANTIBODY
MICROSCOPIC POLYANGIITIS
GENETICS
HLA
SUSCEPTIBILITY

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From the Department of Human Genetics, The University of Tokyo, the Department of Rheumatology and Internal Medicine, Juntendo University, the First Department of Internal Medicine, Kyorin University, and the Division of Nephrology, Hachioji Medical Center of Tokyo Medical University, Tokyo, Japan.

Supported by Health Sciences Research Grants, the Ministry of Health, Labour and Welfare of Japan, the Grant-in-Aid for Scientific Research on Priority Areas (C) Medical Genome Science, and the Grant-in-Aid for Scientific Research (B) from the Ministry of Education, Science, Sports, and Culture of Japan.

N. Tsuchiya, MD, PhD, Associate Professor; A. Kawasaki, BSc, Technician; C. Kyogoku, MSc, Graduate Student; K. Tokunaga, PhD, Professor, Department of Human Genetics, The University of Tokyo; S. Kobayashi, MD, PhD, Assistant Professor; H. Hashimoto, MD, PhD, Director and Professor, Department of Rheumatology and Internal Medicine, Juntendo University; Y. Arimura, MD, PhD, Associate Professor, First Department of Internal Medicine, Kyorin University; M. Yoshida, MD, PhD, Associate Professor, Division of Nephrology, Hachioji Medical Center of Tokyo Medical University. H. Hashimoto is the Director, and T. Tokunaga, S. Kobayashi, Y. Arimura, and M. Yoshida are the members, of the Research Committee on Intractable Vasculitides, The Ministry of Health, Labour and Welfare of Japan.

Address reprint requests to Dr. N. Tsuchiya, Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan 113-0033. E-mail: tsuchiya-tky@umin.ac.jp

Submitted July 11, 2002; revision accepted December 26, 2002.

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