ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 1013

HLA-Class II Associations with ANCA-Associated Vasculitis in the Japanese Population: Different Features from European Populations

Aya Kawasaki1, Fumio Hirano2, Ken-ei Sada3, Shigeto Kobayashi4, Hidehiro Yamada5, Hiroshi Furukawa1, Kenji Nagasaka6, Takahiko Sugihara7, Kunihiro Yamagata8, Takayuki Sumida9, Shigeto Tohma10, Shoichi Ozaki5, Seiichi Matsuo11, Hiroshi Hashimoto12, Hirofumi Makino13, Yoshihiro Arimura14, Masayoshi Harigai15 and Naoyuki Tsuchiya1, 1Molecular and Genetic Epidemiology Laboratory, University of Tsukuba, Faculty of Medicine, Tsukuba, Japan, 2Departments of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan, 3Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan, 4Department of Internal Medicine, Juntendo University Koshigaya Hospital, Koshigaya, Japan, 5Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan, 6Department of Rheumatology, Ome Municipal General Hospital, Ome, Japan, 7Department of Medicine and Rheumatology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan, 8Department of Nephrology, University of Tsukuba, Faculty of Medicine, Tsukuba, Japan, 9Department of Internal Medicine, University of Tsukuba, Faculty of Medicine, Tsukuba, Japan, 10Clinical Research Center for Allergy and Rheumatology, Sagamihara Hospital, National Hospital Organization, Sagamihara, Japan, 11Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan, 12Juntendo University School of Medicine, Tokyo, Japan, 13Okayama University Hospital, Okayama, Japan, 14First Department of Internal Medicine, Kyorin University School of Medicine, Tokyo, Japan, 15Division of Epidemiology and Pharmacoepidemiology of Rheumatic Diseases, Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: , , ,

Session Information

Date: Monday, November 6, 2017

Title: Genetics, Genomics and Proteomics Poster II

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose: HLA-class II region harbors the strongest genetic factors for ANCA-associated vasculitis (AAV), and differences in the genetic background of HLA-class II may partly explain the epidemiologic differences in AAV between European and Asian populations. HLA-DPB1*04:01, highly prevalent in the European populations, is associated with granulomatosis with polyangiitis (GPA)/PR3-AAV prevalent in the European populations, whereas DRB1*09:01, almost exclusively distributed in Asian populations, is associated with microscopic polyangiitis (MPA)/MPO-AAV, which account for the majority of AAV in Japan. Of interest, although DRB1*09:01 is very rare in the European populations, genome-wide association study (GWAS) detected significant association of a single nucleotide polymorphism (SNP) rs5000634 between DQB1 and DQA2 loci with MPA/MPO-AAV. Whether this association is independent from HLA alleles has not been reported. Another unique feature in Japanese AAV is that only half of the patients with GPA are positive for PR3-ANCA, and the other half are positive for MPO-ANCA. This provides a valuable opportunity to distinguish whether the genetic factors are associated with clinical classification of GPA or ANCA specificity. In the present study, we addressed these two issues in Japanese patients with AAV.

Methods: HLA-DRB1 and DPB1 were genotyped using high-resolution allele typing, and rs5000634 using TaqMan SNP assay. Association was tested in 467 Japanese AAV patients (clinical classification: MPA [285], GPA [92], eosinophilic GPA [56], unclassifiable [34], ANCA specificity: MPO-AAV [376], PR3-AAV [62]) and 596 healthy controls. Among GPA, 36 were single positive for PR3-ANCA (PR3-GPA) and 35 were single positive for MPO-ANCA (MPO-GPA).

Results: As shown in Table 1, rs5000634A was slightly decreased in MPO-AAV and MPA. However, when conditioned on DRB1*09:01 or DRB1*13:02, the association was no longer significant, while the association of DRB1 alleles remained significant after conditioned on rs5000634. When the associations of DRB1 and DPB1 were examined in MPO-GPA and PR3-GPA (Table 2), DPB1*04:01 was associated with PR3-GPA, but slightly decreased in MPO-GPA. In contrast, association of DRB1*08:02 was observed in MPO-GPA, but not in PR3-GPA.

Conclusion: In Japanese AAV, the genetic contribution of HLA-DQ region GWAS SNP was the secondary one caused by linkage disequilibrium with HLA-DRB1 alleles. Striking differences in HLA-DRB1 and DPB1 associations were observed between MPO-GPA and PR3-GPA, suggesting that HLA may be more strongly associated with ANCA specificity than with clinical classification of GPA.

Table 1. The association of European GWAS SNP rs5000634 with MPA/MPO-AAV was secondary to DRB1 association in the Japanese population.

unconditioned

Conditioned on DRB1*09:01

Conditioned on DRB1*13:02

Conditioned on rs5000634

P

OR

(95%CI)

P

OR

(95%CI)

P

OR

(95%CI)

P

OR

(95%CI)

MPO-AAV

 

 

 

 

 

 

 

 

DRB1*09:01

1.6E-04

1.58

(1.25-2.00)

–

–

–

–

1.6E-03

1.53

(1.18-1.99)

DRB1*13:02

7.0E-05

0.43

(0.28-0.65)

–

–

–

–

3.9E-04

0.46

(0.30-0.70)

rs5000634

0.044

0.82

(0.68-1.00)

0.64

0.95

(0.77-1.17)

0.33

0.91

(0.75-1.10)

–

–

MPA

 

 

 

 

 

 

DRB1*09:01

6.4E-04

1.56

(1.21-2.02)

–

–

–

–

4.2E-03

1.52

(1.14-2.01)

DRB1*13:02

1.1E-03

0.47

(0.30-0.74)

–

–

–

–

3.9E-03

0.50

(0.32-0.80)

rs5000634

0.074

0.83

(0.68-1.02)

0.67

0.95

(0.76-1.19)

0.35

0.90

(0.73-1.11)

–

–

Conditional logistic regression analysis was performed under the additive model. OR: odds ratio, CI: confidence interval.

 

Table 2. Differential association of DRB1*08:02, DRB1*13:02 and DPB1*04:01 with PR3-ANCA single positive GPA and MPO-ANCA single positive GPA.

 

PR3-GPA

MPO-GPA

Controls

 

AF (%)

P

OR(95%CI)

AF (%)

P

OR(95%CI)

AF (%)

DRB1*08:02

1.4

0.72

0.49

(0.07-3.67)

11.4

1.3E-03

4.53

(2.01-10.22)

2.8

DRB1*13:02

8.3

1.0

0.93

(0.39-2.20)

1.4

0.025

0.15

(0.02-1.08)

8.9

DPB1*04:01

13.9

0.025

2.39

(1.18-4.85)

1.4

0.12

0.21

(0.03-1.57)

6.3

AF: allele frequency, PR3-GPA: PR3-ANCA positive, MPO-ANCA negative GPA, MPO-GPA: MPO-ANCA positive, PR3-ANCA negative GPA, OR: odds ratio, CI: confidence interval. P values were calculated by Fishers exact test.

 

Disclosure: A. Kawasaki, None; F. Hirano, Chugai Pharmaceutical Co., Ltd.; Ono Pharmaceuticals; Mitsubishi Tanabe Pharma Co.; UCB Japan; CSL Behring; Towa Pharmaceutical Co., Ltd.; Abbvie Japan Co., Ltd.; Japan Blood Products Organization; Ayumi Pharmaceutical Co.; and Nippon Kayaku Co., Ltd, 3,Astellas Pharma Inc, 5; K. E. Sada, None; S. Kobayashi, None; H. Yamada, None; H. Furukawa, Bristol-Myers Squibb Co., 2,Ayumi Pharmaceutical Corporation, 5; K. Nagasaka, Chugai Pharmaceutical Co., Ltd., Bristol Myers Squibb K.K., Teijin Pharma Ltd., Actelion Pharmaceuticals Ltd., Ayumi Pharmaceutical Co., Ltd.., 5; T. Sugihara, Takeda Pharmaceutical Co. Ltd., Mitsubishi-Tanabe Pharma Co., Chugai Pharmaceutical Co., Ltd., Ayumi Pharmaceutical Co., Ltd., UCB Japan Co. Ltd, Astellas Pharma Inc., Janssen Pharmaceutical K.K., Pfizer Japan Inc., and Bristol Myers Squibb K.K, 5; K. Yamagata, None; T. Sumida, None; S. Tohma, None; S. Ozaki, None; S. Matsuo, None; H. Hashimoto, None; H. Makino, None; Y. Arimura, None; M. Harigai, Eisai Ltd, Takeda Ltd, Teijin, 2,Eli Lilly and Company, BMS, Chugai, Janssen, 5; N. Tsuchiya, Novartis Pharmaceutical Corporation, 2,Ayumi Pharmaceutical Co, 5.

To cite this abstract in AMA style:

Kawasaki A, Hirano F, Sada KE, Kobayashi S, Yamada H, Furukawa H, Nagasaka K, Sugihara T, Yamagata K, Sumida T, Tohma S, Ozaki S, Matsuo S, Hashimoto H, Makino H, Arimura Y, Harigai M, Tsuchiya N. HLA-Class II Associations with ANCA-Associated Vasculitis in the Japanese Population: Different Features from European Populations [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/hla-class-ii-associations-with-anca-associated-vasculitis-in-the-japanese-population-different-features-from-european-populations/. Accessed .

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