Background/Purpose

Epidemiologic difference between European and Asian populations is observed in antineutrophil cytoplasmic antibody (ANCA) – associated vasculitis (AAV). Granulomatosis with polyangiitis (GPA) is prevalent in European populations, while microscopic polyangiitis (MPA) is common in Japanese. Genetic factors appear to contribute to the difference in epidemiology, which was supported by a recent genome-wide association study (GWAS) (Lyons et al., 2012). The GWAS indicated that GPA / proteinase 3 (PR3)-ANCA was associated with HLA-DP region, whereas MPA / myeloperoxidase (MPO) – ANCA was associated with HLA-DQ region. These results were consistent with the previous studies showing the association of GPA with HLA-DPB1^*04:01 in European populations, as well as our study that reported HLA-DRB1^*09:01-DQB1^*03:03 haplotype was associated with MPA in Japanese (Tsuchiya et al., 2006). However, due to the rarity of AAV, contribution of HLA-DPB1 to either MPA or GPA has not been reported in a Japanese population.

In this study, by means of multicenter collaborative study in Japan, we investigated whether HLA-DPB1 is associated with susceptibility to AAV in Japanese, and whether the differences in HLA-DPB1 allele frequency can in part account for the population difference in AAV subsets.

Methods

Association of HLA-DPB1 was examined in 356 Japanese patients with AAV and 580 healthy controls. According to the European Medicines Agency algorithm, 220 patients were classified as MPA, 69 as GPA and 35 as eosinophilic granulomatosis with polyangiitis (EGPA). Among the patients, 300 were positive for MPO-ANCA and 41 were positive for PR3-ANCA. HLA-DPB1 typing was performed by the PCR-SSOP (Sequence Specific Oligonucleotide probes) method.

Results

HLA-DPB1*04:01, which was reported to be a risk allele to GPA in European populations, is decreased in MPA (dominant model, P=0.031, odds ratio [OR] 0.53), and more strikingly in MPO-ANCA positive AAV (P=0.0026, OR 0.44). DPB1*05:01 was also decreased in MPA (allele model, P=0.0063, OR 0.72). On the other hand, DPB1*04:01 was increased in PR3-ANCA positive AAV (allele model, P=0.010, OR 2.38). Interestingly, although significant association was not detected in GPA as a whole, DPB1*04:01 was significantly increased when only PR3-ANCA positive GPA was examined (P=5.7E-4, OR 3.18), but not in MPO-ANCA positive GPA.

Conclusion

This study demonstrated that DPB1*04:01 is a risk allele to PR3-ANCA positive AAV also in the Japanese population. In contrast. DPB1*04:01 was protective against MPO-ANCA positive AAV. In view of the population difference in the DPB1*04:01 allele frequency in the Japanese (6.1%) and in the European populations (42.5% in USA, The Allele Frequency Net Database), DPB1*04:01 may in part account for the epidemiological difference in the prevalence of MPO-ANCA and PR3-ANCA positive AAV, in addition to the DRB1*09:01-DQB1*03:03 haplotype.

Table 1 Association of DPB1^*04:01 with AAV in a Japanese population.

	n	Allele frequency	P	OR(95%CI)		Carrier frequency	P	OR(95%CI)
MPA	220	16(0.036)	0.050	0.58(0.33-1.00)		15(0.068)	0.031	0.53(0.30-0.95)
GPA	69	12(0.087)	0.24	1.46(0.77-2.76)		10(0.145)	0.56	1.23(0.60-2.52)
MPO+ GPA	39	2(0.026)	0.32	0.40(0.10-1.68)		2(0.051)	0.30	0.39(0.09-1.67)
PR3+ GPA	32	11(0.172)	5.7X10-4	3.18(1.65-6.15)		9(0.281)	0.0084	2.85(1.31-6.21)
MPO+ AAV	300	18(0.030)	0.0046	0.47(0.28-0.79)		17(0.057)	0.0026	0.44(0.26-0.75)
PR3+ AAV	41	11(0.134)	0.010	2.38(1.23-4.60)		9(0.220)	0.066	2.05(0.95-4.41)
Healthy control	580	71(0.061)				70(0.121)

---

« Back to 2014 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/hla-dpb10401-confers-risk-for-pr3-anca-positive-anca-associated-vasculitis-aav-but-protects-against-mpo-anca-positive-aav-in-a-japanese-population/