Effects of HLA-DRB1 alleles on susceptibility and clinical manifestations in Japanese patients with adult onset Still’s disease

Abstract

Background HLA-DRB1 alleles are major determinants of genetic predisposition to rheumatic diseases. We assessed whether DRB1 alleles are associated with susceptibility to particular clinical features of adult onset Still’s disease (AOSD) in a Japanese population by determining the DRB1 allele distributions.Methods DRB1 genotyping of 96 patients with AOSD and 1,026 healthy controls was performed. Genomic DNA samples from the AOSD patients were also genotyped for MEFV exons 1, 2, 3, and 10 by direct sequencing.ResultsIn Japanese patients with AOSD, we observed a predisposing association of DRB1*15:01 (p = 8.60 × 10−6, corrected p (Pc) = 0.0002, odds ratio (OR) = 3.04, 95% confidence interval (95% CI) = 1.91–4.84) and DR5 serological group (p = 0.0006, OR = 2.39, 95% CI = 1.49–3.83) and a protective association of DRB1*09:01 (p = 0.0004, Pc = 0.0110, OR = 0.34, 95% CI = 0.18–0.66) with AOSD, and amino acid residues 86 and 98 of the DRβ chain were protectively associated with AOSD. MEFV variants were identified in 49 patients with AOSD (56.3%). The predisposing effect of DR5 was confirmed only in patients with AOSD who had MEFV variants and not in those without MEFV variants. Additionally, DR5 in patients with AOSD are associated with macrophage activation syndrome (MAS) and steroid pulse therapy.ConclusionThe DRB1*15:01 and DR5 are both associated with AOSD susceptibility in Japanese subjects. A protective association between the DRB1*09:01 allele and AOSD was also observed in these patients. Our data also highlight the effects of DRB1 alleles in susceptibility to AOSD.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-017-1406-x) contains supplementary material, which is available to authorized users.

Characteristic patterns of HLA presentation and T cell differentiation in adult-onset Still’s disease

“…HLA-DRB1*12 and 15 were observed more frequently in Korean patients with AOSD, while HLA-DRB1*15:01 and DR5 were associated with susceptibility to AOSD in Japanese patients. 9 We observed higher proportions of lymphocytes presenting HLA-DP and DR, with HLA-DP levels significantly associated with LDH levels. Furthermore, the proportion of granulocytes expressing HLA-DR was correlated with IL-23 and IL-18.…”

BothHLAclass I and II regions identified as genome-wide significant susceptibility loci for adult-onset Still's disease in Chinese individuals

“…However, only a few genetic loci have been associated with AOSD, and none of them have reached the threshold for genome-wide significance (GWS) of p<5×10 − 8 . 2 3 For example, HLA-DRB1 was strongly associated with AOSD in previous studies (the p value for the most significant association was 8.60×10 − 6 ) 34 which presents similarly to AOSD but differs in age of onset.…”

Human leukocyte antigens in inflammatory bowel disease

“…Rheumatoid arthritis is associated with HLA-DRB1 8 . Furthermore, HLA DRB1 * 15: 01 may have an inducing effect with adult Still's disease (AOSD), while DRB1 * 09: 01 has a protective effect 9 . In addition, a strong relationship between HLA-DRB1 * 11 and systemic juvenile idiopathic arthritis has been identified 10 .…”