http://orcid.org/0000-0003-1353-8056
Figures
Abstract
Objective
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized with joint destructions; environmental and genetic factors were thought to be involved in the etiology of RA. The production of anti-citrullinated peptide antibodies (ACPA) is specifically associated with RA. DRB1 is associated with the susceptibility of RA, especially ACPA-positive RA [ACPA(+)RA]. However, a few studies reported on the independent associations of DPB1 alleles with RA susceptibility. Thus, we investigated the independent association of DPB1 alleles with RA in Japanese populations.
Methods
Association analyses of DPB1 were conducted by logistic regression analysis in 1667 RA patients and 413 controls.
Results
In unconditioned analysis, DPB1*04:02 was nominally associated with the susceptibility of ACPA(+)RA (P = 0.0021, corrected P (Pc) = 0.0275, odds ratio [OR] 1.52, 95% confidence interval [CI] 1.16–1.99). A significant association of DPB1*02:01 with the susceptibility of ACPA(+)RA was observed, when conditioned on DRB1 (Padjusted = 0.0003, Pcadjusted = 0.0040, ORadjusted 1.47, 95%CI 1.19–1.81). DPB1*05:01 was tended to be associated with the protection against ACPA(+)RA, when conditioned on DRB1 (Padjusted = 0.0091, Pcadjusted = 0.1184, ORadjusted 0.78, 95%CI 0.65–0.94). When conditioned on DRB1, the association of DPB1*04:02 with ACPA(+)RA was disappeared. No association of DPB1 alleles with ACPA-negative RA was detected.
Citation: Furukawa H, Oka S, Shimada K, Hashimoto A, Komiya A, Tsunoda S, et al. (2018) Independent association of HLA-DPB1*02:01 with rheumatoid arthritis in Japanese populations. PLoS ONE 13(9): e0204459. https://doi.org/10.1371/journal.pone.0204459
Editor: Qizhai Li, University of the Chinese Academy of Sciences, CHINA
Received: May 27, 2018; Accepted: September 8, 2018; Published: September 20, 2018
Copyright: © 2018 Furukawa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: The work was supported by Grants-in-Aid for Scientific Research (B, C) (26293123, 22591090, 15K09543, 18K08402) and for Young Scientists (B) (24791018) from the Japan Society for the Promotion of Science, Health and Labour Science Research Grants from the Ministry of Health, Labour, and Welfare of Japan, Grants-in-Aid of the Practical Research Project for Allergic Diseases and Immunology (Research on Allergic Diseases and Immunology) from Japan Agency for Medical Research and Development, Grants-in-Aid for Clinical Research from National Hospital Organization, Research Grants from Daiwa Securities Health Foundation, Research Grants from Japan Research Foundation for Clinical Pharmacology, Research Grants from The Nakatomi Foundation, Research Grants from Takeda Science Foundation, Research Grants from Mitsui Sumitomo Insurance Welfare Foundation, Bristol-Myers K.K. RA Clinical Investigation Grant from Bristol-Myers Squibb Co., and research grants from the following pharmaceutical companies: Abbott Japan Co., Ltd., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Mitsuibishi Tanabe Pharma Corporation, Merck Sharp and Dohme Inc., Pfizer Japan Inc., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. The funders had no role in study design, data collection and analysis, decision to publish, or preparing the manuscript.
Competing interests: HF has the following conflicts, and the following funders are supported wholly or in part by the indicated pharmaceutical companies. The Japan Research Foundation for Clinical Pharmacology is run by Daiichi Sankyo, the Takeda Science Foundation is supported by an endowment from Takeda Pharmaceutical Company and the Nakatomi Foundation was established by Hisamitsu Pharmaceutical Co., Inc. The Daiwa Securities Health Foundation was established by Daiwa Securities Group Inc. and Mitsui Sumitomo Insurance Welfare Foundation was established by Mitsui Sumitomo Insurance Co., Ltd. HF was supported by research grants from Bristol-Myers Squibb Co. HF received honoraria from Ajinomoto Co., Inc., Daiichi Sankyo Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Pfizer Japan Inc., and Takeda Pharmaceutical Company, Luminex Japan Corporation Ltd., and Ayumi Pharmaceutical Corporation. ST was supported by research grants from 9 pharmaceutical companies: Abbott Japan Co., Ltd., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Merck Sharp and Dohme Inc., Pfizer Japan Inc., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. ST received honoraria from Asahi Kasei Pharma Corporation, Astellas Pharma Inc., AbbVie GK., Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Pfizer Japan Inc. The other authors declare no financial or commercial conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
Introduction
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized with synovial joint destructions and extra-articular manifestations. The etiology of RA is still unknown, but environmental and genetic factors were thought to be involved in the pathogenesis of RA [1,2,3]. Human leukocyte antigen (HLA) is the strongest genetic factor in RA and it was confirmed in genome wide association studies based on single nucleotide polymorphisms [4]. DRB1 was believed to be the most important locus in HLA for the susceptibility of RA; some DRB1 alleles were associated with the susceptibility of RA and have common motifs of amino acid residues at position 70–74 (QKRAA, RRRAA, or QRRAA) in DRβ chain [5]. These were designated as shared epitope (SE) alleles [6]. DRB1*04:01 was mainly associated with RA in European populations [5] and DRB1*04:05 in Asian [7]. Although both of DRB1*04:01 and DRB1*04:05 are SE alleles, these differences could be explained by the different frequencies of these susceptibility alleles for RA in different ethnic groups. The production of anti-citrullinated peptide antibodies (ACPA) is specifically associated with RA. ACPA-positive RA [ACPA(+)RA] is strongly associated with SE alleles, but ACPA-negative RA [ACPA(-)RA] is weakly [7,8,9].
Some reports also suggested that B, DQB1, or DPB1 would be involved in the pathogenesis of RA [10,11,12,13,14,15,16,17,18,19,20]. Since HLA region is in strong linkage disequilibrium, it is important to eliminate the effects of DRB1 to elucidate the role of other loci in HLA. The independent associations of amino acid residues in B and DPB1 loci were recently reported [21,22,23]. However, few studies reported on the independent associations of DPB1 alleles for RA susceptibility. Since DRB1 is the strongest genetic risk factor for ACPA(+)RA, we investigated the independent association of DPB1 alleles from DRB1 in Japanese ACPA(+)RA.
Materials and methods
Patients
One thousand six hundred sixty seven Japanese RA patients were recruited at Hyogo College of Medicine, Jichi Medical University, Miyakonojo Medical Center, Nagasaki Medical Center, Nagoya Medical Center, Niigata Rheumatic Center, Sagamihara National Hospital, Tochigi Rheumatology Clinic, Tokyo Metropolitan Tama Medical Center, or Yokohama Minami Kyosai Hospital. RA patients fulfilled the 1987 American College of Rheumatology criteria for RA [24] or the 2010 Rheumatoid Arthritis Classification Criteria [25]. Four hundred thirteen Japanese healthy controls (mean age ± SD, 39.3 ± 11.0 years, vs. ACPA(+)RA: P = 6.50X10-130, vs. ACPA(-)RA, P = 5.51X10-71, 61 male [14.8%], vs. ACPA(+)RA: P = 0.0792, vs. ACPA(-)RA, P = 0.2195) were recruited at Kanazawa University, Sagamihara National Hospital, and Teikyo University [26] or by the Pharma SNP Consortium (Tokyo, Japan) [27,28]. Rheumatoid factor and ACPA were measured by N-latex RF kit (Siemens Healthcare Diagnostics, München, Germany) or Mesacup-2 test CCP (Medical & Biological Laboratories, Nagoya, Japan), respectively. This study was reviewed and approved by Hyogo College of Medicine Research Ethics Committee, Jichi Medical University Research Ethics Committee, Miyakonojo Medical Center Research Ethics Committee, Nagasaki Medical Center Research Ethics Committee, Nagoya Medical Center Research Ethics Committee, Niigata Rheumatic Center Research Ethics Committee, Sagamihara National Hospital Research Ethics Committee, Tokyo Metropolitan Tama Medical Center Research Ethics Committee, Yokohama Minami Kyosai Hospital Research Ethics Committee, and University of Tsukuba Research Ethics Committee. Written informed consent was obtained from all study participants. This study was conducted in accordance with the principles expressed in the Declaration of Helsinki.
Genotyping of DRB1 and DPB1
Genotyping of DRB1 and DPB1 was performed by polymerase chain reaction with reverse sequence-specific oligonucleotide probes (WAKFlow HLA typing kit, Wakunaga Pharmaceutical Co., Ltd., Akitakata, Japan) and Bio-Plex 200 (Bio-Rad, Hercules, CA). SE alleles contain DRB1*01:01, DRB1*04:01, DRB1*04:05, DRB1*04:10, DRB1*10:01, and DRB1*14:06 [5]. Genotyping results for some of the RA patients and the healthy controls were previously reported [7,26,29,30,31,32].
Statistical analysis
Clinical features of the RA patients were analyzed by Fisher’s exact test using 2X2 contingency tables or Student’s t-test. Unconditioned logistic regression analysis under the additive model was performed to analyze nominal associations of HLA alleles with the susceptibility of RA. On the other hand, conditioned logistic regression analysis was used to investigate the independent contribution of each DPB1 allele from DRB1 to the susceptibility of RA. Padjusted and ORadjusted were calculated for DPB1 alleles, when conditioned on DRB1. Alleles detected in both case and control groups were tested. The two-locus analysis was also conducted by logistic regression analysis under the additive model to identify the primary role of associated DRB1 or DPB1 alleles. Haplotype frequencies of DRB1-DPB1 were estimated with expectation-maximization algorithm with SNPAlyze ver.8.0.4 Pro (Dynacom, Chiba, Japan) and Permutation P values were established by 100000 permutations. Logistic regression analysis under the additive model was also performed to analyze associations of amino acid residues; conditional logistic regression analysis was used to investigate the independent contribution of each DPβ chain amino acid residue from DRβ chain amino acid residues to the susceptibility of RA. Padjusted values were calculated for amino acid residues in the DPβ chains, when conditioned on DRβ chain amino acid residues. Multiple comparisons were adjusted by Bonferroni method; corrected P (Pc) values were derived from multiplying the P values by the number of alleles or amino acid residues tested.
Results
Clinical manifestations of RA patients
Characteristics of RA patients are shown in Table 1. Steinbrocker stage and class [33] were higher in ACPA(+)RA than ACPA(-)RA. The rheumatoid factor positivity rate was also higher.
Association of DPB1 with ACPA(+)RA
Association of DRB1 with ACPA(+)RA was confirmed (S1 Table), as reported in the previous study [7]; DRB1*04:05 and *04:01 were associated with the susceptibility of ACPA(+)RA and DRB1*04:06, *08:02, *08:03, *13:02, and *14:03 were protectively associated. Next, it was analyzed whether DPB1 was also associated with ACPA(+)RA (Table 2). In unconditioned analysis, DPB1*04:02 was nominally associated with the susceptibility of ACPA(+)RA (P = 0.0021, Pc = 0.0275, odds ratio [OR] 1.52, 95% confidence interval [CI] 1.16–1.99, Table 2, left column). Since DRB1 and DPB1 are in strong linkage disequilibrium, nominal associations of DPB1 alleles were influences by the associations of DRB1 alleles with ACPA(+)RA. In order to clarify whether each DPB1 allele was independently associated with ACPA(+)RA, conditional logistic regression analysis was performed (Table 2, right column). The significant association of DPB1*02:01 with the susceptibility of ACPA(+)RA was observed, when conditioned on DRB1 (Padjusted = 0.0003, Pcadjusted = 0.0040, ORadjusted 1.47, 95%CI 1.19–1.81, Table 2, right column). DPB1*05:01 was tended to be associated with the protection against ACPA(+)RA, when conditioned on DRB1 (Padjusted = 0.0091, Pcadjusted = 0.1184, ORadjusted 0.78, 95%CI 0.65–0.94, Table 2, right column). When conditioned on DRB1, DPB1*04:02 was not associated with the susceptibility of ACPA(+)RA, suggesting the influence of DRB1 on the nominal association of DPB1*04:02. Thus, DPB1*02:01 was independently associated with the susceptibility of ACPA(+)RA.
In order to reveal whether each DRB1 allele influenced on the association of DPB1*02:01 with the susceptibility of ACPA(+)RA, conditional logistic regression analysis was conducted (Table 3). When conditioned on DRB1*04:05, the significant association of DPB1*02:01 with the susceptibility of ACPA(+)RA was observed (Padjusted = 0.0073, ORadjusted 1.29, 95%CI 1.07–1.56, Table 3). Because DRB1*04:05 is the strongest risk factor for RA in Asian [7], the influence of DRB1*04:05 on the nominal association of DPB1*02:01 would be strongest. However, the stronger association of DPB1*02:01 with the susceptibility of ACPA(+)RA was observed, when conditioned on SE alleles (Padjusted = 0.0016, ORadjusted 1.37, 95%CI 1.13–1.66, Table 3) or DRB1 (Padjusted = 0.0003, ORadjusted 1.47, 95%CI 1.19–1.81, Table 3). These data suggested that many DRB1 alleles including DRB1*04:05 had influenced on the nominal association of DPB1*02:01 with the susceptibility of ACPA(+)RA.
The two-locus analysis was conducted to identify the primary role of DRB1*04:05 and DPB1*02:01 for the susceptibility of ACPA(+)RA (S2 Table). The OR for DPB1*02:01 in ACPA(+)RA patients with DRB1*04:05 was 1.45 (P = 0.0688, S2 Table), while the OR for DPB1*02:01 in ACPA(+)RA patients without DRB1*04:05 was 1.26 (P = 0.0356, S2 Table). On the other hand, the OR for DRB1*04:05 in ACPA(+)RA patients with DPB1*02:01 was 4.21 (P = 3.71X10-12, S2 Table), and the OR for DRB1*04:05 in ACPA(+)RA patients without DPB1*02:01 was 3.33 (P = 7.58X10-15, S2 Table). These results suggested the independent roles of DRB1*04:05 and DPB1*02:01 on the susceptibility of ACPA(+)RA.
When haplotype frequencies were compared between ACPA(+)RA patients and controls, three haplotypes including DRB1*04:05 were associated with the susceptibility of ACPA(+)RA (DRB1*04:05-DPB1*02:01; Permutation P<0.0001, DRB1*04:05-DPB1*04:02,; Permutation P = 0.0004, DRB1*04:05-DPB1*05:01; Permutation P<0.0001, S3 Table), suggesting the primary role of DRB1*04:05. On the other hand, some haplotypes including DPB1*02:01 were associated with the ACPA(+)RA susceptibility (DRB1*04:05-DPB1*02:01; Permutation P <0.0001, DRB1*09:01-DPB1*02:01; Permutation P = 0.0048, S3 Table) or the protection (DRB1*04:06-DPB1*02:01; Permutation P = 0.0149, DRB1*08:02-DPB1*02:01; Permutation P<0.0001, DRB1*13:02-DPB1*02:01; Permutation P = 0.0015, DRB1*15:01-DPB1*02:01; Permutation P = 0.0208, S3 Table), suggesting the influences of DRB1 alleles on the effects of DPB1*02:01. These data suggested the stronger effects of DRB1 alleles on the ACPA(+)RA susceptibility or the protection.
Association of DPB1 with ACPA(-)RA
It was analyzed whether DPB1 was also associated with ACPA(-)RA (Table 4). In unconditioned analysis, no DPB1 allele was associated with the susceptibility of ACPA(-)RA (Table 4, left column). In order to elucidate whether each DPB1 allele was independently associated with ACPA(-)RA, conditional logistic regression analysis was performed (Table 4, right column). No association of DPB1 alleles with the susceptibility of ACPA(-)RA was observed, when conditioned on DRB1. Association of DPB1 was also analyzed with overall RA (S4 Table). In unconditioned analysis, no DPB1 allele was associated with the overall RA (S4 Table, left column). When conditioned on DRB1, DPB1*02:01 was associated with the overall RA (S4 Table, right column). However, the association was weaker than ACPA(+)RA.
Association of DPβ chain amino acid residues with ACPA(+)RA
Association of DRβ chain amino acid residues with ACPA(+)RA was confirmed (S1 Fig), as reported in the previous study [7]; 10Y, 11S, 12T, 13H, 33N, 70D, 96Y, and 98K in the DRβ chain showed associations. Two amino acid residues, 36A 55A, in the DPβ chain were slightly associated with ACPA(+)RA in unconditioned analysis (Fig 1A). In order to clarify whether each DPβ chain amino acid residue was independently associated with ACPA(+)RA, conditional logistic regression analysis was performed. Five amino acid residues, 84G (P = 3.20X10-5, Pc = 0.0005, OR = 1.48, 95% CI 1.23–1.79), 85G (P = 3.20X10-5, Pc = 0.0005, OR = 1.48, 95% CI 1.23–1.79), 86P (P = 3.20X10-5, Pc = 0.0005, OR = 1.48, 95% CI 1.23–1.79), 87M (P = 3.20X10-5, Pc = 0.0005, OR = 1.48, 95% CI 1.23–1.79), and 96R (P = 3.94X10-5, Pc = 0.0006, OR = 1.48, 95% CI 1.23–1.78), in the DPβ chain were significantly associated with ACPA(+)RA, when conditioned on DRβ chain amino acid residues (Fig 1B). Since there are three haplotypes of these amino acid residues in the DPβ chain (84G-85G-86P-87M-96R, 84D-85E-86A-87V-96K, 84D-85E-86A-87V-96R), the results might reflect the effects of the haplotype of 84G-85G-86P-87M-96R on the susceptibility of ACPA(+)RA. The haplotype was actually associated with ACPA(+)RA in unconditioned analysis (P = 0.0078, OR = 1.24, 95% CI 1.06–1.44), or when conditioned on DRβ chain amino acid residues (Padjusted = 4.11X10-5, ORadjusted 1.47, 95%CI 1.22–1.77).
(A) Association was established between ACPA(+)RA and controls by logistic regression analysis. (B) Conditional logistic regression analysis was performed to clarify whether each DPβ chain amino acid residue was independently associated with ACPA(+)RA. Padjusted values were calculated for amino acid residues in the DPβ chains, when conditioned on DRβ chain amino acid residues. Corrected P (Pc) values were obtained by multiplying the P value by the number of amino acid residues tested. RA: rheumatoid arthritis, ACPA: anti-citrullinated peptide antibody, ACPA(+)RA: ACPA positive RA.
Discussion
Although many investigations on the associations of DRB1 alleles with the susceptibility of RA were performed, relatively fewer studies on the genetic effects of DPB1 alleles for RA were conducted. There are a few direct reports on the independent association of DPB1 alleles for the susceptibility of RA, though results of some studies suggested the role of DPB1 alleles for RA [10,13,14,16,18]. DPB1*03:01 was associated with rheumatoid factor negative RA in European descent [10]. When arginine at position 71 of DRβ chain was possessed, DPB1*04:01 was associated with European RA [13]. DPB1*02:01 and DPB1*06:01 were associated with European RA without SE, whereas DPB1*04:01 was associated with European RA with SE [14]. DPB1*02:01 was associated with Japanese RA without DRB1*04:05 [16]. The association of DPB1*02:01 with the susceptibility of Japanese ACPA(+)RA and that of DPB1*04:01and DPB1*09:01 with the protection were suggested [18]. However, the results of these previous studies could not conclude the independent association of DPB1*02:01 from DRB1. In the present study, we directly revealed it in Japanese populations.
It was reported that phenylalanine at position 9 in DPβ chain was reported to be independently associated with European ACPA(+)RA [21]. Glycine at position 84 in DPβ chain was also independently associated with Japanese ACPA(+)RA [23]. However, the independently associated DPB1 alleles were not reported in these studies. In the present study, glycine at position 84 in DPβ chain was independently associated with ACPA(+)RA and 84G-85G-86P-87M-96R in DPβ chain was the ACPA(+)RA susceptible haplotype. This ACPA(+)RA associated haplotype was included in DPB1*02:01, DPB1*02:02, DPB1*04:01, DPB1*04:02, and DPB1*41:01. Since the alleles other than DPB1*02:01 were not directly associated with ACPA(+)RA susceptibility (Table 2, right column), DPB1*02:01 would be mainly contributed to the risk of ACPA(+)RA among them. The independent association of phenylalanine at position 9 in DPβ chain was not confirmed in the present study, though this amino acid residue was included in DPB1*02:01 and other alleles. This could be explained by the different distribution of HLA alleles in other ethnic populations. The amino acid residues 84, 85, 86, and 87 form the pocket 1 of DP peptide-binding groove [34]. This information suggested the involvement of peptides loaded on DP2 in the generation of ACPA or rheumatoid factor.
The association of DPB1*02:01 with ACPA(-)RA was not detected in the present study (Table 4), because of the limited sample size of ACPA(-)RA. Although the association of DPB1with ACPA(-)RA was not found in the study on European populations [22], weak association was shown around DP loci in the other study on Japanese populations [23]. Therefore, this could be detected in future large scale studies. The independent association of DPB1*02:01 with ACPA(+)RA should be replicated in future studies in Japanese populations and should be also analyzed in other populations. It was the limitation of this study that the population stratification was not excluded [35,36]. Thus, the present study revealed the independent association of DPB1*02:01 with ACPA(+)RA in Japanese populations.
Supporting information
S1 Fig. Associations of amino acid residues in the DRβ chains with ACPA(+)RA.
Association was established between ACPA(+)RA and controls by logistic regression analysis. Corrected P (Pc) values were obtained by multiplying the P value by the number of amino acid residues tested. RA: rheumatoid arthritis, ACPA: anti-citrullinated peptide antibody, ACPA(+)RA: ACPA positive RA.
https://doi.org/10.1371/journal.pone.0204459.s001
(PDF)
S1 Table. Logistic regression analysis of DRB1 alleles in ACPA(+) RA and controls.
RA: rheumatoid arthritis, ACPA: anticitrullinated peptide antibody, ACPA(+)RA: ACPA positive RA, OR: odds ratio, CI: confidence interval, P c: corrected P value, NS: not significant. Allele frequencies are shown in parenthesis (%). Association was tested by logistic regression analysis.
https://doi.org/10.1371/journal.pone.0204459.s002
(PDF)
S2 Table. Logistic regression analysis in the ACPA(+)RA patients and controls with or without DRB1*04:05 or DPB1*02:01.
RA: rheumatoid arthritis, ACPA: anti-citrullinated peptide antibody, ACPA(+)RA: ACPA positive RA, OR: odds ratio, CI: confidence interval. Association was tested between the RA patients and the controls with or without DRB1*04:05 or DPB1*02:01 by logistic regression analysis.
https://doi.org/10.1371/journal.pone.0204459.s003
(PDF)
S3 Table. DRB1-DPB1 haplotype frequency in the ACPA(+)RA patients and controls.
RA: rheumatoid arthritis, ACPA: anti-citrullinated peptide antibody, ACPA(+)RA: ACPA positive RA. Haplotypes with more than 1% frequency in controls are shown.
https://doi.org/10.1371/journal.pone.0204459.s004
(PDF)
S4 Table. Conditional logistic regression analysis of HLA-DPB1 alleles in the RA patients and controls.
RA: rheumatoid arthritis, OR: odds ratio, CI: confidence interval. Association was tested between the RA patients and the controls by Logistic regression analysis.
https://doi.org/10.1371/journal.pone.0204459.s005
(PDF)
Acknowledgments
We thank Ms. Mayumi Yokoyama and Ms. Tomomi Hanawa (Clinical Research Center for Allergy and Rheumatology, Sagamihara National Hospital) for secretarial assistance.
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