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. 2020 Aug 18;15(8):e0237890. doi: 10.1371/journal.pone.0237890

HLA-DRB1 allele and autoantibody profiles in Japanese patients with inclusion body myositis

Munenori Oyama 1, Yuko Ohnuki 2, Michio Inoue 3, Akinori Uruha 4, Satoshi Yamashita 5, Sachiko Yutani 6, Jantima Tanboon 3, Jin Nakahara 1, Shingo Suzuki 7, Takashi Shiina 7, Ichizo Nishino 3, Shigeaki Suzuki 1,*
Editor: Frederick W Miller8
PMCID: PMC7437458  PMID: 32810190

Abstract

Introduction

Inclusion body myositis (IBM) is an idiopathic inflammatory myopathy, characterized by unique clinical features including finger flexor and quadriceps muscle weakness and a lack of any reliable treatment. The human leukocyte antigen (HLA)-DRB1 allele and autoantibody profiles in Japanese IBM patients have not been fully elucidated.

Methods

We studied 83 Japanese IBM patients with a mean age of 69 years (49 males and 34 females) who participated in the ‘Integrated Diagnosis Project for Inflammatory Myopathies’ from January 2011 to September 2016. IBM was diagnosed by histological diagnosis. Various autoantibodies were screened by RNA immunoprecipitation and enzyme-linked immunosorbent assays. HLA-DRB1 genotyping was performed using polymerase chain reaction-sequence based typing. A total of 460 unrelated healthy Japanese controls were also studied.

Results

The allele frequencies of DRB1*01:01, DRB1*04:10, and DRB1*15:02 were significantly higher in the IBM group than in the healthy control group (Corrected P = 0.00078, 0.00038 and 0.0046). There was a weak association between the DRB1*01:01 allele and severe leg muscle weakness and muscle atrophy. While hepatitis type C virus infection and autoantibodies to cytosolic 5’-nucleotidase 1A were found in 18 and 28 patients, respectively, no significant association with HLA-DRB1 alleles was observed.

Conclusion

Japanese IBM patients had the specific HLA-DRB1 allele and autoantibody profiles.

Introduction

Inclusion body myositis (IBM) is a slowly progressive skeletal muscle disease with unique clinical and pathological features including finger flexor and quadriceps weakness and the presence of infiltrating cytotoxic T cells in muscle [1]. Degenerative abnormalities such as numerous protein aggregates are believed to occur following the action of several autoimmunity mechanisms. In fact, IBM is categorized as an inflammatory myopathy. We created the "Integrated Diagnosis Project for Inflammatory Myopathies" to determine the correlation between autoantibodies and muscle pathology [2]. The strength of our project was to fully exclude various metabolic and genetic myopathies from inflammatory myopathies based on comprehensive histological, genetic, and chemical analyses of muscle specimen. We have demonstrated that pathological subsets of inflammatory myopathies were clearly defined by autoantibodies. Autoantibodies to cytosolic 5’-nucleotidase 1A (cN1A or 5NTC1A) were more frequently detected in IBM than in other inflammatory myopathies, even though the autoantibodies were not highly specific to it [3–7].

Certain polymorphic genes of the human major histocompatibility complex have been associated with inflammatory myopathies [8]. The strongest disease association with alleles of the human leukocyte antigen (HLA) 8.1 ancestral haplotype—HLA-DRB1*03:01 and HLA-B*08:01—occurs in the clinical diagnosis of polymyositis and dermatomyositis [8]. Similarly, a disease association between DRB1*03:01 and Caucasian patients with IBM was reported by several investigators [9–12]. However, it is noted that DRB1*0301 is rarely detectable in the Japanese population. Although the clinical profiles of Japanese patients with IBM are similar to those of Caucasian patients [13], the immunogenetic background and autoantibody profiles have not been fully elucidated.

The purpose of the present study is to investigate autoimmune features in Japanese patients with IBM.

Material and methods

Patients

We studied 83 Japanese patients with IBM who participated in the ‘Integrated Diagnosis Project for Inflammatory Myopathies’ from January 2011 to September 2016 (S1 Table). The diagnoses were made based upon the criteria of Lloyd et al. [14]. These patients were not included in the previous reports [15,16]. We received frozen muscle biopsy blocks and blood from patients with tentative diagnoses of inflammatory myopathies, from all over Japan. Each patient’s clinical information was provided by his or her referring physician, who completed detailed charts that included the clinical course and, neurological examination and laboratory findings. Previous infection with hepatitis type C virus (HCV) was determined by anti-HCV enzyme-linked immunosorbent assay (ELISA) kit (Aria HCB Ab ELISA, CTK Biotech, Poway, CA). This study was approved by the Institutional Review Boards of the Keio University (No. 20090278), National Center of Neurology and Psychiatry, and Tokai University. All of the clinical materials used in this study were obtained for diagnostic purposes with written informed consent.

Autoantibodies detection

Frozen sera were stored at -30°C until autoantibodies detection was performed. The screening of various autoantibodies was done by RNA immunoprecipitation and ELISAs. RNA immunoprecipitation was performed as previously described [17]. Ten-μl aliquots of serum were mixed with 2 mg of protein A-Sepharose CL-4B (Pharmacia Biotech AB) in 500 μl of immunoprecipitation buffer and incubated for 2 h. After being washed three times with immunoprecipitation buffer, antigen-bound Sepharose beads were mixed with 100 μl of HeLa cell extract (6 × 106 cell equivalents per sample) for 2 h, and then 30 μl of 3 M sodium acetate, 30 μl of 10% sodium dodecyl sulfate, and 300 μl of phenol:chloroform:isoamyl alcohol (50:50:1, containing 0.1% 8-hydroxyquinoline) were added to extract the bound RNA. After ethanol precipitation, the RNA was resolved using a 7-M urea-8% polyacrylamide gel, and the gel was silver-stained.

ELISAs of anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and anti-cN1A antibodies were performed using C-terminal recombinant HMGCR protein (Sigma) and recombinant cN1A protein (Origene, Rockville, MD) [18].

HLA-DRB1 genotyping

Genomic DNA was extracted from peripheral blood using standard methods. HLA-DRB1 genotyping was performed using polymerase chain reaction-sequence based typing [19]. A total of 460 unrelated healthy Japanese control subjects were also studied.

Statistical analyses

All analyses were performed using R software (version R-3.2.3) and IBM/SPSS V.20 (Armonk, New York, USA). Comparisons of relative frequencies were tested for significance using the χ2 test for 2×2 tables. Bonferroni-corrected P (corrected P) values were obtained by multiplying the observed p values by the number of DRB1 alleles (× 29). Continuous variables were compared using the Mann-Whitney U-test. Values of p<0.05 were considered significant.

Results

Clinical features and autoantibody profiles

Table 1 shows the clinical features and autoantibody profiles of Japanese patients with IBM (n = 83, 49 males and 34 females). The mean age of disease onset was 69 years (range 51–85). Statin exposure preceded the development of IBM in 4 patients (pitavastatin in 2 patients, atorvastatin in 1, and pravastatin in 1). Two patients had cancers within 2 years before the diagnosis of IBM (breast cancer and bladder cancer). There were five systemic autoimmune diseases including Sjögren syndrome, systemic sclerosis, rheumatoid arthritis, polymyalgia rheumatic, and microscopic polyangiitis. HCV infection was found in 18 patients (22%).

Table 1. Clinical features and autoantibody profiles of 83 Japanese patients with inclusion body myositis.

Number (%) (n = 83)
Age, average 69 years
Males:females 49:34
Background
 Statin exposure 4 (5%)
 Cancer 2 (2%)
 Systemic autoimmune disease 5 (6%)
 Hepatitis C virus infection 18 (22%)
Muscle symptoms
 Severe leg muscle weakness 37 (45%)
 Finger flexion weakness 47 (57%)
 Facial muscle involvement 4 (5%)
 Dysphagia 26 (31%)
 Neck muscle weakness 32 (39%)
 Cardiac muscle involvement 4 (5%)
 Respiratory muscle involvement 1 (1%)
 Muscle atrophy 67 (81%)
 Myalgia 9 (11%)
Extramuscular symptoms
 Skin rash 8 (10%)
 Arthropathy 4 (5%)
 Raynaud’s phenomenon 2 (2%)
 Interstitial lung disease 2 (2%)
Laboratory findings
 Creatine kinase, average 676 IU/L
 Elevated C-reactive protein 0
 Antinuclear antibody positivity 6 (7%)
Autoantibodies
RNA immunoprecipitation
 Anti-signal recognition particle 0
 Anti-aminoacyl transfer RNA synthetase 0
 Anti-SSA 3 (3%)
 Anti-SSB 2 (2%)
 Anti-U1RNP 1 (1%)
 Anti-Ku 1 (1%)
Enzyme-linked immunosorbent assays
 Anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase 0
 Anti-cytosolic 5’-nucleotidase 1A 28 (34%)
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All patients exhibited objective limb muscle weakness especially in finger flexion and knee extension. Severe leg muscle weakness with grade ≤ 3/5 as assessed by manual muscle strength (Medical Research Council scale grade), usually involving the iliopsoas muscles, was seen in 37 patients. Finger flexion weakness was found in 47 patients. Dysphagia was observed in 26 patients. Although 32 patients showed neck muscle weakness, facial, cardiac, and respiratory muscle involvement was infrequent. Neurological examination revealed muscle atrophy in 67 patients. Deep tendon reflexes were decreased or absent in 40 patients. Muscle pain was reported in only 9 patients. With regard to extramuscular manifestations, skin rash, arthropathy, interstitial lung disease, Raynaud’s phenomenon, and interstitial lung disease were relatively infrequent.

The mean peak serum creatine kinase activity was 676 IU/L. Out of 83 patients, 13 had creatine kinase activity greater than 1,000 IU/L. No patients had elevation of C-reactive protein (≥ 1 mg/dL). Positivity for antinuclear antibodies (≥ 1:160) was detected in only 6 patients. RNA immunoprecipitation revealed no major autoantigens such as signal recognition particle (SRP) or aminoacyl transfer RNA synthetases, but some minor autoantigens were found including SSA (n = 3), SSB (n = 2), U1 RNP (n = 1), and Ku (n = 1). Additional ELISAs showed that none had anti-HMGCR antibodies, but 28 IBM patients (33%) had anti-cN1A antibodies.

HLA association with DRB1 alleles

The DRB1 allele frequencies of the 83 Japanese patients with IBM were compared to those of 460 healthy controls (Table 2). There were significant differences between the two groups. DRB1*01:01 (17% vs. 6%, P = 0.000027, corrected P = 0.00078), DRB1*04:10 (8% vs. 2%, P = 0.000013, corrected P = 0.00038), and DRB1*15:02 (24% vs. 12%, P = 0.00016, corrected P = 0.0046) were detected in the Japanese IBM patients at higher rates than in healthy controls using Bonferroni-correction. In contrast to these risk alleles, we found that DRB1*04:06, DRB1*08:03, DRB1*09:01, and DRB1*12:01 were protective alleles for the development of IBM. Among these alleles, DRB1*09:01 showed still significant after a Bonferroni correction for multiple comparisons (P = 5.4 × 10−9, corrected P = 1.6× 10−7). In fact, DRB1*09:01 was only found in one IBM patient, although it was a relatively common allele in the Japanese population.

Table 2. DRB1 allele frequencies of Japanese patients with inclusion body myositis (IBM) and healthy controls.

IBM (n = 166) Healthy controls (n = 920) P Odds ratio (95% confidence intervals), corrected P*
DRB1*01:01 28 (17%) 58 (6%) 0.000027 3.0 (1.7–5.0), 0.00078
DRB1*03:01 2 (1%) 1 (0.1%) 0.063
DRB1*04:01 1 (0.6%) 11 (1%) 0.50
DRB1*04:03 3 (2%) 23 (3%) 0.59
DRB1*04:05 26 (16%) 103 (11%) 0.23
DRB1*04:06 0 33 (4%) 0.0059 0 (0–0.64)
DRB1*04:07 0 5 (0.5%) 1.0
DRB1*04:10 14 (8%) 14 (2%) 0.000013 5.9 (2.6–13.8), 0.00038
DRB1*07:01 0 1 (0.1%) 1.0
DRB1*08:02 9 (5%) 53 (6%) 0.86
DRB1*08:03 3 (2%) 71 (8%) 0.0038 0.2 (0.04–0.68)
DRB1*09:01 1 (0.6%) 128 (14%) 5.4 × 10−9 0.04 (0.0009–0.21), 1.6 × 10−7
DRB1*10:01 2 (1%) 2 (0.2%) 0.11
DRB1*11:01 6 (4%) 23 (3%) 0.43
DRB1*12:01 0 32 (4%) 0.0099 0 (0–0.66)
DRB1*12:02 2 (1%) 19 (2%) 0.76
DRB1*13:01 2 (1%) 3 (0.3%) 0.17
DRB1*13:02 6 (4%) 68 (7%) 0.076
DRB1*13:03 0 1 (0.1%) 1.0
DRB1*13:07 0 1 (0.1%) 1.0
DRB1*14:02 1 (0.6%) 0 0.15
DRB1*14:03 0 13 (1%) 0.24
DRB1*14:05 3 (2%) 25 (3%) 0.79
DRB1*14:06 4 (2%) 12 (1%) 0.28
DRB1*14:12 0 1 (0.1%) 0.18
DRB1*14:54 1 (0.6%) 37 (4%) 0.027
DRB1*15:01 9 (5%) 62 (7%) 0.53
DRB1*15:02 40 (24%) 114 (12%) 0.00016 2.2 (1.5–3.4), 0.0046
DRB1*16:02 4 (2%) 6 (0.7%) 0.052
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*Corrected P values are evaluated using Bonferroni-correction and are presented only in significance.

We next examined differences in the clinical features of IBM patients between the presence and absence of the risk alleles of HLA-DRB1. IBM patients with DRB1*01:01 (n = 28) tended to have severe leg muscle weakness (64% vs. 35%, P = 0.01) and muscle atrophy (93% vs. 75%, P = 0.046) compared to those without DRB1*01:01 (n = 55) (S2 Table). However, DRB1*04:10 and DRB1*15:02 alleles were not associated with particular clinical manifestations (S3 and S4 Tables).

HCV infection and anti-cN1A antibodies

To disclose the relationship between the particular subsets of IBM and HLA-DRB1, 83 IBM patients were stratified by HCV infection and anti-cN1A antibodies. We compared the clinical features and DRB1 alleles between the IBM patients with and without HCV infection. IBM patients with HCV infection (n = 18) tended to have finger flexion weakness (78% vs. 51%, P = 0.0046), dysphagia (61% vs. 23%, P = 0.002), and neck muscle weakness (61% vs. 32%, P = 0.026) compared to those without HVC infection (n = 65) (S5 Table). Next, we compared the clinical features and DRB1 alleles between the IBM patients with and without anti-cN1A antibodies (n = 28 and 55, respectively), revealing no differences between the two groups (S6 Table).

Among the 83 IBM patients, 11 (13%) had both HCV infection and anti-cN1A antibodies. The frequencies of HCV infection were significantly higher in IBM patients with anti-cN1A antibodies than in those without (39% vs. 13%, P = 0.006). When we compared the clinical features and DRB1 alleles between the IBM patients with both HCV infection and anti-cN1A antibodies (n = 11) and the others (n = 72), there were no differences between the two groups (S7 Table).

Discussion

The present study can be summarized as follows: (i) the frequencies of DRB1*01:01, DRB1*04:10, and DRB1*15:02 were significantly higher in the Japanese patients with IBM than in healthy controls (Corrected P = 0.00078, 0.00038 and 0.0046); (ii) there was a weak association between the DRB1*01:01 allele and clinical features (severe leg muscle weakness and muscle atrophy); and (iii) HCV infection and anti-cN1A antibodies were not associated with HLA-DRB1 alleles.

We demonstrated the strong association of DRB1*01:01, DRB1*04:10, and DRB1*15:02 with IBM in the Japanese population. The disease’s association with DRB1*15:02 was similar to that found in a previous report [15]. Among these alleles, DRB1*01:01 was associated with the specific clinical features of severe leg muscle weakness and muscle atrophy. However, we cannot find the significant association after the Bonferroni-correction. In this regard, a future larger study with more IBM patients would be needed to fully assess the association. Although DRB1*03:03 was the most common allele in Caucasian patients with IBM [9–12], two studies found an additional association with IBM. Rothwell et al. indicated that DRB1*01:01 was an independent effect associated with IBM in 252 Caucasian patients who were recruited from 11 European countries through the Myositis Genetic Consortium [9]. In addition, Rojana-Udomsart et al. showed that DRB1*01:01 was a risk allele of IBM in 105 Australian patients [20]. We conclude from these various findings that DRB1*01:01 allele is a common factor in the susceptibility to IBM across the populations. With regard to other autoimmune muscle disorders, the DRB1*01:01 allele was associated with myasthenia gravis induced by D-penicillamine and with anti-melanoma differentiation-associated gene 5-positive dermatomyositis [21,22].

IBM is closely associated with autoimmunity following immune cell dysfunction in patients infected with human immunodeficiency virus or human T cell lymphotropic virus type 1 [1]. Compared to such patients, the prevalence of HCV infection was much higher in the Japanese population; it was estimated to be 3.4% in patients aged in their 60s in 2000 [23]. Our previous study revealed that a significantly higher number of Japanese IBM patients had anti-HCV antibodies as compared with patients with polymyositis (28% vs. 5%) [16]. HCV infection is also associated with extrahepatic disorders including mixed cryoglobulinemia, Sjögren syndrome, and lymphoproliferative disorders. In our cohort, 3 of 5 IBM patients with systemic autoimmune diseases had anti-HCV antibodies. A genome-wide association study showed that DQB1*03:03 affected the susceptibility to chronic infection with HCV in the Japanese population [24]. Since DRB1 alleles in disequilibrium with DQB1*03:03 do not correspond to DRB1*01:01, DRB1*04:10, and DRB1*15:02, we think these risk alleles are associated with Japanese IBM patients independently of HCV infection.

Our comprehensive screening of autoantibodies revealed that only anti-cN1A antibodies were detected in IBM patients with a seropositive rate of 34%. The diagnostic sensitivity of anti-cN1A antibodies for IBM has varied among research groups [3–7,25]. In addition, it was also pointed out that anti-cN1A antibodies were found in other autoimmune disorders including Sjögren syndrome, systemic lupus erythematosus, and dermatomyositis [6,7]. We speculate that the discrepancy in these findings may be due to technical differences among various detection assays including ELISAs and cell-based assays. In this regard, conventional methods such as radioimmunoassay of anti-acetylcholine receptor antibodies will be required.

Our study did not detect any specific HLA-DRB1 allele associated with anti-cN1A antibodies. Similarly, Rothwell et al. reported no significant differences in HLA association between the 35 anti-cN1A-positive IBM patients and 68 anti-cN1A-negative IBM patients [9]. On the other hand, our previous study involving patients with immune-mediated necrotizing myopathy clearly showed the association between DRB1*08:03 and anti-SRP-positive patients and that between DRB1*11:01 and anti-HMGCR-positive patients [26]. Interestingly, DRB1*08:03 was the risk allele for SRP-positive immune-mediated necrotizing myopathy; however, it was the protective allele for IBM. We found that anti-cN1A-postive patients tended to have HCV infection more commonly (39% vs. 13%), a finding that was the opposite of that of the report by Tawara et al. (5% vs. 27%) [25]. Further investigation will be necessary to elucidate the relationship between anti-cN1A antibodies and HCV infection.

A limitation of the present study was that we did not evaluate the outcomes of the IBM patients. IBM patients are usually unresponsive to treatment with glucocorticoids and conventional immunosuppressive agents [1]. It is possible that information of regarding HLA or other genetic risk factors will be useful for predicting a favorable response to immunotherapies or other therapies for IBM patients. In the future, an ethnographic study comparing Caucasian and Asian patients would give us important information.

Conclusion

Japanese IBM patients had the specific HLA-DRB1 alleles and autoantibody profiles.

Supporting information

S1 Table. The whole dataset of 83 Japanese patients with inclusion body myositis (IBM) subjected to the present analysis.

(DOCX)

Click here for additional data file. (106KB, docx)
S2 Table. Differences in clinical features of IBM patients between the presence and absence of DBB1*01:01.

(DOCX)

Click here for additional data file. (50.4KB, docx)
S3 Table. Differences in clinical features of IBM patients between the presence and absence of DRB1*04:10.

(DOCX)

Click here for additional data file. (50KB, docx)
S4 Table. Differences in clinical features of IBM patients between the presence and absence of DRB1*15:02.

(DOCX)

Click here for additional data file. (50.3KB, docx)
S5 Table. Differences in clinical features and DRB1 alleles between the IBM patients with hepatitis C virus infection and without.

(DOCX)

Click here for additional data file. (57.1KB, docx)
S6 Table. Differences in clinical features and DRB1 alleles between the IBM patients with anti- cytosolic 5’-nucleotidase 1A (cN1A) antibodies and without.

(DOCX)

Click here for additional data file. (56.4KB, docx)
S7 Table. Differences in clinical features and DRB1 alleles between the IBM patients with both HCV infection and anti-cN1A antibodies and others.

(DOCX)

Click here for additional data file. (56.7KB, docx)

Data Availability

All relevant data are within the manuscript and its Supporting Information files.

Funding Statement

This work was supported by JSPC KAKENHI Grant Number JP20H03592 (Shigeaki Suzuki), JSPC KAKENHI Grant Number 20K07911 (Yuko Ohnuki), and partly by Intramural Research Grant (2-5, 29-4) for Neurological and Psychiatric Disorders of NCNP (Ichizo Nishino).

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  • 26.Ohnuki Y, Suzuki S, Shiina T, Uruha A, Watanabe Y, Suzuki S, et al. HLA-DRB1 alleles in immune-mediated necrotizing myopathy. Neurology. 2016;87(18):1954–5. 10.1212/WNL.0000000000003160 [DOI] [PubMed] [Google Scholar]

Decision Letter 0

Frederick W Miller

16 Jul 2020

PONE-D-20-16597

HLA-DRB1 allele and autoantibody profiles in Japanese patients with inclusion body myositis

PLOS ONE

Dear Dr. Suzuki,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

In particular address all the critical points raised by reviewer 2 and change the statistical significance of the results and conclusions and the future plans and implications of the study accordingly.

Please submit your revised manuscript by Aug 30 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

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We look forward to receiving your revised manuscript.

Kind regards,

Frederick W. Miller, MD, PhD

Academic Editor

PLOS ONE

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'Munenori Oyama, Yuko Ohnuki, Michio Inoue, Akinori Uruha, Satoshi Yamashita, Sachiko Yutani, Jantima Tanboon, Jin Nakahara, Shingo Suzuki, Takashi Shiina, and Ichizo Nishino declare no competing interests. Shigeaki Suzuki received personal fees from Alexion Pharmaceuticals, the Japan Blood Products Organization, and Asahi Kasei Medical. '

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Reviewers' comments:

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Comments to the Author

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Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: No

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

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Reviewer #1: Yes

Reviewer #2: Yes

**********

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Reviewer #2: Yes

**********

5. Review Comments to the Author

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Reviewer #1: The manuscript is clearly written and well-organized. The authors describe a study of 83 IBM patients and 460 Japanese matched-controls. High-resolution HLA DRB1 sequencing revealed multiple alleles significantly associated with IBM. Also, certain clinical signs and symptoms were likewise associated with disease-susceptibility alleles. Additional analyses of autoantibody profiles and Hepatitis C status revealed some non-significant although interesting trends. I recommend the manuscript for publication in PLOS ONE without further comment.

Reviewer #2: Many thanks for asking me to review this HLA study of patients with IBM in a Japanese poulation. The findings are of some interest and confirm an association of HLA-DRB*01:01, which has previously been confirmed in other ethnic populations in IBM. The manuscript is well written with excellent English and no obvious grammatical errors - the authors should be commended for this.

The study is somewhat small in number, and the fundamental issue with the methodology is that no attempt has been made to correct for multiple comparisons. Paragraph in table 1, there are 29 alleles therefore, if a Bonferroni correction for multiple comparisons is applied the P value must be multiplied by 29. The DRB1*01:01 and DRB1*04:10 associations do persist after this correction.

Therefore, it is more than likely that given the lack of statistical power, the described HLA/clinical associations analysed are likely by chance and again a correction for multiple comparisons must be applied here. Any associations with clinical features or serology described are at best speculative.

At the end of the study discussion, there is no research agenda or suggestions for further work based on the findings.

Surely an ethnographic study comparing Caucasian and Japanese patients would be of some interest here.

I don't feel that the Venn diagram in figure 1 is necessary and adds anything to the manuscript.

**********

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Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2020 Aug 18;15(8):e0237890. doi: 10.1371/journal.pone.0237890.r002

Author response to Decision Letter 0

24 Jul 2020

Reviewer #1

The manuscript is clearly written and well-organized. The authors describe a study of 83 IBM patients and 460 Japanese matched-controls. High-resolution HLA DRB1 sequencing revealed multiple alleles significantly associated with IBM. Also, certain clinical signs and symptoms were likewise associated with disease-susceptibility alleles. Additional analyses of autoantibody profiles and Hepatitis C status revealed some non-significant although interesting trends. I recommend the manuscript for publication in PLOS ONE without further comment.

We appreciate the kindly comment.

Reviewer #2

Many thanks for asking me to review this HLA study of patients with IBM in a Japanese population. The findings are of some interest and confirm an association of HLA-DRB*01:01, which has previously been confirmed in other ethnic populations in IBM. The manuscript is well written with excellent English and no obvious grammatical errors - the authors should be commended for this.

1. The study is somewhat small in number, and the fundamental issue with the methodology is that no attempt has been made to correct for multiple comparisons. Paragraph in table 1, there are 29 alleles therefore, if a Bonferroni correction for multiple comparisons is applied the P value must be multiplied by 29. The DRB1*01:01 and DRB1*04:10 associations do persist after this correction. Therefore, it is more than likely that given the lack of statistical power, the described HLA/clinical associations analyzed are likely by chance and again a correction for multiple comparisons must be applied here. Any associations with clinical features or serology described are at best speculative.

As suggested, we performed the statistical analyses with a Bonferroni correction for multiple comparisons. We added the following sentences.

Page 6

“Bonferroni-corrected p values were obtained by multiplying the observed p values by the number of DRB1 alleles (× 29).”

Page 9

“Further analyses using Bonferroni-corrected p value also revealed that these alleles showed a tight association with Japanese IBM patients.”

“Among these alleles, DRB1*09:01 showed still significant after a Bonferroni correction for multiple comparisons. In fact, DRB1*09:01 was only found in one IBM patient, although it was a relatively common allele in the Japanese population.”

Page 12

“(ii) there was a weak association between the DRB1*01:01 allele and clinical features (severe leg muscle weakness and muscle atrophy);”

2. At the end of the study discussion, there is no research agenda or suggestions for further work based on the findings. Surely an ethnographic study comparing Caucasian and Japanese patients would be of some interest here.

As suggested, we modified the final sentences.

Page 14

“It is possible that information of regarding HLA or other genetic risk factors will be useful for predicting a favorable response to immunotherapies or other therapies for IBM patients. In the future, an ethnographic study comparing Caucasian and Asian patients would give us important information.”

3. I don't feel that the Venn diagram in figure 1 is necessary and adds anything to the manuscript.

We appreciate the thoughtful suggestion. We deleted the figure 1.

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file. (22.7KB, docx)

Decision Letter 1

Frederick W Miller

30 Jul 2020

PONE-D-20-16597R1

HLA-DRB1 allele and autoantibody profiles in Japanese patients with inclusion body myositis

PLOS ONE

Dear Dr. Suzuki,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

The authors claim to have adjusted P values as requested in the Methods, but have not done so in the Abstract, Results, Tables or Discussion, which are essentially unchanged.  It is possible to list the unadjusted P values and data, but the adjusted data needs to be included as the main findings, along with the implications of these findings and the minimal numbers of associations found after adjustment.  They should also state that a future larger study would be needed to more fully assess these associations.

==============================

Please submit your revised manuscript by Sep 13 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Frederick W. Miller, MD, PhD

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2020 Aug 18;15(8):e0237890. doi: 10.1371/journal.pone.0237890.r004

Author response to Decision Letter 1

2 Aug 2020

Academic Editor

The authors claim to have adjusted P values as requested in the Methods, but have not done so in the Abstract, Results, Tables or Discussion, which are essentially unchanged. It is possible to list the unadjusted P values and data, but the adjusted data needs to be included as the main findings, along with the implications of these findings and the minimal numbers of associations found after adjustment. They should also state that a future larger study would be needed to more fully assess these associations.

We all appreciate critical suggestion. As suggested, we added and modified the following sentences.

Page 3

“The allele frequencies of DRB1*01:01, DRB1*04:10, and DRB1*15:02 were significantly higher in the IBM group than in the healthy control group (Corrected P=0.00078, 0.00038 and 0.0046).”

“There was a weak association between the DRB1*01:01 allele and severe leg muscle weakness and muscle atrophy.”

Page 6

“Bonferroni-corrected P (corrected P) values were obtained by multiplying the observed p values by the number of DRB1 alleles (× 29).”

Page 9

“DRB1*01:01 (17% vs. 6%, P=0.000027, corrected P=0.00078), DRB1*04:10 (8% vs. 2%, P=0.000013, corrected P=0.00038), and DRB1*15:02 (24% vs. 12%, P=0.00016, corrected P=0.0046) were detected in the Japanese IBM patients at higher rates than in healthy controls using Bonferroni-correction.”

“Among these alleles, DRB1*09:01 showed still significant after a Bonferroni correction for multiple comparisons (P=5.4 × 10-9, corrected P=1.6× 10-7).”

Table 2

We added the corrected P values and foot note.

Page 12

“(i) the frequencies of DRB1*01:01, DRB1*04:10, and DRB1*15:02 were significantly higher in the Japanese patients with IBM than in healthy controls (Corrected P=0.00078, 0.00038 and 0.0046);”

Page 13

“However, we cannot find the significant association after the Bonferroni-correction. In this regard, a future larger study with more IBM patients would be needed to fully assess the association.”

Attachment

Submitted filename: Response (2nd revision).docx

Click here for additional data file. (21.8KB, docx)

Decision Letter 2

Frederick W Miller

5 Aug 2020

HLA-DRB1 allele and autoantibody profiles in Japanese patients with inclusion body myositis

PONE-D-20-16597R2

Dear Dr. Suzuki,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

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Kind regards,

Frederick W. Miller, MD, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Acceptance letter

Frederick W Miller

7 Aug 2020

PONE-D-20-16597R2

HLA-DRB1 allele and autoantibody profiles in Japanese patients with inclusion body myositis

Dear Dr. Suzuki:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Frederick W. Miller

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Table. The whole dataset of 83 Japanese patients with inclusion body myositis (IBM) subjected to the present analysis.

    (DOCX)

    Click here for additional data file. (106KB, docx)
    S2 Table. Differences in clinical features of IBM patients between the presence and absence of DBB1*01:01.

    (DOCX)

    Click here for additional data file. (50.4KB, docx)
    S3 Table. Differences in clinical features of IBM patients between the presence and absence of DRB1*04:10.

    (DOCX)

    Click here for additional data file. (50KB, docx)
    S4 Table. Differences in clinical features of IBM patients between the presence and absence of DRB1*15:02.

    (DOCX)

    Click here for additional data file. (50.3KB, docx)
    S5 Table. Differences in clinical features and DRB1 alleles between the IBM patients with hepatitis C virus infection and without.

    (DOCX)

    Click here for additional data file. (57.1KB, docx)
    S6 Table. Differences in clinical features and DRB1 alleles between the IBM patients with anti- cytosolic 5’-nucleotidase 1A (cN1A) antibodies and without.

    (DOCX)

    Click here for additional data file. (56.4KB, docx)
    S7 Table. Differences in clinical features and DRB1 alleles between the IBM patients with both HCV infection and anti-cN1A antibodies and others.

    (DOCX)

    Click here for additional data file. (56.7KB, docx)
    Attachment

    Submitted filename: Response to Reviewers.docx

    Click here for additional data file. (22.7KB, docx)
    Attachment

    Submitted filename: Response (2nd revision).docx

    Click here for additional data file. (21.8KB, docx)

    Data Availability Statement

    All relevant data are within the manuscript and its Supporting Information files.

    Articles from PLoS ONE are provided here courtesy of PLOS

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