Background
Methods
Sample collection
MS (n = 45) | NMOSD (n = 31) | |
---|---|---|
Sex (male/female) | 10/35 | 7/24 |
Age (years) | 43.6 (20–65) | 52.7 (17–82) |
Age at onset (years) | 34.3 (5–58) | 47.4 (15–81) |
Disease duration (years) | 9.3 (1–38) | 5.3 (0–18) |
EDSS | 3.1 (0–8) | 4.6 (0–9) |
IgG index | 0.73 (n = 34) | 0.57 (n = 13) |
Oligo clonal band | 21/38 | – |
Anti-AQP4 antibody | – | 29/31 |
NGS-based HLA genotyping of classical and non-classical HLA genes
The statistical framework for analysis
HLA amino acid 3D-structure models
Results
NGS-based genotyping of the HLA genes in the Japanese MS and NMOSD patients and controls
Associations of HLA alleles with MS susceptibility
Variant | Frequency | Nominal analysis | |||
---|---|---|---|---|---|
HLA gene | MS (n = 45) | Control (n = 429) | OR (95% CI) |
P
| Fisher |
HLA-B*15:01 | 0.200 | 0.078 | 2.95 (1.66–5.24) | 2.2 × 10−4 | |
HLA-B*39:01 | 0.122 | 0.043 | 3.09 (1.52–6.29) | 0.0019 | |
HLA-B*52:01 | 0.044 | 0.127 | 0.32 (0.08–0.88) | 0.017 | * |
HLA-C*07:02 | 0.233 | 0.145 | 1.80 (1.07–3.04) | 0.028 | |
HLA-C*12:02 | 0.044 | 0.127 | 0.32 (0.08–0.88) | 0.017 | * |
HLA-DMB*01:07 | 0.044 | 0.008 | 5.64 (1.19–22.7) | 0.015 | * |
HLA-DOA*01:01 | 0.978 | 0.997 | 0.15 (0.03–0.94) | 0.042 | |
HLA-DPB1*05:01 | 0.522 | 0.356 | 1.98 (1.28–3.07) | 0.0021 | |
HLA-DQA1*01:02 | 0.267 | 0.156 | 1.96 (1.19–3.25) | 0.0084 | |
HLA-DQA1*03:03 | 0.222 | 0.141 | 1.74 (1.02–2.96) | 0.042 | |
HLA-DQB1*03:01 | 0.033 | 0.104 | 0.30 (0.06–0.93) | 0.037 | * |
HLA-DQB1*04:01 | 0.222 | 0.100 | 2.56 (1.49–4.42) | 7.0 × 10−4 | |
HLA-DQB1*06:02 | 0.200 | 0.068 | 3.45 (1.93–6.17) | 3.0 × 10−5 | |
HLA-DRA*01:01 | 0.733 | 0.579 | 2.00 (1.23–3.25) | 0.0053 | |
HLA-DRA*01:02 | 0.267 | 0.421 | 0.50 (0.31–0.81) | 0.0053 | |
HLA-DRB1*04:05 | 0.233 | 0.120 | 2.23 (1.31–3.79) | 0.0030 | |
HLA-DRB1*15:01 | 0.211 | 0.072 | 3.44 (1.95–6.07) | 2.1 × 10−5 | |
HLA-DRB1*15:02 | 0.033 | 0.120 | 0.25 (0.05–0.79) | 0.012 | * |
Variant | Frequency | Conditional association | ||
---|---|---|---|---|
DRB1*15:01, DRB1*04:05, B*39:01, and B*15:01 | ||||
HLA gene | MS (n = 45) | Control (n = 429) | OR (95% CI) |
P
|
HLA-DRB1*15:01 | 0.211 | 0.072 | 4.06 (2.22–7.45) | 5.7 × 10−6 |
HLA-DRB1*04:05 | 0.233 | 0.120 | 3.02 (1.72–5.31) | 1.2 × 10−4 |
HLA-B*39:01 | 0.122 | 0.043 | 4.13 (1.96–8.71) | 1.9 × 10− 4 |
HLA-B*15:01 | 0.200 | 0.078 | 3.10 (1.70–5.65) | 2.3 × 10−4 |
HLA alleles with MS susceptibility and MS clinical phenotype
Number of patients | EDSS | P (Student’s t) | |
A | |||
HLA-DRB1*15:01 positive | 18 | 3.08 | 0.990 |
HLA-DRB1*15:01 negative | 27 | 3.09 | |
HLA-DQB1*06:02 positive | 17 | 3.41 | 0.472 |
HLA-DQB1*06:02 negative | 28 | 2.89 | |
HLA-B*15:01 positive | 15 | 4.20 | 0.098 |
HLA-B*15:01 negative | 30 | 2.53 | |
HLA-B*39:01 positive | 11 | 3.50 | 0.504 |
HLA-B*39:01 negative | 34 | 2.96 | |
Number of patients | Age of onset | P (Student’s t) | |
B | |||
HLA-DRB1*15:01 positive | 18 | 33.3 | 0.618 |
HLA-DRB1*15:01 negative | 27 | 35.0 | |
HLA-DQB1*06:02 positive | 17 | 33.0 | 0.545 |
HLA-DQB1*06:02 negative | 28 | 35.1 | |
HLA-B*15:01 positive | 15 | 35.1 | 0.752 |
HLA-B*15:01 negative | 30 | 33.9 | |
HLA-B*39:01 positive | 11 | 30.0 | 0.142 |
HLA-B*39:01 negative | 34 | 35.7 |
Association of HLA amino acid polymorphisms with MS susceptibility
HLA-DQβ1 Phe9 independently confers MS risk with HLA-DRB1*15:01
Associations of the HLA alleles with NMOSD susceptibility
Variant | Frequency | Nominal analysis | |||
---|---|---|---|---|---|
HLA gene | NMOSD (n = 31) | Control (n = 429) | OR (95% CI) |
P
| Fisher |
HLA-A*26:03 | 0.065 | 0.020 | 3.40 (0.81–10.9) | 0.047 | * |
HLA-B*07:02 | 0.129 | 0.059 | 2.34 (1.06–5.19) | 0.036 | |
HLA-DPB1*05:01 | 0.516 | 0.356 | 1.93 (1.15–3.24) | 0.012 | |
HLA-DQA1*01:01 | 0.129 | 0.058 | 2.39 (1.08–5.30) | 0.031 | |
HLA-DQA1*03:02 | 0.048 | 0.147 | 0.30 (0.06–0.93) | 0.035 | * |
HLA-DQA1*05:03 | 0.097 | 0.015 | 6.96 (2.55–19.0) | 1.5 × 10−4 | |
HLA-DQB1*03:01 | 0.210 | 0.104 | 2.29 (1.20–4.39) | 0.012 | |
HLA-DQB1*03:03 | 0.048 | 0.149 | 0.29 (0.06–0.91) | 0.024 | * |
HLA-DRB1*01:01 | 0.129 | 0.058 | 2.39 (1.08–5.30) | 0.031 | |
HLA-DRB1*09:01 | 0.016 | 0.135 | 0.10 (0.003–0.62) | 0.0027 | * |
HLA-DRB1*14:06 | 0.081 | 0.012 | 7.40 (1.92–24.8) | 0.0021 | * |