Background
Methods
Participants
HLA-DRB1 and HLA-DPB1 genotyping
Statistical analysis
Results
Demographic features
Total patients (n = 434) | Northern patients (n = 247) | Southern patients (n = 187) |
p value | |
---|---|---|---|---|
Number of males/females (ratio) | 120/314 (1:2.6) | 62/185 (1:3.0) | 58/129 (1:2.2) | NS |
Age (years)a
| 41 (33–50) | 41 (34–50) | 40 (32–50) | NS |
Age at onset (years)a
| 29 (22–38) | 29 (22–36) | 30 (23–40) | NS |
SPMS (%) | 73/427 (17.1) | 53/245 (21.6) | 20/182 (11.0) | 0.0039 |
Disease duration (years)a
| 9 (4–15) | 10 (6–17) | 6.5 (3–13) | <0.0001 |
EDSSa
| 2.0 (1.0–3.5) | 2.0 (1.0–3.5) | 2.0 (1.0–3.5) | NS |
MSSSa
| 2.60 (0.94–5.50) | 2.13 (0.69–5.24) | 3.54 (1.45–5.90) | 0.003 |
ARRa
| 0.41 (0.22–0.75) | 0.41 (0.24–0.73) | 0.40 (0.20–0.89) | NS |
Barkhof criteria (%) | 318/428 (74.3) | 198/247 (80.2) | 120/181 (66.3) | 0.0012 |
Positive OB and/or increased IgG index (%) | 193/329 (58.7) | 130/177 (73.5) | 63/152 (41.5) | <0.0001 |
Phenotypic frequency of HLA-DRB1*04:05 (%) | 172 (39.6) | 92 (37.3) | 80 (42.8) | NS |
Phenotypic frequency of HLA-DRB1*15:01 (%) | 125 (28.8) | 75 (30.4) | 50 (26.7) | NS |
Frequencies of the HLA-DRB1 and HLA-DPB1 alleles
DRB1
| Phenotype frequency, n (%) | OR | 95 % CI |
p
uncorr
|
p
corr
| |
---|---|---|---|---|---|---|
MS (n = 434) | HCs (n = 394) | |||||
01:01 | 24 (5.5) | 53 (13.5) | 0.38 | 0.23–0.62 | <0.0001 | 0.003 |
03:03 | 1 (0.2) | 0 | NA | NA | 1.0000 | NS |
04:01 | 7 (1.6) | 9 (2.3) | 0.70 | 0.26–1.90 | 0.6151 | NS |
04:03 | 42 (9.7) | 22 (5.6) | 1.81 | 1.06–3.09 | 0.0276 | NS |
04:04 | 2 (0.5) | 2 (0.5) | 0.91 | 0.13–6.47 | 1.0000 | NS |
04:05 | 172 (39.6) | 100 (25.4) | 1.93 | 1.43–2.60 | <0.0001 | 0.0004 |
04:06 | 42 (9.7) | 26 (6.6) | 1.52 | 0.91–2.52 | 0.1071 | NS |
04:07 | 2 (0.5) | 4 (1.0) | 0.45 | 0.08–2.48 | 0.4317 | NS |
04:10 | 24 (5.5) | 8 (2.0) | 2.82 | 1.25–6.36 | 0.0091 | NS |
07:01 | 1 (0.2) | 2 (0.5) | 0.45 | 0.04–5.01 | 0.6073 | NS |
07:10 | 1 (0.2) | 0 | NA | NA | 1.0000 | NS |
08:01 | 1 (0.2) | 1 (0.3) | 0.91 | 0.06–14.56 | 1.0000 | NS |
08:02 | 38 (8.8) | 29 (7.4) | 1.21 | 0.73–2.00 | 0.4622 | NS |
08:03 | 63 (14.5) | 56 (14.2) | 1.02 | 0.69–1.51 | 0.9012 | NS |
09:01 | 72 (16.6) | 104 (26.4) | 0.55 | 0.40–0.78 | 0.0006 | 0.0198 |
10:01 | 2 (0.5) | 2 (0.5) | 0.91 | 0.13–6.47 | 1.0000 | NS |
11:01 | 18 (4.2) | 19 (4.8) | 0.85 | 0.44–1.65 | 0.6388 | NS |
12:01 | 26 (6.0) | 38 (9.6) | 0.60 | 0.36–1.00 | 0.0493 | NS |
12:02 | 5 (1.2) | 15 (3.8) | 0.29 | 0.11–0.82 | 0.0211 | NS |
13:01 | 3 (0.7) | 2 (0.5) | 1.36 | 0.23–8.21 | 1.0000 | NS |
13:02 | 20 (4.6) | 46 (11.7) | 0.37 | 0.21–0.63 | 0.0002 | 0.0066 |
13:07 | 0 | 1 (0.3) | 0 | NA | 0.4758 | NS |
14:01 | 3 (0.7) | 0 | NA | NA | 0.2508 | NS |
14:02 | 1 (0.2) | 1 (0.3) | 0.91 | 0.06–14.56 | 1.0000 | NS |
14:03 | 20 (4.6) | 14 (3.6) | 1.31 | 0.65–2.63 | 0.4449 | NS |
14:05 | 17 (3.9) | 15 (3.8) | 1.03 | 0.51–2.09 | 0.9347 | NS |
14:06 | 11 (2.5) | 6 (1.5) | 1.68 | 1.62–4.59 | 0.3371 | NS |
14:07 | 0 | 2 (0.5) | 0 | NA | 0.2261 | NS |
14:54 | 20 (4.6) | 28 (7.1) | 0.63 | 0.35–1.14 | 0.1245 | NS |
15:01 | 125 (28.8) | 67 (17.0) | 1.97 | 1.41–2.76 | <0.0001 | 0.0019 |
15:02 | 55 (12.7) | 83 (21.1) | 0.54 | 0.37–0.79 | 0.0012 | 0.0396 |
15:10 | 1 (0.2) | 0 | NA | NA | 1.0000 | NS |
16:02 | 4 (0.9) | 4 (1.0) | 0.91 | 0.23–3.65 | 1.0000 | NS |
Comparison of clinical characteristics between northern and southern patients
Comparison of clinical characteristics between HLA-DRB1*04:05-positive and HLA-DRB1*04:05-negative patients
DRB1 | Total patients | Northern patients | Southern patients | ||||||
---|---|---|---|---|---|---|---|---|---|
04:05 (+) (n = 172) |
04:05 (−) (n = 262) |
p value |
04:05 (+) (n = 92) |
04:05 (−) (n = 155) |
p value |
04:05 (+) (n = 80) |
04:05 (−) (n = 107) |
p value | |
Number of males/females (ratio) | 52/120 (1:2.3) | 68/194 (1:2.9) | NS | 27/65 (1:2.4) | 35/120 (1:3.4) | NS | 25/55 (1:2.2) | 33/74 (1:2.2) | NS |
Age (years)a
| 39 (31–49) | 42 (34.2–51.5) | 0.0259 | 41 (34–49.5) | 42 (35–51) | NS | 36 (28–49) | 42 (34–52) | 0.0334 |
Age at onset (years)a
| 26 (21–34.8) | 30.2 (24–40) | 0.0003 | 27 (21–34) | 29 (24–37) | NS | 25 (20–36.8) | 33 (26–43) | 0.0001 |
SPMS (%) | 26/170 (15.3) | 47/257 (18.3) | NS | 19/92 (20.7) | 34/153 (22.2) | NS | 7/78 (9.0) | 13/104 (12.5) | NS |
Disease duration (years)a
| 9 (5.3–16) | 9 (4–14) | NS | 10 (6–17) | 11 (5–17) | NS | 7.5 (4–14.8) | 5.5 (3–10.3) | 0.0133 |
EDSSa
| 2.0 (1.0–3.5) | 2.0 (1.0–3.5) | NS | 2.0 (1.0–3.5) | 2.0 (1.0–3.5) | NS | 2.0 (1.0–3.0) | 2.5 (1.5–4.0) | 0.0263 |
MSSSa
| 2.10 (0.78–5.24) | 3.17 (1.16–5.87) | 0.0415 | 1.97 (0.56–5.63) | 2.33 (0.88–4.94) | NS | 2.28 (1.04–4.97) | 4.32 (1.77–6.33) | 0.0021 |
ARRa
| 0.40 (0.22–0.71) | 0.43 (0.22–0.85) | NS | 0.40 (0.25–0.71) | 0.42 (0.22–0.75) | NS | 0.37 (0.17–0.71) | 0.48 (0.21–0.95) | NS |
Barkhof criteria (%) | 113/170 (66.5) | 205/258 (79.5) | 0.0026 | 69/92 (75.0) | 129/155 (83.2) | NS | 44/78 (56.4) | 76/103 (73.8) | 0.0143 |
Positive OB and/or increased IgG index (%) | 58/129 (45.0) | 135/200 (67.5) | <0.0001 | 41/69 (59.4) | 89/108 (82.4) | 0.0007 | 17/60 (28.3) | 46/92 (50.0) | 0.008 |
Comparison of clinical characteristics between HLA-DRB1*15:01-positive and HLA-DRB1*15:01-negative patients
Comparison of clinical characteristics of HLA-DRB1*04:05- or HLA-DRB1*15:01-positive patients between northern and southern Japanese populations
Northern patients (n = 92) | Southern patients (n = 80) |
p value | |
---|---|---|---|
Number of males/females (ratio) | 27/65 (1:2.4) | 25/55 (1:2.2) | NS |
Age (years)a
| 41 (34–49.5) | 36 (28–49) | NS |
Age at onset (years)a
| 27 (21–34) | 25 (20–36.8) | NS |
SPMS (%) | 19/92 (20.7) | 7/78 (9.0) | 0.035 |
Disease duration (years)a
| 10 (6–17) | 7.5 (4–14.8) | NS |
EDSSa
| 2.0 (1.0–3.5) | 2.0 (1.0–3.0) | NS |
MSSSa
| 1.97 (0.56–5.63) | 2.28 (1.04–4.97) | NS |
ARRa
| 0.40 (0.25–0.71) | 0.37 (0.17–0.71) | NS |
Barkhof criteria (%) | 69/92 (75.0 %) | 44/78 (56.4 %) | 0.0105 |
Positive OB and/or increased IgG index (%) | 41/69 (59.4 %) | 17/60 (28.3 %) | 0.0004 |
Multivariate regression analyses of factors contributing to clinical features and laboratory findings
Age at disease onset
|
β
|
t
value
|
p
value
|
Region (northern Japan) | −0.0918 | −1.94 | NS |
Sex (female) | −0.0127 | −0.27 | NS |
HLA-DRB1*04:05 allele (+) | −0.1970 | −4.12 | <0.0001 |
HLA-DRB1*15:01 allele (+) | −0.0239 | −0.50 | NS |
MSSS (Q1/Q2–Q4)
|
Adjusted OR
|
95 % CI
|
p
value
|
Region (northern Japan) | 3.64 | 2.15–6.33 | <0.0001 |
Sex (female) | 0.98 | 0.55–1.76 | NS |
Age at onset | 0.97 | 0.95–0.99 | 0.0159 |
SPMS | 0.06 | 0.009–0.20 | <0.0001 |
ARR | 0.15 | 0.07 − 0.31 | <0.0001 |
HLA-DRB1*04:05 allele (+) | 1.81 | 1.07–3.07 | 0.0266 |
HLA-DRB1*15:01 allele (+) | 1.46 | 0.83–2.56 | NS |
Benign MS
|
Adjusted OR
|
95 % CI
|
p
value
|
Region (northern Japan) | 2.63 | 1.18–6.09 | 0.0206 |
Sex (female) | 0.87 | 0.37–2.00 | NS |
Age at onset | 0.97 | 0.94–1.01 | NS |
SPMS | 0.04 | 0.008–0.12 | <0.0001 |
ARR | 0.43 | 0.11–1.42 | NS |
HLA-DRB1*04:05 allele (+) | 2.49 | 1.12–5.74 | 0.0275 |
HLA-DRB1*15:01 allele (+) | 1.72 | 0.76–4.04 | NS |
Barkhof criteria
|
Adjusted OR
|
95 % CI
|
p
value
|
Region (northern Japan) | 1.63 | 1.01–2.63 | 0.0434 |
Sex (female) | 0.80 | 0.46–1.35 | NS |
Age at onset | 0.97 | 0.95–0.99 | 0.0132 |
SPMS | 2.55 | 1.05–6.80 | 0.0384 |
Disease duration (years) | 0.98 | 0.95–1.01 | NS |
ARR | 1.05 | 0.67–1.74 | NS |
EDSS | 0.98 | 0.85–1.13 | NS |
HLA-DRB1*04:05 allele (+) | 0.49 | 0.30–0.80 | 0.0043 |
HLA-DRB1*15:01 allele (+) | 1.45 | 0.85–2.53 | NS |
Positive OB and/or increased IgG index
|
Adjusted OR
|
95 % CI
|
p
value
|
Region (northern Japan) | 3.80 | 2.31–6.36 | <0.0001 |
Sex (female) | 1.36 | 0.78–2.36 | NS |
Age at onset | 1.00 | 0.98–1.02 | NS |
SPMS | 1.43 | 0.60–3.51 | NS |
ARR | 0.99 | 0.66–1.49 | NS |
EDSS | 1.00 | 0.87–1.16 | NS |
HLA-DRB1*04:05 allele (+) | 0.39 | 0.23–0.65 | 0.0004 |
HLA-DRB1*15:01 allele (+) | 1.65 | 0.95–2.88 | NS |