Background
Polymyositis (PM) and dermatomyositis (DM) are idiopathic inflammatory myopathies (IIM), a group of autoimmune disorders characterized by inflammation present predominantly in muscle tissues. The chief clinical presentations include symmetric proximal muscle weakness, other organ involvement, and presence of autoantibodies [
1]. Although the underlying pathogenesis for PM and DM remains unclear, evidence has suggested that, like many other autoimmune conditions, these disorders likely result from a combination of environmental exposure and genetic susceptibility [
2]. Genetic variability in the human leukocyte antigen (
HLA) genes is thought to play an important role in DM and PM pathogenesis [
3,
4]. This may be partly attributed to the influence of HLA molecules on T-cell receptor development, peripheral tolerance, and immune response to environmental agents. It has been established that geographic locations and ethnicities may affect susceptibility to autoimmune diseases [
5,
6]. The
HLA-DRB1*0301 and
HLA-DQA1*0501 alleles have been reported as risk factors for myositis in Western populations [
7,
8], whereas
DRB1*0803 may increase PM susceptibility among the Japanese population [
9]. In studies of 52 DM and PM patients from Northern China, Han
et al. reported positive associations between the
HLA-DRB1*04,
HLA-DRB1*07, and
HLA-DRB1*12 alleles and DM development [
10]. They also observed that
HLA-DQB1*0401 is a risk factor for DM and PM [
11]. However, the sample sizes of these studies were small; therefore, the possible role of
HLA class II alleles in myopathies in Chinese patients requires further investigation.
To assess the effect of polymorphisms in HLA-DRB1, HLA-DQA1, and HLA-DQB1 on DM and PM susceptibility, we conducted a study of 91 adult patients with DM or PM and 113 healthy controls in a Han Chinese population. Our results demonstrate that HLA class II alleles may influence adult DM and PM susceptibility in the Han Chinese population.
Results
Of the 91 patients, 71 had been diagnosed with DM and 20 with PM (66 female and 25 male [2.64:1]). Although most of the patients were positive for antinuclear antibodies, few were positive for either MSA or MAA. The frequencies of MSA and MAA were higher in the PM group than in the DM group (10% vs. 1.4%,
p = 0.06 for MSA; 20% vs. 5.63%,
p = 0.05 for MAA). As expected, cutaneous involvement such as rash or cuticular overgrowth was present only in DM patients. Approximately half of the patients had ILD, with a higher prevalence among patients with PM than those with DM (76.5% vs. 37.7%,
p = 0.04). No significant differences in other clinical features were observed between the two groups (Table
1).
Table 1
Clinical features of patients with DM and PM
Serologic group | | | |
MSA (anti-Jo-1) | 1 (1.4) | 2 (10) | 0.06 |
MAA (SSA, SSB or Scl) | 4 (5.63) | 4 (20) | 0.05 |
Clinical presentations | | | |
Fever | 4 (5.6) | 1 (5) | 0.92 |
Raynaud’s disease | 0.00 | 1 (5) | 0.06 |
Arthritis | 1 (1.4) | 0.00 | 0.59 |
Interstitial lung disease | 261 (37.7) | 132 (76.5) | 0.04 |
Palpitations | 1 (1.4) | 0.00 | 0.59 |
Dysphagia | 10 (14.1) | 4 (20) | 0.51 |
V-sign | 26 (36.6) | 0.00 | n/a |
Gottron papules | 24 (33.8) | 0.00 | n/a |
Periorbital edematous rash | 11 (15.5) | 0.00 | n/a |
Shawl sign | 13 (18.3) | 0.00 | n/a |
Cuticular overgrowth | 3 (4.2) | 0.00 | n/a |
Genotyping analyses of the
HLA-DQA1 and
HLA-DQB1 loci were performed to study the relationship between the
HLA class II alleles and susceptibility to DM and PM. Because there are several lines of evidence to suggest that DM and PM may be distinct diseases with different genetic backgrounds [
17], we analyzed the influence of the
HLA alleles on susceptibility to DM and PM individually rather than analyzing the combined DM/PM group (Table
2). Compared with the controls, the frequency of
HLA-DQA1*
0104 was significantly higher in the DM group than in the PM group (16.42% vs. 8.18%,
p = 0.01,
p
corr
NS; OR = 2.58; 95% CI: 1.18–5.74), implying a possible positive correlation between
HLA-DQA1*
0104 and the risk of DM. Of the
HLA-DQB1 alleles analyzed, only the
HLA-DQB1*
0303 frequency was lower in patients with ILD than in the controls (6.76% vs. 19.03%,
p = 0.01,
p
corr
NS; OR = 0.25; 95% CI: 0.07 − 0.73), implying that patients with this allele are less likely to develop the lung complication. This was further confirmed by the fact that the
HLA-DQB1*
0303 frequency was lower among those who developed ILD (
p < 0.01; OR = 0.19; 95% CI: 0.038–0.37) than those who did not develop ILD.
HLA-DRB1 typing analysis showed that compared to controls, DM patients had a considerably lower prevalence of
HLA-DRB1*
03 (3.08% vs. 11.27%,
p = 0.01,
p
corr
NS; OR = 0.26; 95% CI: 0.06–0.81) and a higher frequency of
HLA-DRB1*
07 (20.77% vs. 13.24%,
p = 0.01,
p
corr
NS, OR = 2.26, 95% CI, 1.12–4.59). Both
HLA-DRB1*04 and
HLA-DRB1*12 alleles are likely linked to the lung disease (
p = 0.01,
p
corr
NS; OR = 2.82; 95% CI: 1.15–6.76 and
p = 0.02,
p
corr
NS; OR = 2.52; 95% CI: 1.02–6.07, respectively). A similar effect of
HLA-DRB1*04 on ILD development was also observed when the allele frequencies between patients with and without the lung complication were compared (
p = 0.026; OR = 3.32; 95% CI: 1.22–9.08). Comparison of
HLA-DRB1*12 allele frequencies between myositis patients with and without ILD showed a similar trend of being higher among those with ILD than among those without, although the difference between the two groups was not statistically significant (
p = 0.35; OR = 1.59; 95% CI: 0.63–4.00). This is likely attributable to the small numbers in the groups examined. Moreover, the
HLA-DRB1*07 allele showed a possible influence on the development of esophageal/muscle complications (30.00% vs. 13.24%,
p = 0.01,
p
corr
NS; OR = 4.78; 95% CI: 1.03–24.42). A similar trend for a higher
HLA-DRB1*07 allele frequency was also noted among patients who had dysphagia as compared to those who did not (
p = 0.057; OR = 3.55; 95% CI: 0.91–13.82).
Table 2
HLA-DQA1
,
HLA-DQB1,
and
HLA-DRB1
allele frequencies in PM and DM patients and controls
HLA-DRB1
| N = 65 | N = 19 | N = 37 | N = 10 | N = 113 | | | | |
*01 | 1 (0.77) | 0 (0.00) | 1 (1.35) | 0 (0.00) | 5 (2.45) | n/s | n/a | n/s | n/a |
*03 | 4 (3.08) | 4 (10.53) | 4 (5.41) | 1 (5.00) | 23 (11.27) | 0.011; 0.26 | n/s | n/s | n/s |
(0.06–0.81) |
*04 | 17 (13.08) | 6 (15.79) | 15 (20.27) | 2 (10.00) | 22 (10.78) | n/s | n/s | 0.011; 2.82 | n/s |
(1.15–6.76) |
*07 | 27 (20.77) | 1 (2.63) | 14 (18.92) | 6 (30.00) | 27 (13.24) | 0.011; 2.26 | n/s | n/s | 0.011; 4.78 |
(1.12–4.59) | (1.03–24.42) |
*08 | 13 (10.00) | 4 (10.53) | 7 (9.46) | 2 (10.00) | 17 (8.33) | n/s | n/s | n/s | n/s |
*09 | 20 (15.38) | 2 (5.26) | 3 (4.05) | 3 (15.00) | 26 (12.75) | n/s | n/s | n/s | n/s |
*10 | 2 (1.54) | 1 (2.63) | 2 (2.70) | 0 (0.00) | 3 (1.47) | n/s | n/s | n/s | n/a |
*11 | 3 (2.31) | 3 (7.89) | 2 (2.70) | 0 (0.00) | 9 (4.41) | n/s | n/s | n/s | n/a |
*12 | 20 (15.38) | 7 (18.42) | 14 (18.92) | 1 (5.00) | 22 (10.78) | n/s | n/s | 0.021; 2.52 | n/s |
(1.02–6.07) |
*13 | 7 (5.38) | 1 (2.63) | 2 (2.70) | 1 (5.00) | 8 (3.92) | n/s | n/s | n/s | n/s |
*14 | 2 (1.54) | 3 (7.89) | 1 (1.35) | 2 (10.00) | 9 (4.41) | n/s | n/s | n/s | n/s |
*15 | 10 (7.69) | 4 (10.53) | 7 (9.46) | 1 (5.00) | 29 (14.22) | n/s | n/s | n/s | n/s |
*16 | 4 (3.08) | 2 (5.26) | 2 (2.70) | 1 (5.00) | 4 (1.96) | n/s | n/s | n/s | n/s |
HLA-DQA1
| N = 67 | N = 20 | N = 39 | N = 12 | N = 110 | | | | |
*0101 | 9 (6.72) | 0 (0.00) | 5 (6.41) | 1 (4.17) | 11 (5.00) | n/s | n/a | n/s | n/s |
*0102 | 18 (13.43) | 10 (25.00) | 16 (20.51) | 4 (16.67) | 44 (20.00) | n/s | n/s | n/s | n/s |
*0103 | 26 (19.40) | 6 (15.00) | 10 (12.82) | 6 (25.00) | 28 (12.73) | n/s | n/s | n/s | n/s |
*0104 | 22 (16.42) | 4 (10.00) | 11 (14.10) | 4 (16.67) | 18 (8.18) | 0.011; 2.58 | n/s | n/s | n/s |
1.18–5.64) |
*0201 | 1 (0.75) | 2 (5.00) | 1 (1.28) | 0 (0.00) | 1 (0.45) | n/s | n/s | n/s | n/a |
*0301 | 44 (32.84) | 9 (22.50) | 26 (33.33) | 9 (37.50) | 85 (38.64) | n/s | n/s | n/s | n/s |
*0302 | 1 (0.75) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 1 (0.45) | n/s | n/a | n/a | n/a |
*0401 | 1 (0.75) | 2 (5.00) | 2 (2.56) | 0 (0.00) | 3 (1.36) | n/s | n/s | n/s | n/a |
*0501 | 11 (8.21) | 6 (15.00) | 6 (7.69) | 0 (0.00) | 28 (12.73) | n/s | n/s | n/s | n/a |
*0507 | 1 (0.75) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | n/a | n/a | n/a | n/a |
*0601 | 0 (0.00) | 1 (2.50) | 1 (1.28) | 0 (0.00) | 1 (0.45) | n/a | n/s | | |
HLA-DQB1
| N = 67 | N = 17 | N = 37 | N = 10 | N = 113 | | | | |
*0201 | 31 (23.48) | 6 (16.67) | 16 (21.62) | 5 (25.00) | 44 (19.47) | n/s | n/s | n/s | n/s |
*0301 | 20 (15.15) | 9 (25.00) | 15 (20.27) | 0 (0.00) | 35 (15.49) | n./s | n/s | n/s | n/a |
*0302 | 9 (6.82) | 2 (5.56) | 7 (9.46) | 1 (5.00) | 12 (5.31) | n/s | n/s | n/s | n/s |
*0303 | 24 (18.18) | 2 (5.56) | 5 (6.76) | 5 (25.00) | 43 (19.03) | n/s | n/s | 0.011; 0.25 | n/s |
(0.07–0.73) |
*0401 | 6 (4.55) | 2 (5.56) | 6 (8.11) | 1 (5.00) | 7 (3.10) | n/s | n/s | n/s | n/s |
*0402 | 0 (0.00) | 1 (2.78) | 1 (1.35) | 0 (0.00) | 1 (0.44) | n.a. | n/s | n/s | n/a |
*0501 | 1 (0.76) | 2 (5.56) | 3 (4.05) | 0 (0.00) | 8 (3.54) | n/s | n/s | n/s | n/a |
*0502 | 5 (3.79) | 2 (5.56) | 5 (6.76) | 0 (0.00) | 7 (3.10) | n/s | n/s | n/s | n/a |
*0503 | 4(3.03) | 1 (2.78) | 0 (0.00) | 2 (10.00) | 8 (3.54) | n/s | n/s | n/a | n/s |
*0601 | 20 (15.15) | 7 (19.44) | 11 (14.86) | 3 (15.00) | 33 (14.60) | n/s | n/s | n/s | n/s |
*0602 | 4 (3.03) | 2 (5.56) | 2 (2.70) | 2 (10.00) | 16 (7.08) | n/s | n/s | n/s | n/s |
*0604 | 5 (3.79) | 0 (0.00) | 2 (2.70) | 0 (0.00) | 5 (2.21) | n/s | n/a | n/s | n/a |
*0608 | 3 (2.27) | 0 (0.00) | 1 (1.35) | 1 (5.00) | 7 (3.10) | n/s | n/a | n/s | n/s |
We then examined the association between putative haplotypes involving the
DRB1-DQA1-DQB1 loci and susceptibility to DM, PM, lung, and esophageal complications. In this analysis, only the putative haplotypes present in at least 3% of the controls were selected for further study. Of the 12 putative haplotypes selected, the frequency of
DRB1*07-DQA1*01-DQB1*02 was higher in the DM group (
p = 0.03,
p
corr
NS; OR = 2.90; 95% CI: 1.02–8.93) and in patients with ILD (
p = 0.02,
p
corr
NS; OR = 3.45; 95% CI: 1.04–11.58) than in the controls, indicating that this putative haplotype might increase the risk of DM and the lung complication (Table
3). A further comparison of the
DRB1*07-DQA1*01-DQB1*02 frequency in patients who developed dysphagia with those who did not showed a trend for a higher frequency of this haplotype among patients with dysphagia, although the difference between the groups was not statistically significant (
p = 0.23; OR = 2.27; 95% CI: 0.68–7.72). Again, we consider that this result is likely due to the small sample sizes in both groups.
Table 3
Comparisons of frequencies of
HLA
class II putative haplotypes between DM and PM and controls
03-05-02 | 2 (1.59) | 2 (5.56) | 2 (2.78) | 0 (0.00) | 11 (5.50) | n/s | n/s | n/s | n/s |
04-03-03 | 6 (4.36) | 1 (2.78) | 5 (6.94) | 1 (5.56) | 9 (4.50) | n/s | n/s | n/s | n/s |
04-03-04 | 5 (3.97) | 2 (5.56) | 5 (6.94) | 1 (5.56) | 6 (3.00) | n/s | n/s | n/s | n/s |
07-01-02 | 12 (9.52) | 1 (2.78) | 8 (11.11) | 2 (11.11) | 7 (3.50) | 0.031; 2.90 | n/s | 0.021; 3.45 | n/s |
(1.02–8.93) | (1.04–11.58) |
07-03-02 | 6 (4.76) | 0 (0.00) | 3 (4.17) | 2 (11.11) | 11 (5.50) | n/s | n/s | n/s | n/s |
08-01-06 | 13 (10.32) | 3 (8.33) | 6 (8.33) | 2 (11.11) | 13 (6.50) | n/s | n/s | n/s | n/s |
09-03-03 | 17 (13.49) | 2 (5.56) | 3 (4.17) | 3 (16.67) | 20 (10.00) | n/s | n/s | n/s | n/s |
11-05-03 | 3 (2.38) | 1 (2.78) | 1 (1.39) | 0 (0.00) | 7 (3.50) | n/s | n/s | n/s | n/s |
12-01-03 | 11 (8.73) | 2 (5.56) | 8 (11.11) | 0 (0.00) | 11 (5.50) | n/s | n/s | n/s | n/s |
13-01-06 | 7 (5.56) | 0 (0.00) | 2 (2.78) | 1 (5.56) | 7 (3.50) | n/s | n/s | n/s | n/s |
14-01-05 | 2 (1.59) | 1 (2.78) | 0 (0.00) | 2 (11.11) | 7 (3.50) | n/s | n/s | n/s | n/s |
15-01-06 | 7 (5.56) | 3 (8.33) | 3 (4.17) | 1 (5.56) | 19 (9.50) | n/s | n/s | n/s | n/s |
Discussion
There are differences in the clinical features of DM and PM between our cohort of Han Chinese patients and Western patients [
1,
18]. There are more DM cases in our cohort and among Mesoamerican patients, whereas PM is the major subtype among Caucasian patients [
19]. Compared to Caucasian patients, our cohort had a higher prevalence of the lung complication [
20]. The frequencies of dysphagia were comparable between our cohort and those reported in the West [
1,
21]. Approximately 30–40% of Caucasian and African American IIM patients are positive for MSA/MAA autoantibodies [
19,
22]. Although the proportion of patients who were positive for autoantibodies was relatively low in our cohort, it is nonetheless comparable to findings from other studies in Chinese patients [
23,
24].
There is a growing body of evidence to suggest that differences in the impact of
HLA class II alleles on the susceptibility to DM and PM may exist among different ethnic groups and geographic locations [
19,
20,
25‐
27]. It has been well documented that
HLA class II alleles that form the 8.1 ancestral haplotype (8.1 AH),
DRB1*03-DQA1*05-DQB1*02, are closely linked to DM and PM in Western populations [
4,
7,
28]. Previous studies suggest that
HLA-DQA1*0501 and
HLA-DRB1*0301 may be risk factors for PM, whereas
HLA-DQA1*0201 and
HLA-DRB1*0401 confer protection against the disease in Caucasians [
4,
28‐
30]. Moreover,
HLA-DRB1*07 has been reported to protect against PM and IIM in Caucasians and African Americans [
4,
22,
28]. In their study of African American patients with IIM, O’Hanlon
et al.[
22] demonstrated that
HLA-DRB1*14 and
HLA-DRB1*0301 increase the risk of DM, while
HLA-DRB1*0301 influences PM susceptibility. Furuya
et al.[
9,
26] found that both
HLA-DRB1*0803 and
HLA-DQA1*0501 provide an increased risk of DM but a reduced risk of PM in a Japanese population. In a study of 25 Korean patients with IIM, Rider
et al. [
27] reported that
HLA-DRB1*14 as a protective factor for DM and PM. To date, most studies on the subject have been focused on Western populations. In their studies of 52 DM and PM patients from Northern China, Han
et al. reported that
HLA-DRB1*04,
HLA-DRB1*07, and
HLA-DRB1*12 may render an increased risk of DM [
10], while
HLA-DQB1*0401 may have an impact on IIM susceptibility [
11]. Our data demonstrate that the
HLA-DQA1*0104 and
HLA-DRB1*07 alleles are likely associated with an increased risk of DM, whereas
HLA-DRB1*03 may provide protection against DM. Although 8.1 AH is known as a risk factor for IIM among individuals of Northwestern European descent [
4,
7,
28], such an association has not been established in other ethnic groups [
25].
DRB1*03-
DQA1*05-
DQB1*02 is not a major haplotype in our cohort and does not influence DM and PM susceptibility. Our results suggest that the
HLA-DRB1*07-DQA1*01-DQB1*02 haplotype may be associated with DM and ILD.
It is interesting to note that
HLA-DRB1*07 influences IIM susceptibility among various ethnic groups. In our study of Han Chinese patients, the
HLA-DRB1*07 allele in the putative haplotype
DRB1*07-
DQA1*01-
DQB1*02 was found to be a risk factor for DM, but the same allele present in the
DRB1*07-
DQA1*02-
DQB1*02 haplotype was reported to be a protector against IIM in Caucasians and African Americans [
4,
22,
25,
28]. These findings imply that
HLA-DRB1*07 might have opposite effects on the diseases in different ethnic groups. Similar phenomena have been observed for the effect of
HLA-DQA1*0501 on IIM. This allele was reported as a protective factor against IIM in a Japanese population [
9] but as a risk factor for IIM among US Caucasians [
29]. Although it is unclear what might cause such different effects, possible explanations include referral bias, small sample sizes resulting in nonrepresentative populations, different pathogeneses, various environmental risk triggers around the world, and unidentified genetic loci responsible for disease development.
Furuya
et al. [
26] reported a positive relationship between
HLA-DRB1*0405 and anti-aminoacyl-tRNA synthetase autoantibodies in Japanese IIM patients. In addition, O’Hanlon
et al. found that the
HLA-DRB1*0302 allele is closely linked to myositis-specific anti-Mi-2 autoantibodies in DM [
4]. In our study, the numbers of patients with MSA and MAA were too small to have sufficient statistical power for further analysis of the relationship between
HLA alleles and MSA/MAA autoantibodies. It is also noteworthy that a greater frequency of myositis autoantibodies was found among PM patients from our cohort and the cohort reported by Chinoy and colleagues [
20]. However, both cohorts were small in size, and in our study we analyzed only a limited number of autoantibodies.
Previous studies suggest that DM and PM may have different pathogeneses. It has been proposed that DM is likely the result of an autoimmune process induced by a humoral response, whereas PM may be caused by a cell-mediated autoimmune process [
17]. Thus, it is plausible that DM and PM might have distinctive genetic susceptibilities. Further investigation is warranted to better understand the pathogeneses of these two diseases.
Possible explanations for the differences between the results from our study and those from other studies include the fact that the studies were conducted in different geographic locations with various environmental exposures, the heterogeneity in genetic backgrounds among the different ethnic groups and populations, the number of
HLA polymorphic alleles analyzed, the different study methodologies used, referral bias, and the age and sex composition of the different study cohorts. The differences in the clinical and immunogenetic features between adult and childhood DM and PM are well documented [
8,
31].
Our study has some limitations. Although DM and PM are rare conditions and the number of patients in our cohort is the largest compared with similar studies in Chinese patients, it is still a relatively small cohort. It is likely that there are many genes and genetic polymorphisms that may influence DM and PM susceptibility, and we analyzed only a few of them. The data from our study should be validated by further analysis of multiple genes and alleles and their combined impacts on disease susceptibility. Nevertheless, our data shed some light on the genetic susceptibility of adult DM and PM, and may aid in stratifying disease subtypes according to genetic and ethnic backgrounds.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
LB, LL and XG conceived the study design and manuscript preparation; LB, LL, XG, LY, LH, HS, and YY participated in data interpretation; XG, YY, LH, LY, HS, and GG collected data and conducted experiments and data analysis. All authors read and approved the final manuscript.