1. Introduction
Aplastic anemia (AA) is an organ-specific and cell-mediated immune disease, as well as a low or acellular hematopoietic failure syndrome. The incidence of AA in China is currently remarkable in all age groups.[1] Besides, while autoimmune damage caused by abnormal activation and hyperfunction of T lymphocytes may result in AA, its pathogenesis was still elusive.[2–4] The immune response induced by oligoclonal cytotoxic T cells, targeting hematopoietic stem cells and progenitor cells may lead to cell apoptosis and bone marrow failure, and symptoms of anemia, hemorrhage, and infection may consequently appear.[2,5]
The human leukocyte antigen (HLA) system or complex is a group of related proteins that are encoded by the major histocompatibility complex gene complex in humans. These cell-surface proteins are responsible for the regulation of the immune system.[5,6] The HLA system is the largest cluster in the human genome, and it is divided into 3 main sub-regions: the genes of class I, class II, and class III, which are all involved in immune response and suppression. In addition, its genetic polymorphism is closely associated with the susceptibility of a variety of autoimmune diseases, and several studies have assessed its important position in the human immune system.[7–9]
HLA, as an important genetic marker of the immune system, is closely correlated to AA. A large number of researches have suggested that some specific types of HLA are susceptible or inhibitory factors of AA.[10] Scholars pointed out that HLA with high polymorphism determining the function of the immune system may be closely associated with the pathogenesis of AA.[11,12] A recent meta-analysis reported by Liu et al[13] observed that HLA-DRB1*15 and HLA-DRB1*15:01 polymorphisms might be associated with increased AA risk in Asians. However, whether HLA-DRB1 polymorphisms have associations with AA cases who had not accepted therapy has not been systemically summarized. Therefore, exploring the relationship between AA and HLA-DRB1 polymorphism is essential to further elucidate the pathogenesis of AA, which is of great significance in clinical prognosis, bone marrow transplantation, and the development of more effective preventive and treatment strategies. This meta-analysis was conducted to assess the association between HLA-DRB1 polymorphism and AA.
2. Materials and methods
The study was performed according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement.[14] This study was approved by the Ethics Committee of Henan Cancer Hospital, Zhengzhou, China.
2.1. Search strategy
Multiple electronic databases were used to search relevant studies from January 2000 to June 2022, including PubMed, Embase, Web of Science, Science Direct, SinoMed, WanFang Data, China National Knowledge Infrastructure, and Chongqing VIP Chinese Science Database (VIP). The following key terms were used jointly and separately to conduct the literature search: aplastic anemia OR AA, human leukocyte antigen-DRB1 OR HLA-DRB1. No restriction was considered for the language of publication. The studies were initially reviewed by titles and abstracts, and references of eligible studies were also examined for finding further relevant studies.
2.2. Inclusion and exclusion criteria
The inclusion criteria were as follows:
- (a) Case-control studies;
- (b) Studies that compared patients with AA and healthy individuals;
- (c) Studies that analyzed the association between HLA-DRB1 polymorphism and AA.
The exclusion criteria were as follows:
- (a) Case studies/meta-analyses/letters to editors/cellular or animal experiments;
- (b) Patients with congenital AA;
- (c) Limitation in recorded data;
- (d) Duplicate studies.
2.3. Data extraction
Two reviewers independently extracted needed information using a customized and standardized form. If the two authors disagree in their judgments, a third author made the final decision. For each study, the following information was extracted: year of publication, surname, and address of the first author, the sample size of cases and controls, genotyping method, source of controls, diagnostic criteria, and HLA-DRB1 polymorphism.
2.4. Quality assessment
Two authors independently evaluated the included studies using the Newcastle–Ottawa Scale (NOS).[15] Disagreement was resolved by discussion to produce final scores. Three domains of NOS were assessed: selection of study groups (4 stars); comparability of groups (2 stars); and ascertainment of exposure and outcomes (3 stars) for case-control, respectively. NOS score ranges from 0 to 9. Studies were then classified according to NOS score as poor (0–4), moderate (5–6), or high quality (7–9).
2.5. Statistical analysis
Continuous data were presented as mean with the standardized mean difference, and binary data were expressed as odds ratio (OR) with 95% confidence intervals (CIs) to estimate the differences in relationships among HLA-DRB1 polymorphism. Heterogeneity was assessed by the I² statistic and P values of heterogeneity in this study. If I² was > 50% and the P value of heterogeneity < .05, the studies were heterogeneous and the random-effects model was adopted; otherwise, a fixed-effects model was employed for making comparisons. A 2-side P value < .05 was considered statistically significant. We carried out a sensitivity analysis with the leave-one-out method to assess the robustness of our results. To be specific, each publication was removed from the total dataset, and testing of heterogeneity was performed among the remaining publications. The Begg rank correlation[16] and Egger weighted regression methods[17] were used to assess the publication bias (P < .05 was considered indicative of a statistically significant publication bias).
Comprehensive Meta-analysis Software (Version 3.0, The Biostat Inc, Englewood, CO) was used for the generation of forest plots and statistical analyses. The Begg and Egger tests were assessed by STATA 15.0 (Stata Corporation, College Station, TX).
3. Results
3.1. Search results
A total of 649 articles were eventually screened after completing the search process. After reading those articles, 446 articles met the preliminary criteria. Further screening resulted in the exclusion of 405 articles due to the study design, incomplete data, or type of articles. Finally, 16 studies[8,12,18–31] were included for analysis. The flowchart of the study selection process is presented in Figure 1.
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Figure 1.: Flowchart of study selection process.
3.2. Characteristics of the included studies
An overview of included studies with the main study and baseline characteristics is presented in Table 1. The analysis included 16 studies that were published from 2001 to 2018 with a total number of 4428 subjects. The sample size ranged from 142 to 909, and there were 698 controls and 3730 cases in the AA group and control group, respectively. Besides, HLA-DRB1 typing was achieved by polymerase chain reaction (PCR) amplification.
Table 1 -
Characteristics of the studies included in the meta-analysis.
| Author |
Country |
Region |
Sample size |
Genotyping method |
Source of controls |
Diagnostic criteria of cases |
HLA-DRB1 polymorphism |
| Cases |
Controls |
| Wang, 2018[26]
|
China |
Asia |
65 |
772 |
PCR-SSO |
Hospital |
Red Blood Cell Disease Group |
0101, 0102, 0301, 0401, 0405, 0406, 0701, 0803, 0901, 1101, 1201, 1202, 1302, 1401, 1403, 1404, 1405, 1501, 1502, 1601, 1602 |
| Yang, 2016[30]
|
China |
Asia |
50 |
183 |
PCR-SSP |
Population |
Diagnostic criteria |
0101, 0301, 0401, 0701, 0801, 0901, 1001, 1101, 1201, 1301, 1401, 1501, 1601 |
| Wang, 2014a[27]
|
China |
Asia |
43 |
200 |
PCR-SSP |
Population |
Diagnostic criteria |
0101, 0301, 0401, 0701, 0801, 0901, 1001, 1101, 1201, 1302, 1418, 1501, 1601, 1701 |
| Wang, 2014b[28]
|
China |
Asia |
96 |
600 |
PCR-SBT |
Population |
Camitta and on the International Agranulocytosis and Aplastic Anaemia criteria |
0101, 0102, 0110, 0301, 0401, 0403, 0404, 0405, 0406, 0407, 0408, 0410, 0701, 0801, 0802, 0803, 0809, 0814, 0901, 1001, 1101, 1104, 1106, 1201, 1202, 1210, 1301, 1302, 1312, 1401, 1402, 1403, 1404, 1405, 1407, 1418, 1425, 1454, 1501, 1502, 1601, 1602 |
| Chen, 2012[18]
|
China |
Asia |
80 |
109 |
PCR-SSP |
Population |
The criteria set out by the British Committee |
0301, 0901, 1101 |
| Fernández-Torres, 2012[20]
|
Mexican Republic |
North America |
36 |
201 |
PCR-SSP |
Hospital |
Camitta and on the International Agranulocytosis and Aplastic Anemia Study (IAAAS) criteria |
01, 03, 04, 07, 08, 11, 13, 14, 15, 16 |
| Dhaliwal, 2011[19]
|
Malaysia |
Asia |
33 |
109 |
PCR-SSP |
Hospital |
The guidelines enacted by the International Study of Agranulocytosis and Aplastic Anemia |
0301, 0403, 0405, 0803, 0901, 1101, 1104, 1106, 1202, 1302, 1404, 1405, 15, 1501, 1502, 1514, 1602 |
| Huo, 2011[12]
|
China |
Asia |
115 |
2264 |
PCR-SSP |
Hospital |
NA |
01, 03, 04, 07, 08, 09, 10, 11, 12, 13, 14, 15, 16 |
| Rehman, 2009[23]
|
Pakistani |
Asia |
61 |
200 |
PCR-SSP |
Population |
NA |
01, 03, 04, 07, 09, 1001, 11, 12, 13, 1302, 14, 15 |
| Song, 2008[24]
|
Korea |
Asia |
109 |
800 |
PCR-SSO PCR-SSCP |
Population |
The criteria of the International Study of Agranulocytosis and Aplastic Anemia |
0101, 0301, 0401, 0403, 0404, 0405, 0406, 0407, 0408, 0410, 0701, 0802, 0803, 0901, 1001, 1101, 1111, 1201, 1202, 1301, 1302, 1339, 1401, 1402, 1403, 1404, 1405, 1406, 1407, 1412, 1501, 1502, 1602 |
| Yari, 2008[31]
|
Iran |
Asia |
35 |
466 |
PCR-SSP |
Hospital |
NA |
01, 03, 04, 07, 08, 09, 10, 11, 12, 13, 14, 15, 16 |
| Liang, 2007[22]
|
China |
Asia |
82 |
400 |
PCR-SSP |
Hospital |
Diagnostic criteria |
0101, 0301, 0401, 0701, 0801, 0901, 1101, 1201, 1301, 1401, 1501, 1601 |
| Sugimori, 2007[25]
|
Japan |
Asia |
140 |
491 |
PCR-SSP |
Population |
NA |
0101, 0301, 0401, 0403, 0404, 0405, 0406, 0407, 0409, 0410, 0701, 0801, 0802, 0803, 0901, 1001, 1101, 1201, 1202, 1301, 1302, 1401, 1402, 1403, 1405, 1406, 1407, 1501, 1502, 1602 |
| Wang, 2007[29]
|
China |
Asia |
56 |
1000 |
PCR-SSP |
Hospital |
NA |
01, 03, 04, 07, 08, 09, 10, 11, 12, 13, 14, 15, 16 |
| Oguz, 2002[8]
|
Turkish |
Europe |
33 |
97 |
PCR-SSP |
Population |
NA |
01, 15(02), 03, 04, 11(05), 13(06), 14(06), 07, (08/09/10/12/16) |
| Kapusitin, 2001[21]
|
Russia |
Euroupe |
44 |
100 |
PCR-SSO |
Population |
Camitta |
0101, 0102, 0103, 1501, 1502, 1601, 1602, 0301, 0401, 0402, 0403/6, 0404, 0407, 0408, 0410, 0416, 1101, 1102, 1104, 1201, 1301, 1302, 1303, 1305, 14, 0701, 0801, 0803, 0901, 1001 |
PCR = polymerase chain reaction, PCR-SSCP = PCR single-strand conformation polymorphism, PCR-SSO = PCR sequence-specific oligonucleotide, PCR-SSP = PCR sequence-specific primers.
3.3. Quality assessment
NOS for the eligible studies were presented in Table 2. Four studies were evaluated as 7 stars, 6 studies as 6 stars, and the remaining 3 studies as 5 stars. Therefore, 4 studies were classified as high-quality, and 9 studies were assigned as moderate.
Table 2 -
Quality assessment of included studies by NOS.
| Study |
Is the case definition adequate? |
Representativeness of the cases |
Selection of controls |
Definition of controls |
Comparability of cases and controls on the basis of the design or analysis |
Ascertainment of intervention |
Same method of ascertainment for cases and controls |
Non-response rate |
Total quality scores |
| Wang, 2018 |
☆ |
☆ |
— |
☆ |
☆ |
☆ |
☆ |
☆ |
7 |
| Yang, 2016 |
☆ |
☆ |
☆ |
— |
☆ |
☆ |
☆ |
☆ |
7 |
| Wang, 2014a |
☆ |
☆ |
☆ |
☆ |
☆ |
☆ |
☆ |
☆ |
8 |
| Wang, 2014b |
☆ |
☆ |
☆ |
— |
☆ |
☆ |
☆ |
☆ |
7 |
| Chen, 2012 |
☆ |
☆ |
☆ |
☆ |
☆ |
☆ |
☆ |
☆ |
8 |
| Fernández-Torres, 2012 |
☆ |
☆ |
— |
☆ |
☆ |
☆ |
☆ |
☆ |
7 |
| Dhaliwal, 2011 |
☆ |
☆ |
— |
☆ |
☆ |
☆ |
☆ |
☆ |
7 |
| Huo, 2011 |
☆ |
☆ |
— |
☆ |
— |
☆ |
☆ |
☆ |
6 |
| Rehman, 2009 |
☆ |
☆ |
☆ |
— |
☆ |
☆ |
☆ |
☆ |
7 |
| Song, 2008 |
☆ |
☆ |
☆ |
— |
☆ |
☆ |
☆ |
☆ |
7 |
| Yari, 2008 |
☆ |
☆ |
— |
— |
☆ |
☆ |
☆ |
☆ |
6 |
| Liang, 2007 |
☆ |
☆ |
— |
☆ |
— |
☆ |
☆ |
☆ |
6 |
| Sugimori, 2007 |
☆ |
☆ |
☆ |
— |
☆ |
☆ |
☆ |
☆ |
7 |
| Wang, 2007 |
☆ |
☆ |
— |
☆ |
— |
☆ |
☆ |
— |
5 |
| Oguz, 2002 |
☆ |
☆ |
☆ |
— |
— |
☆ |
☆ |
☆ |
6 |
| Kapusitin, 2001 |
☆ |
☆ |
☆ |
☆ |
☆☆ |
☆ |
☆ |
☆ |
9 |
NOS = Newcastle–Ottawa Scale.
3.4. Pooled effect size and heterogeneity
3.4.1. The association between HLA-DRB1*0301 and AA.
Nine articles that investigated the association between HLA-DRB1*0301 polymorphism and AA were included (Table 3). The forest plot for the association between HLA-DRB1*0301 polymorphism and AA is shown in Figure 2A. The results suggested that HLA-DRB1*0301 was protective against AA (OR = 0.600, 95% CI: 0.427–0.843) with no evidence of significant heterogeneity (I² = 0.0%, PHeterogeneity = 0.552, Q = 8.000).
Table 3 -
Summary results of
HLA-DRB1 polymorphism and
aplastic anemia.
| HLA-DRB1 |
N |
OR |
95% CI |
P
|
I
2 (%) |
P
Heterogeneity
|
Q value |
Begg’s test |
|
Z
|
P
|
| *01 |
6 |
0.706 |
0.309, 1.614 |
.409 |
56.7 |
.041 |
11.547 |
1.50 |
.133 |
| *0101 |
8 |
0.745 |
0.545, 1.019 |
.066 |
14.2 |
.319 |
8.159 |
1.11 |
.266 |
| *0102 |
3 |
0.823 |
0.248, 2.733 |
.750 |
0.0 |
.940 |
2.000 |
0.00 |
1.000 |
| *03 |
6 |
0.617 |
0.312, 1.220 |
.165 |
56.5 |
.043 |
11.494 |
0.38 |
.707 |
| *0301 |
9 |
0.600 |
0.427, 0.843 |
.003 |
0.0 |
.552 |
8.000 |
0.94 |
.348 |
| *04 |
6 |
0.551 |
0.317, 0.956 |
.034 |
64.0 |
.016 |
13.889 |
1.13 |
.260 |
| *0401 |
8 |
1.183 |
0.848, 1.650 |
.322 |
39.0 |
.119 |
11.475 |
0.62 |
.536 |
| *0403 |
4 |
0.659 |
0.381, 1.138 |
.135 |
59.6 |
.059 |
7.426 |
1.02 |
.308 |
| *0404 |
4 |
0.714 |
0.311, 1.641 |
.428 |
0.0 |
.932 |
3.000 |
−0.34 |
1.000 |
| *0405 |
5 |
1.174 |
0.696, 1.980 |
.547 |
67.0 |
.016 |
12.121 |
0.24 |
.806 |
| *0406 |
4 |
0.456 |
0.260, 0.797 |
.006 |
0.0 |
.648 |
3.000 |
−0.34 |
1.000 |
| *0407 |
4 |
3.895 |
0.800, 18.971 |
.092 |
13.3 |
.326 |
3.460 |
1.70 |
.089 |
| *0408 |
3 |
10.526 |
0.765, 146.865 |
.080 |
0.0 |
.461 |
2.000 |
0.00 |
1.000 |
| *0410 |
4 |
0.574 |
0.253, 1.304 |
.185 |
0.0 |
.519 |
3.000 |
−0.34 |
1.000 |
| *07 |
6 |
1.312 |
0.951, 1.811 |
.098 |
17.8 |
.298 |
6.083 |
0.38 |
.707 |
| *0701 |
8 |
0.998 |
0.774, 1.287 |
.990 |
64.2 |
.007 |
19.553 |
−0.12 |
1.000 |
| *08 |
4 |
1.111 |
0.745, 1.655 |
.606 |
25.0 |
.262 |
4.000 |
1.02 |
.308 |
| *0801 |
6 |
1.469 |
0.946, 2.281 |
.087 |
88.5 |
<.001 |
43.478 |
0.38 |
.707 |
| *0802 |
3 |
0.526 |
0.301, 0.919 |
.024 |
0.0 |
.785 |
2.000 |
0.00 |
1.000 |
| *0803 |
5 |
0.639 |
0.471, 0.868 |
.004 |
28.3 |
.233 |
5.579 |
1.22 |
.221 |
| *09 |
4 |
1.342 |
0.952, 1.879 |
.087 |
54.9 |
.084 |
6.652 |
−0.34 |
1.000 |
| *0901 |
10 |
1.591 |
1.045, 2.424 |
.030 |
96.6 |
<.001 |
264.706 |
0.00 |
1.000 |
| *10 |
3 |
0.781 |
0.313, 1.949 |
.596 |
0.0 |
.748 |
2.000 |
0.00 |
1.000 |
| *1001 |
7 |
0.639 |
0.351, 1.164 |
.143 |
0.0 |
.465 |
6.000 |
0.60 |
.548 |
| *11 |
5 |
0.916 |
0.662, 1.268 |
.597 |
0.0 |
.942 |
4.000 |
0.73 |
.462 |
| *1101 |
9 |
0.909 |
0.648, 1.276 |
.583 |
26.0 |
.213 |
10.811 |
0.31 |
.754 |
| *12 |
4 |
0.959 |
0.678, 1.358 |
.815 |
20.0 |
.290 |
3.750 |
0.34 |
.734 |
| *1201 |
8 |
1.146 |
0.777, 1.691 |
.492 |
48.6 |
.058 |
13.619 |
1.86 |
.063 |
| *1202 |
4 |
0.644 |
0.416, 0.998 |
.049 |
0.0 |
.505 |
3.000 |
0.34 |
.734 |
| *13 |
5 |
1.075 |
0.761, 1.514 |
.677 |
0.0 |
.587 |
4.000 |
0.24 |
.806 |
| *1301 |
6 |
0.537 |
0.350, 0.823 |
.004 |
0.0 |
.693 |
5.000 |
0.00 |
1.000 |
| *1302 |
7 |
0.649 |
0.473, 0.889 |
.007 |
31.7 |
.186 |
8.785 |
0.30 |
.764 |
| *14 |
6 |
0.643 |
0.451, 0.916 |
.014 |
0.0 |
.428 |
5.000 |
0.38 |
.707 |
| *1401 |
6 |
0.959 |
0.655, 1.403 |
.827 |
70.9 |
.004 |
17.182 |
0.75 |
.452 |
| *1402 |
3 |
1.701 |
0.126, 22.977 |
.689 |
70.6 |
.033 |
6.803 |
1.04 |
.296 |
| *1403 |
4 |
0.976 |
0.434, 2.197 |
.954 |
0.0 |
.944 |
3.000 |
0.34 |
.734 |
| *1404 |
3 |
0.768 |
0.212, 2.785 |
.688 |
0.0 |
.735 |
2.000 |
0.00 |
1.000 |
| *1405 |
4 |
1.106 |
0.678, 1.804 |
.687 |
0.0 |
.561 |
3.000 |
0.34 |
.734 |
| *1407 |
3 |
0.306 |
0.024, 3.840 |
.359 |
0.0 |
.999 |
2.000 |
1.04 |
.296 |
| *15 |
6 |
2.716 |
1.608, 4.588 |
<.001 |
70.2 |
.005 |
16.779 |
1.13 |
.260 |
| *1501 |
9 |
2.145 |
1.501, 3.063 |
<.001 |
69.6 |
.001 |
26.316 |
0.10 |
.917 |
| *1502 |
7 |
1.691 |
1.272, 2.249 |
<.001 |
78.8 |
<.001 |
28.302 |
0.90 |
.368 |
| *16 |
4 |
0.910 |
0.522, 1.588 |
.741 |
0.0 |
.736 |
3.000 |
1.02 |
.308 |
| *1601 |
6 |
1.182 |
0.675, 2.071 |
.558 |
77.9 |
<.001 |
22.624 |
0.00 |
1.000 |
| *1602 |
5 |
0.725 |
0.403, 1.303 |
.282 |
23.8 |
.265 |
5.249 |
0.24 |
.806 |
CIs = confidence intervals, HLA-DRB1 = human leukocyte antigen-DRB1, OR = odds ratio.
Figure 2.: (A–D) A meta-analysis of the HLA-DRB1-0301, HLA-DRB1-0901, and HLA-DRB1-1501 polymorphism and the results of sensitivity analysis of HLA-DRB1-0301. HLA-DRB1 = human leukocyte antigen-DRB1.
3.4.2. The association between HLA-DRB1*0901 and AA.
Ten articles that investigated the association between HLA-DRB1*0901 polymorphism and AA were included (Table 3). HLA-DRB1*0901 could function as a risk factor of AA, and the pooled OR was 1.591 (95% CI: 1.045–2.424). In addition, significant heterogeneity was observed (I2 = 96.6%, PHeterogeneity < 0.001, Q = 264.706) (Fig. 2B).
3.4.3. The association between HLA-DRB1*1501 and AA.
Nine articles that investigated the association between HLA-DRB1-1501 polymorphism and AA were included (Table 3). HLA-DRB1*1501 was positively associated with AA (OR = 2.145, 95% CI: 1.501–3.063), with significant heterogeneity among studies (I2 = 69.6%, PHeterogeneity = 0.001, Q = 26.316) (Fig. 2C).
3.5. Sensitivity analysis
As shown in Figure 2D, the pooled results were not significantly shaped by any of the studies, indicating that our results are robust.
3.6. Publication bias
The analysis was not suggestive of potential publication bias among the included trials according to Begg rank correlation analysis and Egger weighted regression analysis (P > .05). The detailed potential publication bias can be found in Table S1, Supplemental Digital Content, https://links.lww.com/MD/I787.
4. Discussion
In the current meta-analysis, we systematically reviewed and summarized the articles on the associations of HLA-DRB1 polymorphism and AA. Sixteen studies with a total number of 4428 patients were included and analyzed. The results suggested that HLA-DRB1*0301 might be protective against AA, whereas HLA-DRB1*0901 and HLA-DRB1*1501 are probably the risk factors.
AA is characterized by bone marrow hypocellularity and peripheral cytopenia, but the detailed pathophysiology is still in exploration. Previous studies found that antigen-driven and auto-immune dysregulated T-cell homeostasis results in hematopoietic stem cell injury, which may be a pathogenesis of AA.[32,33] In addition, studies have indicated that several genes such as HLA-A, -B, -DRB1 alleles were associated with the pathogenesis and development of AA. In the previous meta-analysis,[13] cases who carried HLA-DRB1*15 or HLA-DRB1*15:01 alleles might have a good response rate for the immunosuppressive therapy among AA patients, suggestive of close associations between the HLA gene and AA. Meanwhile, the HLA gene could involve in mediating immune response and cause an abnormal immune response, which has been observed with the occurrence of immune disease.[8]
The protective function of HLA-DRB1*03 in Crohn’s disease and sickle cell anemia was previously reported, and the mechanisms included the immunomodulatory effects of HLA-DRB1*03.[34] In the current meta-analysis, HLA-DRB1*0301 was protective against AA, which was in line with the above findings. Deng et al[33] reported that the frequency of the HLA-DRB1*0901 gene in the HLA-II group was significantly higher than that in the control group, which indicated the HLA-DRB1*0901 might have a potential influence on AA. The finding was in concordance with ours, in which the HLA-DRB1*0901 gene may be a risk factor for AA. Oguz et al[8] demonstrated that the expression of HLA-DRBl*1501 was significantly higher in the muscles of Chinese (especially those living in northern China), Slavic, Japanese, and Korean than that in the healthy controls. In addition, the association of HLA-DR2 or its split DR15 (HLA-DRB1*1501) with susceptibility to AA has been well documented in different ethnic groups, which once again corroborated the results of this meta-analysis. Regarding the high expression level of HLA-DRBl*1501 in the AA group, this gene may act as a risk factor for AA.
However, this study contains some limitations. Firstly, relatively limited studies were included in this meta-analysis, thus a greater number of research on HLA-DRB1 polymorphism should be conducted. Secondly, a high level of heterogeneity was observed in the analysis of HLA-DRBl*0901, which might be attributed to limited sample size, different study designs, and population heterogeneity. Therefore, the random effects model should be employed to decline this negative influence.
5. Conclusion
In conclusion, HLA-DRBl*0301 could be protective against AA, while HLA-DRBl*0901 and HLA-DRBl*1501 might act as risk factors for AA.
Author contributions
Conceptualization: Baijun Fang.
Data curation: Ning Li, Lijie Liang.
Formal analysis: Ning Li.
Funding acquisition: Baijun Fang.
Investigation: Lijie Liang, Yaomei Wang, Suxia Luo, Yongping Song.
Methodology: Yaomei Wang, Suxia Luo.
Software: Yaomei Wang, Suxia Luo.
Writing – original draft: Ning Li.
Writing – review & editing: Yongping Song, Baijun Fang.
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