Association of HLA class II (-DRB1,-DQB1,-DPB1) alleles and haplotypes on susceptibility to aplastic anemia in northern Chinese Han

doi:10.1016/j.humimm.2020.07.001

Human Immunology

Volume 81, Issue 12, December 2020, Pages 685-691

https://doi.org/10.1016/j.humimm.2020.07.001 Get rights and content

Abstract

The Human Leukocyte Antigen (HLA) genes, playing key roles in mediating the immune response, especially HLA class II alleles were suggested to play a role in the activation of autoreactive T-cells in aplastic anemia (AA). Previous studies in different ethnic groups have indicated that some of HLA-A,-B,-DRB1 alleles had a protective or susceptive association with the prevalence, pathogenesis and development of AA. HLA class II genes, especially HLA-DQB1 and -DPB1 alleles or haplotypes at high-resolution level associated with AA have not been fully identified in northern Chinese Han populations. The aim of this study was to identify association of the variations in HLA class II region with AA in northern Chinese Han population. A recent case-control study, including 96 AA patients and 824 healthy controls was performed. The high-resolution HLA genotyping was conducted by PCR-SBT, -SSO and NGS-ION S5^TM platform. Based on genotypic data of the three loci, haplotype estimation was carried out. HLA-DRB1*15:01 (Pc = 2.87 × 10^-3; OR = 2.11, 95% CI = 1.45–3.07) and HLA-DQB1*06:02 (Pc = 1.86 × 10^-2; OR = 2.01, 95% CI = 1.32–3.06) were the risk and predisposition alleles to AA in northern Chinese Han after considering multiple testing. Moreover, the HLA-DRB1*15:01-DQB1*06:02 (Pc = 4.90 × 10^-3; OR = 2.09, 95% CI = 1.37–3.19) and HLA-DRB1*14:05-DQB1*05:03 (Pc = 2.65 × 10^-2; OR = 2.82, 95%CI = 1.45–5.50) haplotypes had direct strong relevance to AA and were the susceptible haplotypes. HLA-DPB1 alleles and 23 polymorphic amino acid residues spanning exon 2 ~ 4 of DPβ1 molecules have showed no statistically significant associations between AA and controls. The present findings establish a novel link between inherited HLA-DRB1,-DQB1,-DPB1 risk alleles and haplotypes in northern Chinese Han with AA, and open new avenues for development of targeted therapies to prevent or redirect immunopathology in AA.

Introduction

Aplastic anemia (AA) is a rare and life-threatening hematopoietic stem cell disease characterized by cytopenia in peripheral blood and hypoplasia in bone marrow. AA incidence in Asia is 2–3 times higher than United States and Europe where is below 2.5 per million [1], [2]. In China, the prevalence of AA is 7.4 per million [3].

The Human Leukocyte Antigen (HLA) genes, playing key roles in mediating the immune response, especially class II alleles were suggested to play a role in the activation of autoreactive T-cells in AA [4], [5] and other types of autoimmune diseases [6], [7]. Many collaborative studies in different ethnic group are indicated that some of HLA-A,-B,-DRB1 alleles had a protective or susceptive association with the prevalence, pathogenesis and development of AA; however, the results showed considerable controversy [4], [8], [9], [10], [11], [12]. Meanwhile, most of related studies focus on the relationship between HLA-A,-B,-DRB1 alleles and AA, lacking of evaluating the association of HLA-DQB1,-DPB1 allele and haplotype polymorphisms with AA by a large recent case-control study in northern Chinese Han.

In addition, reflecting distinct features of its polymorphism, HLA-DPB1 has been the first locus being explored as a model for clinical permissive HLA mismatches [13]. More recently, new strategies for exploiting mismatched HLA-DPB1 in adoptive cellular immunotherapy of malignant blood disorders are emerging [14]. However, the data on HLA-DPB1 polymorphisms of Chinese Han with AA was relatively rare. Whether or not differential HLA-DPB1 alleles contribute to the prevalence and pathogenesis of AA in northern Chinese Han is unknown.

The aim of our present study was to investigate the association of the variations in the HLA class II region with AA in northern Chinese Han population. It is the first study to evaluate the role of HLA class II loci haplotypes in AA patients from northern Chinese Han populations. We analyzed a relatively large and homogenous AA cohort with HLA class II alleles at high resolution-level, including HLA-DRB1,-DQB1, and -DPB1 loci, discussing the relationship of HLA typical class II gene and haplotype polymorphisms with AA.

Section snippets

Study subjects

A total of 920 individuals were enrolled in the study: 96 patients with AA and 824 healthy control participants. The patients were recruited from the hematopoietic stem cell transplantation (HSCT) program in Shaanxi Blood Center from June 2016 to May 2019. The AA patients were selected from primary acquired aplastic anemia with unknown causes prior to onset, initially diagnosed according to Chinese expert consensus on the diagnosis and treatment of aplastic anemia (2017) [15]. General or

Clinical characteristics and Hardy-Weinberg equilibrium test

The distributions of sex, age, ethnic and genetic family history of subjects showed no statistical differences between the AA group and healthy controls (Table 1).

Hardy-Weinberg equilibrium was estimated by Fisher’s exact test using Arlequin 3.5.2.2 software. In order to be accordant with HWE, some HLA-DPB1 alleles detected in this study were classified G group, including HLA-DPB1*104:01 (DPB1*03:01:01G) with the frequencies of 0.52% and 0.67% in AA patients and controls, respectively;

Discussion

Most cases of AA are acquired and idiopathic and has been recognized as an autoimmune disease with hematopoietic stem/progenitor cells (HSPCs) as the target attacked by the activated T lymphocytes and secreting proinflammatory cytokines, which induce apoptosis of CD34 + cells [8]. In AA, there is overrepresentation of HLA-DRB1*15 and class I HLA-B*40:02 and HLA-A*02:06 [20], [21]. The reason of higher incidence of AA in Asia than in the USA and Europe might be more contributing to the impact of

Data availability statement

The data used to support the findings of this study are available from the corresponding author upon request.

Funding information

Project supported by Weigao Research Fundation of Chinese Society of Blood Transfusion (CSBT-WG-2017-06) and the Natural Science Foundation of Xi’an Health Commission (J201701003). Additional supporting information was provided by China Marrow Donor Program (CMDP).

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

This work was supported by Weigao Research Fundation of Chinese Society of Blood Transfusion (CSBT-WG-2017-06) and the Natural Science Foundation of Xi’an Health Commission (J201701003). Additional supporting information was provided by China Marrow Donor Program (CMDP). We are grateful to all the volunteers who were willing to participate into the study.

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HLA-DQ belongs to the MHC-II molecular family. Research discovered that HLA-DRB1*15:01 and HLA-DQB1*06:02 were the risk and predisposition alleles to AA in northern Chinese Han, the HLA-DRB1*15:01-DQB1*06:02 and HLA-DRB1*14:05-DQB1*05:03 haplotypes had direct strong relevance to AA and were the susceptible haplotypes [25]. In this study, we explored the role of HLA-DQ in the immune response of SAA through investigating the HLA-DQ expression level in SAA patient–derived cDCs and its impact on the downstream effector T cells in systemic immunity.
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Research articleAssociation of HLA class II (-DRB1,-DQB1,-DPB1) alleles and haplotypes on susceptibility to aplastic anemia in northern Chinese Han

Abstract

Introduction

Section snippets

Study subjects

Clinical characteristics and Hardy-Weinberg equilibrium test

Discussion

Data availability statement

Funding information

Declaration of Competing Interest

Acknowledgments

Hum. Immunol.

Hum. Immunol.

Blood

Malaysia. Hum Immunol.

Lancet Oncol.

Hematol Oncol Clin North Am.

Blood

Blood

Biol Blood Marrow Transplant.

Blood

Blood

Hum Immunol.

Hum Immunol.

Vaccine.

Am. J. Hum. Genet.

Blood Adv.

Incidence of adult acquired severe aplastic anemia was not increased in Shanghai China

Ann Hematol.

Epidemiological, clinical and genetic characterization of aplastic anemia patients in Pakistan

Ann Hematol.

Value of HLA-DR genotype in systemic lupus erythematosus and lupus nephritis: a meta-analysis

Int. J. Rheumat. Dis.

Meta-analysis of the association of HLA-DRB1 with rheumatoid arthritis in Chinese populations

BMC Musculoskeletal Disorders.

Association of aplastic anaemia and Fanconi’s disease with HLA-DRB1 alleles

Int J Immunogenet.

Association of HLA DRB1 polymorphism with susceptibility to myelodysplastic syndrome and aplastic anemia in Chinese Han population

Zhonghua Yi Xue Yi Chuan Xue Za Zhi.

Correlation of HLA-alleles with aplastic anemia

Zhongguo Shi Yan Xue Ye Xue Za Zhi.

Research article
Association of HLA class II (-DRB1,-DQB1,-DPB1) alleles and haplotypes on susceptibility to aplastic anemia in northern Chinese Han