Identification of HLA-DRB1*04:10 allele as risk allele for Japanese moyamoya disease and its association with autoimmune thyroid disease: A case-control study

PLoS One. 2019 Aug 14;14(8):e0220858. doi: 10.1371/journal.pone.0220858. eCollection 2019.


Background and purpose: Moyamoya disease (MMD) is a progressive cerebrovascular disease with unknown etiology. Growing evidence suggest its involvement of autoimmune and genetic mechanisms in the pathogenesis of MMD. This study aims to clarify the association between HLA allele and MMD.

Methods: Case-control study: the DNA of 136 MMD patients in Japan was extracted and the genotype of human leukocyte antigen (HLA) from this DNA was determined by super-high-resolution single-molecule sequence-based typing using next-generation sequencing. Next, the frequency of each HLA allele (HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1, and HLA-DPB1) was compared with those in the Japanese control database. In addition, haplotype estimation was performed using the expectation maximization algorithm.

Results: The frequencies of the HLA-DRB1*04:10 allele (4.77% vs. 1.47% in the control group; P = 1.7 × 10-3; odds ratio [OR] = 3.35) and of the HLA-DRB1*04:10-HLA-DQB1*04:02 haplotype (haplotype frequency 4.41% vs. 1.35% in the control group; P = 2.0 × 10-3; OR = 3.37) significantly increased. The frequency of thyroid diseases, such as Graves' disease and Hashimoto thyroiditis, increased in HLA-DRB1*04:10-positive MMD patients compared with that in HLA-DRB1*04:10-negative MMD patients.

Conclusions: HLA-DRB1*04:10 is a risk allele and HLA-DRB1*04:10-HLA-DQB1*04:02 a risk haplotype for MMD. In addition, HLA-DRB1*04:10 is associated with thyroid disease in MMD patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alleles
  • Case-Control Studies
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Genotype
  • HLA-DRB1 Chains / genetics*
  • Humans
  • Japan
  • Male
  • Middle Aged
  • Moyamoya Disease / genetics*
  • Thyroiditis, Autoimmune / genetics*


  • HLA-DRB1 Chains
  • HLA-DRB1*04 antigen

Grants and funding

This work was supported by Ministry of Health, Labour and Welfare (MHLW) Grant Number S17310031, Japan Agency for Medical Research and Development (AMED) Grant Number J170001344 and Japan Society for the promotion of Science (JSPS) KAKENHI Grant Number 17K10815. GenoDive Pharma Inc. provided support in the form of salaries for H. I., but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.