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Protective association of HLA-DPB1*04:01:01 with acute encephalopathy with biphasic seizures and late reduced diffusion identified by HLA imputation

Genes & Immunity volume 23, pages 123–128 (2022)Cite this article

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Abstract

Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a severe syndrome of acute encephalopathy that affects infants and young children. AESD is a polygenic disorder preceded by common viral infections with high fever. We conducted an association study of human leukocyte antigen (HLA) regions with AESD using HLA imputation. SNP genotyping was performed on 254 Japanese patients with AESD and 799 healthy controls. We conducted 3-field HLA imputation for 14 HLA genes based on Japanese-specific references using data from our previous genome-wide association study. After quality control, 208 patients and 737 controls were included in the analysis of HLA alleles. We then compared the carrier frequencies of HLA alleles and haplotypes between the patients and controls. HLA-DPB1*04:01:01 showed a significant association with AESD, exerting a protective effect against the disease (p = 0.0053, pcorrected = 0.042, odds ratio = 0.43, 95% confidence interval = 0.21–0.80). The allele frequency of HLA-DPB1*04:01:01 was lower in East Asians than in Caucasians, which may partially account for the higher incidence of AESD in the Japanese population. The present results demonstrate the importance of fine-mapping of the HLA region to investigate disease susceptibilities and elucidate the pathogenesis of AESD.

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Fig. 1: Regional plot around the HLA region in the discovery GWAS for AESD.

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Acknowledgements

The authors are grateful to Ms. Aya Shoda for her technical assistance and to the Collaborative Research Supporting Committee of the Japanese Society of Child Neurology for promoting this study. We wish to thank all the pediatricians for providing patient samples, and the patients and their parents for participating in this study.

Funding

This research was supported by a Grant-in-Aid for Scientific Research, No. 15H04872, from the Japan Society for the Promotion of Science, and a Grant-in-Aid for Policy Research for Intractable Diseases, No. H30-Nanchi-Ippan-007, from the National Institute of Public Health, Japan.

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Authors and Affiliations

  1. Department of Developmental Medical Sciences, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Mariko Kasai, Akiko Shibata, Ai Hoshino & Masashi Mizuguchi

  2. Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Mariko Kasai & Akiko Shibata

  3. Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan

    Yosuke Omae, Seik-Soon Khor & Katsushi Tokunaga

  4. Department of Pediatrics, National Rehabilitation Center for Children with Disabilities, Tokyo, Japan

    Masashi Mizuguchi

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  1. Mariko Kasai
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Contributions

MK performed genotyping, conducted statistical analyses, and wrote the original draft; AH and MM collected samples; YO, KS-S, AS, AH, MM, and KT contributed to the materials and methods of the research and reviewed the manuscript; MM and KT conceived this study.

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Correspondence to Mariko Kasai.

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Kasai, M., Omae, Y., Khor, SS. et al. Protective association of HLA-DPB1*04:01:01 with acute encephalopathy with biphasic seizures and late reduced diffusion identified by HLA imputation. Genes Immun 23, 123–128 (2022). https://doi.org/10.1038/s41435-022-00170-y

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