Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Aug 5;16(1):162.
doi: 10.1186/s12974-019-1551-z.

Next-generation sequencing identifies contribution of both class I and II HLA genes on susceptibility of multiple sclerosis in Japanese

Kotaro Ogawa  1   2 , Tatsusada Okuno  2 , Kazuyoshi Hosomichi  3 , Akiko Hosokawa  2   4 , Jun Hirata  1   5 , Ken Suzuki  1 , Saori Sakaue  1 , Makoto Kinoshita  2 , Yoshihiro Asano  6 , Katsuichi Miyamoto  7 , Ituro Inoue  8 , Susumu Kusunoki  7 , Yukinori Okada  9   10 , Hideki Mochizuki  2
Affiliations

Next-generation sequencing identifies contribution of both class I and II HLA genes on susceptibility of multiple sclerosis in Japanese

Kotaro Ogawa et al. J Neuroinflammation. .

Abstract

Background: The spectrum of classical and non-classical HLA genes related to the risk of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) in the Japanese population has not been studied in detail. We conducted a case-control analysis of classical and non-classical HLA genes.

Methods: We used next-generation sequencing (NGS)-based HLA genotyping methods for mapping risk for 45 MS patients, 31 NMOSD patients, and 429 healthy controls. We evaluated the association of the HLA variants with the risk of MS and NMOSD using logistic regression analysis and Fisher's exact test.

Results: We confirmed that HLA-DRB1*15:01 showed the strongest association with MS (P = 2.1 × 10-5; odds ratio [OR] = 3.44, 95% confidence interval [95% CI] = 1.95-6.07). Stepwise conditional analysis identified HLA-DRB1*04:05, HLA-B*39:01, and HLA-B*15:01 as being associated with independent MS susceptibility (PConditional < 8.3 × 10-4). With respect to amino acid polymorphisms in HLA genes, we found that phenylalanine at HLA-DQβ1 position 9 had the strongest effect on MS susceptibility (P = 3.7 × 10-8, OR = 3.48, 95% CI = 2.23-5.43). MS risk at HLA-DQβ1 Phe9 was independent of HLA-DRB1*15:01 (PConditional = 1.5 × 10-5, OR = 2.91, 95% CI = 1.79-4.72), while HLA-DRB1*15:01 was just significant when conditioned on HLA-DQβ1 Phe9 (PConditional = 0.037). Regarding a case-control analysis for NMOSD, HLA-DQA1*05:03 had a significant association with NMOSD (P = 1.5 × 10-4, OR = 6.96, 95% CI = 2.55-19.0).

Conclusions: We identified HLA variants associated with the risk of MS and NMOSD. Our study contributes to the understanding of the genetic architecture of MS and NMOSD in the Japanese population.

Keywords: HLA; Multiple sclerosis; Neuromyelitis optica spectrum disorder; Next-generation sequencing.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Multiple sclerosis risk-associated amino acid positions of the HLA genes in three-dimensional structure models. HLA amino acid positions with significant MS risk in HLA-DQ molecules. The protein structure is based on Protein Data Bank (PDB) entries 1jk8 and prepared using UCSF Chimera (version 1.7). Residues at the amino acid positions with significant MS risk is highlighted in red
Fig. 2
Fig. 2
Multiple sclerosis risk-associated amino acid positions of the HLA genes. Diamonds represent the –log10(P) of the amino acid positions of the tested HLA genes. Labeled red diamonds represent the –log10(P) values of the amino acid positions significantly associated with MS. The horizontal lines represent the association P value of HLA-DRB1*15:01. a No amino acid polymorphisms of HLA-B was significantly associated with MS. b No amino acid polymorphisms of HLA-DRB1 is significantly associated with MS. c The HLA-DQβ1 position 9 and 70 were associated with MS more significantly than HLA-DRB1*15:01
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

  • A Metagenome-Wide Association Study of Gut Microbiome in Patients With Multiple Sclerosis Revealed Novel Disease Pathology.
    Kishikawa T, Ogawa K, Motooka D, Hosokawa A, Kinoshita M, Suzuki K, Yamamoto K, Masuda T, Matsumoto Y, Nii T, Maeda Y, Nakamura S, Inohara H, Mochizuki H, Okuno T, Okada Y. Kishikawa T, et al. Front Cell Infect Microbiol. 2020 Dec 11;10:585973. doi: 10.3389/fcimb.2020.585973. eCollection 2020. Front Cell Infect Microbiol. 2020. PMID: 33363050 Free PMC article.
  • HLA genotype-clinical phenotype correlations in multiple sclerosis and neuromyelitis optica spectrum disorders based on Japan MS/NMOSD Biobank data.
    Watanabe M, Nakamura Y, Sato S, Niino M, Fukaura H, Tanaka M, Ochi H, Kanda T, Takeshita Y, Yokota T, Nishida Y, Matsui M, Nagayama S, Kusunoki S, Miyamoto K, Mizuno M, Kawachi I, Saji E, Ohashi T, Shimohama S, Hisahara S, Nishiyama K, Iizuka T, Nakatsuji Y, Okuno T, Ochi K, Suzumura A, Yamamoto K, Kawano Y, Tsuji S, Hirata M, Sakate R, Kimura T, Shimizu Y, Nagaishi A, Okada K, Hayashi F, Sakoda A, Masaki K, Shinoda K, Isobe N, Matsushita T, Kira JI. Watanabe M, et al. Sci Rep. 2021 Jan 12;11(1):607. doi: 10.1038/s41598-020-79833-7. Sci Rep. 2021. PMID: 33436735 Free PMC article.
  • Blood DNA virome associates with autoimmune diseases and COVID-19.
    Sasa N, Kojima S, Koide R, Hasegawa T, Namkoong H, Hirota T, Watanabe R, Nakamura Y, Oguro-Igashira E, Ogawa K, Yata T, Sonehara K, Yamamoto K, Kishikawa T, Sakaue S, Edahiro R, Shirai Y, Maeda Y, Nii T, Chubachi S, Tanaka H, Yabukami H, Suzuki A, Nakajima K, Arase N, Okamoto T, Nishikawa R, Namba S, Naito T, Miyagawa I, Tanaka H, Ueno M, Ishitsuka Y, Furuta J, Kunimoto K, Kajihara I, Fukushima S, Miyachi H, Matsue H, Kamata M, Momose M, Bito T, Nagai H, Ikeda T, Horikawa T, Adachi A, Matsubara T, Ikumi K, Nishida E, Nakagawa I, Yagita-Sakamaki M, Yoshimura M, Ohshima S, Kinoshita M, Ito S, Arai T, Hirose M, Tanino Y, Nikaido T, Ichiwata T, Ohkouchi S, Hirano T, Takada T, Tazawa R, Morimoto K, Takaki M, Konno S, Suzuki M, Tomii K, Nakagawa A, Handa T, Tanizawa K, Ishii H, Ishida M, Kato T, Takeda N, Yokomura K, Matsui T, Uchida A, Inoue H, Imaizumi K, Goto Y, Kida H, Fujisawa T, Suda T, Yamada T, Satake Y, Ibata H, Saigusa M, Shirai T, Hizawa N, Nakata K; Japan COVID-19 Task Force; Imafuku S, Tada Y, Asano Y, Sato S, Nishigori C, Jinnin M, Ihn H, Asahina A, Saeki H, Kawamura T, Shimada S, Katayama I, Poisner HM, Mack TM, Bick AG, Higasa K, Okuno T, Mochizuki H, Ishii M, Koike R, K… See abstract for full author list ➔ Sasa N, et al. Nat Genet. 2025 Jan;57(1):65-79. doi: 10.1038/s41588-024-02022-z. Epub 2025 Jan 3. Nat Genet. 2025. PMID: 39753770 Free PMC article.
  • CTSO and HLA-DQA1 as biomarkers in sepsis-associated ARDS: insights from RNA sequencing and immune infiltration analysis.
    Shen YZ, Yao YD, Li HL, Li Y, Hu YC. Shen YZ, et al. BMC Infect Dis. 2025 Mar 7;25(1):326. doi: 10.1186/s12879-025-10726-8. BMC Infect Dis. 2025. PMID: 40055592 Free PMC article.
  • A Comprehensive Review on the Role of Genetic Factors in Neuromyelitis Optica Spectrum Disorder.
    Ghafouri-Fard S, Azimi T, Taheri M. Ghafouri-Fard S, et al. Front Immunol. 2021 Oct 5;12:737673. doi: 10.3389/fimmu.2021.737673. eCollection 2021. Front Immunol. 2021. PMID: 34675927 Free PMC article. Review.
See all "Cited by" articles

References

    1. Trowsdale J, Knight JC. Major histocompatibility complex genomics and human disease. Annu Rev Genomics Hum Genet. 2013;14:301–323. - PMC - PubMed
    1. Dendrou CA, Petersen J, Rossjohn J, et al. HLA variation and disease. Nat Rev Immunol. 2018;18(5):325–339. - PubMed
    1. Kanai M, Akiyama M, Takahashi A, et al. Genetic analysis of quantitative traits in the Japanese population links cell types to complex human diseases. Nat Genet. 2018;50(3):390–400. - PubMed
    1. Silman AJ, Pearson JE. Epidemiology and genetics of rheumatoid arthritis. Arthritis Res. 2002;4(Suppl 3):S265–S272. - PMC - PubMed
    1. Noble JA. Immunogenetics of type 1 diabetes: a comprehensive review. J Autoimmun. 2015;64:101–112. - PubMed