HLA genotype-clinical phenotype correlations in multiple sclerosis and neuromyelitis optica spectrum disorders based on Japan MS/NMOSD Biobank data

doi:10.1038/s41598-020-79833-7

. 2021 Jan 12;11(1):607.

doi: 10.1038/s41598-020-79833-7.

HLA genotype-clinical phenotype correlations in multiple sclerosis and neuromyelitis optica spectrum disorders based on Japan MS/NMOSD Biobank data

Mitsuru Watanabe¹, Yuri Nakamura^{1

2

3}, Shinya Sato¹, Masaaki Niino⁴, Hikoaki Fukaura⁵, Masami Tanaka^{6

7}, Hirofumi Ochi⁸, Takashi Kanda⁹, Yukio Takeshita⁹, Takanori Yokota¹⁰, Yoichiro Nishida¹⁰, Makoto Matsui¹¹, Shigemi Nagayama¹¹, Susumu Kusunoki¹², Katsuichi Miyamoto¹², Masanori Mizuno¹³, Izumi Kawachi^{14

15}, Etsuji Saji¹⁴, Takashi Ohashi¹⁶, Shun Shimohama¹⁷, Shin Hisahara¹⁷, Kazutoshi Nishiyama¹⁸, Takahiro Iizuka¹⁸, Yuji Nakatsuji^{19

20}, Tatsusada Okuno¹⁹, Kazuhide Ochi²¹, Akio Suzumura²², Ken Yamamoto²³, Yuji Kawano^{1

24}, Shoji Tsuji²⁵, Makoto Hirata²⁶, Ryuichi Sakate²⁶, Tomonori Kimura²⁶, Yuko Shimizu²⁷, Akiko Nagaishi²⁸, Kazumasa Okada²⁹, Fumie Hayashi¹, Ayako Sakoda^{1

2}, Katsuhisa Masaki¹, Koji Shinoda¹, Noriko Isobe^{1

30}, Takuya Matsushita¹, Jun-Ichi Kira^{31

32

33}

Affiliations

¹ Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
² Department of Neurology, Brain and Nerve Center, Fukuoka Central Hospital, 2-6-11 Yakuin, Chuo-ku, Fukuoka, 810-0022, Japan.
³ School of Pharmacy at Fukuoka, International University of Health and Welfare, 137-1 Enokizu, Okawa, Fukuoka, 831-8501, Japan.
⁴ Department of Clinical Research, National Hospital Organization Hokkaido Medical Center, 1-1, 5-7 Yamanote, Nishi-ku, Sapporo, 063-0005, Japan.
⁵ Department of Neurology, Saitama Medical Center, 1981 Kamoda, Kawagoe, Saitama, 350-8550, Japan.
⁶ Multiple Sclerosis Center, National Hospital Organization Utano National Hospital, 8 Ondoyama, Narutaki, Ukyo-ku, Kyoto, 616-8255, Japan.
⁷ Kyoto MS Center, Kyoto Min-Iren Chuo Hospital, 2-1 Tsuchimoto-Cho, Kyoto, 616-8147, Japan.
⁸ Department of Neurology and Geriatric Medicine, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon, Ehime, 791-0295, Japan.
⁹ Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi, 755-8505, Japan.
¹⁰ Department of Neurology and Neurological Science, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
¹¹ Department of Neurology, Kanazawa Medical University, 1-1 Uchinada, Kahoku, Ishikawa, 920-0293, Japan.
¹² Department of Neurology, Faculty of Medicine, Kindai University, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan.
¹³ Division of Neurology and Gerontology, Department of Internal Medicine, Iwate Medical University, 2-1-1 Idaidoori, Yahaba, Iwate, 028-3695, Japan.
¹⁴ Department of Neurology, Brain Research Institute, Niigata University, 1-757 Asahimachi, Chuo-ku, Niigata, 951-8585, Japan.
¹⁵ Comprehensive Medical Education Center, Niigata University School of Medicine, 1-757 Asahimachi, Chuo-ku, Niigata, 951-8585, Japan.
¹⁶ Division of Neurology, Department of Internal Medicine, Tokyo Women's Medical University Yachiyo Medical Center, 477-96 Owadashinden, Yachiyo, Chiba, 276-8524, Japan.
¹⁷ Department of Neurology, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo, 060-8543, Japan.
¹⁸ Department of Neurology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan.
¹⁹ Department of Neurology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
²⁰ Department of Neurology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
²¹ Department of Clinical Neuroscience and Therapeutics, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
²² Department of Neurology, Kaikokai-Jousai Hospital, 1-4 Kitabatake, Nakamura-ku, Nagoya, 453-0815, Japan.
²³ Department of Medical Biochemistry, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan.
²⁴ Department of Neurology, National Hospital Organization Omuta National Hospital, 1044-1 Oaza Tachibana, Omuta, Fukuoka, 837-0911, Japan.
²⁵ Department of Neurology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
²⁶ Laboratory of Rare Disease Resource Library, Center for Rare Disease Research, National Institutes of Biomedical Innovation, Health and Nutrition, 7‑6‑8, Saito‑Asagi, Ibaraki, Osaka, 567‑0085, Japan.
²⁷ Department of Neurology, School of Medicine, Tokyo Women's Medical University, 8-1, Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan.
²⁸ Department of Neurology, National Hospital Organization Nagasaki Kawatana Medical Center, 2005-1 Shimogumigo, Kawatana-machi, Nagasaki, 859-3615, Japan.
²⁹ Department of Neurology, University of Occupational and Environmental Health School of Medicine, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka, 807-8555, Japan.
³⁰ Department of Neurological Therapeutics, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
³¹ Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. kira@neuro.med.kyushu-u.ac.jp.
³² Department of Neurology, Brain and Nerve Center, Fukuoka Central Hospital, 2-6-11 Yakuin, Chuo-ku, Fukuoka, 810-0022, Japan. kira@neuro.med.kyushu-u.ac.jp.
³³ Translational Neuroscience Center, Graduate School of Medicine, and School of Pharmacy at Fukuoka, International University of Health and Welfare, 137-1 Enokizu, Okawa, Fukuoka, 831-8501, Japan. kira@neuro.med.kyushu-u.ac.jp.

PMID: 33436735
PMCID: PMC7804194
DOI: 10.1038/s41598-020-79833-7

HLA genotype-clinical phenotype correlations in multiple sclerosis and neuromyelitis optica spectrum disorders based on Japan MS/NMOSD Biobank data

Mitsuru Watanabe et al. Sci Rep. 2021.

. 2021 Jan 12;11(1):607.

doi: 10.1038/s41598-020-79833-7.

Authors

Affiliations

¹ Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
² Department of Neurology, Brain and Nerve Center, Fukuoka Central Hospital, 2-6-11 Yakuin, Chuo-ku, Fukuoka, 810-0022, Japan.
³ School of Pharmacy at Fukuoka, International University of Health and Welfare, 137-1 Enokizu, Okawa, Fukuoka, 831-8501, Japan.
⁴ Department of Clinical Research, National Hospital Organization Hokkaido Medical Center, 1-1, 5-7 Yamanote, Nishi-ku, Sapporo, 063-0005, Japan.
⁵ Department of Neurology, Saitama Medical Center, 1981 Kamoda, Kawagoe, Saitama, 350-8550, Japan.
⁶ Multiple Sclerosis Center, National Hospital Organization Utano National Hospital, 8 Ondoyama, Narutaki, Ukyo-ku, Kyoto, 616-8255, Japan.
⁷ Kyoto MS Center, Kyoto Min-Iren Chuo Hospital, 2-1 Tsuchimoto-Cho, Kyoto, 616-8147, Japan.
⁸ Department of Neurology and Geriatric Medicine, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon, Ehime, 791-0295, Japan.
⁹ Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi, 755-8505, Japan.
¹⁰ Department of Neurology and Neurological Science, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
¹¹ Department of Neurology, Kanazawa Medical University, 1-1 Uchinada, Kahoku, Ishikawa, 920-0293, Japan.
¹² Department of Neurology, Faculty of Medicine, Kindai University, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan.
¹³ Division of Neurology and Gerontology, Department of Internal Medicine, Iwate Medical University, 2-1-1 Idaidoori, Yahaba, Iwate, 028-3695, Japan.
¹⁴ Department of Neurology, Brain Research Institute, Niigata University, 1-757 Asahimachi, Chuo-ku, Niigata, 951-8585, Japan.
¹⁵ Comprehensive Medical Education Center, Niigata University School of Medicine, 1-757 Asahimachi, Chuo-ku, Niigata, 951-8585, Japan.
¹⁶ Division of Neurology, Department of Internal Medicine, Tokyo Women's Medical University Yachiyo Medical Center, 477-96 Owadashinden, Yachiyo, Chiba, 276-8524, Japan.
¹⁷ Department of Neurology, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo, 060-8543, Japan.
¹⁸ Department of Neurology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan.
¹⁹ Department of Neurology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
²⁰ Department of Neurology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
²¹ Department of Clinical Neuroscience and Therapeutics, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
²² Department of Neurology, Kaikokai-Jousai Hospital, 1-4 Kitabatake, Nakamura-ku, Nagoya, 453-0815, Japan.
²³ Department of Medical Biochemistry, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan.
²⁴ Department of Neurology, National Hospital Organization Omuta National Hospital, 1044-1 Oaza Tachibana, Omuta, Fukuoka, 837-0911, Japan.
²⁵ Department of Neurology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
²⁶ Laboratory of Rare Disease Resource Library, Center for Rare Disease Research, National Institutes of Biomedical Innovation, Health and Nutrition, 7‑6‑8, Saito‑Asagi, Ibaraki, Osaka, 567‑0085, Japan.
²⁷ Department of Neurology, School of Medicine, Tokyo Women's Medical University, 8-1, Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan.
²⁸ Department of Neurology, National Hospital Organization Nagasaki Kawatana Medical Center, 2005-1 Shimogumigo, Kawatana-machi, Nagasaki, 859-3615, Japan.
²⁹ Department of Neurology, University of Occupational and Environmental Health School of Medicine, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka, 807-8555, Japan.
³⁰ Department of Neurological Therapeutics, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
³¹ Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. kira@neuro.med.kyushu-u.ac.jp.
³² Department of Neurology, Brain and Nerve Center, Fukuoka Central Hospital, 2-6-11 Yakuin, Chuo-ku, Fukuoka, 810-0022, Japan. kira@neuro.med.kyushu-u.ac.jp.
³³ Translational Neuroscience Center, Graduate School of Medicine, and School of Pharmacy at Fukuoka, International University of Health and Welfare, 137-1 Enokizu, Okawa, Fukuoka, 831-8501, Japan. kira@neuro.med.kyushu-u.ac.jp.

PMID: 33436735
PMCID: PMC7804194
DOI: 10.1038/s41598-020-79833-7

Abstract

HLA genotype-clinical phenotype correlations are not established for multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). We studied HLA-DRB1/DPB1 genotype-phenotype correlations in 528 MS and 165 NMOSD cases using Japan MS/NMOSD Biobank materials. HLA-DRB1*04:05, DRB1*15:01 and DPB1*03:01 correlated with MS susceptibility and DRB1*01:01, DRB1*09:01, DRB1*13:02 and DPB1*04:01 were protective against MS. HLA-DRB1*15:01 was associated with increased optic neuritis and cerebellar involvement and worsened visual and pyramidal functional scale (FS) scores, resulting in higher progression index values. HLA-DRB1*04:05 was associated with younger onset age, high visual FS scores, and a high tendency to develop optic neuritis. HLA-DPB1*03:01 increased brainstem and cerebellar FS scores. By contrast, HLA-DRB1*01:01 decreased spinal cord involvement and sensory FS scores, HLA-DRB1*09:01 decreased annualized relapse rate, brainstem involvement and bowel and bladder FS scores, and HLA-DRB1*13:02 decreased spinal cord and brainstem involvement. In NMOSD, HLA-DRB1*08:02 and DPB1*05:01 were associated with susceptibility and DRB1*09:01 was protective. Multivariable analysis revealed old onset age, long disease duration, and many relapses as independent disability risks in both MS and NMOSD, and HLA-DRB1*15:01 as an independent risk only in MS. Therefore, both susceptibility and protective alleles can influence the clinical manifestations in MS, while such genotype-phenotype correlations are unclear in NMOSD.

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Conflict of interest statement

M.W. received speaker honoraria and consultant fees from Novartis Pharma, and received a research grant from JSPS KAKENHI (Grant No. 19K07995). Y. Nakamura received a grant and salary from Mitsubishi Tanabe Pharma, Bayer Yakuhin, Ltd., and the Japan Blood Products Organization, received speaker honoraria from Novartis Pharma and received a grant from JSPS KAKENHI (Grant Nos. 18H06214 and 19K21317). M.N. received consultancy fees, speaking fees and/or honoraria from Novartis Pharma, Mitsubishi Tanabe Pharma, the Takeda Pharmaceutical Company, and Biogen Japan. M. Tanaka received speaker honoraria from Biogen Idec Japan, Takeda Pharma, Novartis Pharma, Eisai and Mitsubishi Tanabe Pharma, and served on the scientific advisory board for Biogen Idec Japan. H.O. is a scientific advisory board member of Biogen Japan and Novartis Pharma, and has received honoraria from Biogen Japan, Novartis Pharma, Mitsubishi Tanabe Pharma, and the Takeda Pharmaceutical Company. I.K. received a grant from JSPS KAKENHI (Grant No. 17K09776), funding for research, travel and/or speaker honoraria from Novartis Pharma, Biogen, Alexion Pharmaceuticals, Bristol-Myers Squibb, Bayer Yakuhin Limited, Mitsubishi Tanabe Pharma, the Takeda Pharmaceutical Company, the Japan Blood Products Organization, Teijin Pharma and Astellas Pharma, and is a scientific advisory board member for Biogen, Novartis Pharma, the Takeda Pharmaceutical Company and Alexion Pharmaceuticals. E.S. received a grant from JSPS KAKENHI (Grant No. 18K15443). T. Ohashi received speaker honoraria from Biogen Japan, Novartis Pharma and the Takeda Pharmaceutical Company. T.I. received a grant from The Japan Epilepsy Research Foundation and research support from Astellas Pharma Inc. Y. Kawano received a grant from JSPS KAKENHI (Grant No. 19K07997). Y.S. received speaker honoraria and consultant fees from Bayer Yakuhin, Biogen Idec Japan, the Takeda Pharmaceutical Company, and Novartis Pharma. K.S. received speaker honoraria from Biogen Idec Japan and the Takeda Pharmaceutical Company. A. Sakoda received grant support from Yazuya. N.I. received grant support from Mitsubishi Tanabe Pharma, Osoegawa Neurology Clinic, Bayer Yakuhin, Ltd., and Japan Blood Products Organization, and received a research grant from JSPS KAKENHI (Grant No. 18K07529). T.M. received speaker honoraria payments from Mitsubishi Tanabe Pharma, Takeda Pharmaceutical Company, and Biogen Japan, and received a research grant from JSPS KAKENHI (Grant No. 20K07869). J.K. received consultant fees, speaking fees and/or honoraria from Novartis Pharma, Mitsubishi Tanabe Pharma, Boehringer Ingelheim, Teijin Pharma, Takeda Pharmaceutical Company, Otsuka Pharmaceutical, Astellas Pharma, Pfizer Japan, Sumitomo Dainippon Pharma, and Eisai, and is supported by grants from JSPS KAKENHI (Grant Nos. 16H02657 and 19H01045), the Japan Agency for Medical Research and Development (AMED) (JP16ek0109039) and Health and Labour Sciences Research Grants on Intractable Diseases (H23-Nanchi-Ippan-017; H26-Nanchitou (Nan)-Ippan-074; H26-Itaku (Nan)-Ippan-050; H29-Nanchitou (Nan)-Ippan-043) and a Health and Labour Sciences Research Grant on Intractable Diseases (Neuroimmunological Diseases) (20FC1030). The other authors declare no competing interests.

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References

1. Osoegawa M, et al. Temporal changes and geographical differences in multiple sclerosis phenotypes in Japanese: Nationwide survey results over 30 years. Mult. Scler. 2009;15:159–173. doi: 10.1177/1352458508098372. - DOI - PubMed
1. Browne P, et al. Atlas of multiple sclerosis 2013: A growing global problem with widespread inequity. Neurology. 2014;83:1022–1024. doi: 10.1212/wnl.0000000000000768. - DOI - PMC - PubMed
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[1] Osoegawa M, et al. Temporal changes and geographical differences in multiple sclerosis phenotypes in Japanese: Nationwide survey results over 30 years. Mult. Scler. 2009;15:159–173. doi: 10.1177/1352458508098372. - DOI - PubMed

[2] Osoegawa M, et al. Temporal changes and geographical differences in multiple sclerosis phenotypes in Japanese: Nationwide survey results over 30 years. Mult. Scler. 2009;15:159–173. doi: 10.1177/1352458508098372. - DOI - PubMed

[3] Browne P, et al. Atlas of multiple sclerosis 2013: A growing global problem with widespread inequity. Neurology. 2014;83:1022–1024. doi: 10.1212/wnl.0000000000000768. - DOI - PMC - PubMed

[4] Browne P, et al. Atlas of multiple sclerosis 2013: A growing global problem with widespread inequity. Neurology. 2014;83:1022–1024. doi: 10.1212/wnl.0000000000000768. - DOI - PMC - PubMed

[5] Houzen H, Kondo K, Horiuchi K, Niino M. Consistent increase in the prevalence and female ratio of multiple sclerosis over 15 years in northern Japan. Eur. J. Neurol. 2018;25:334–339. doi: 10.1111/ene.13506. - DOI - PubMed

[6] Houzen H, Kondo K, Horiuchi K, Niino M. Consistent increase in the prevalence and female ratio of multiple sclerosis over 15 years in northern Japan. Eur. J. Neurol. 2018;25:334–339. doi: 10.1111/ene.13506. - DOI - PubMed

[7] Piccolo L, et al. Multiple sclerosis in Japan appears to be a milder disease compared to the UK. J. Neurol. 2015;262:831–836. doi: 10.1007/s00415-015-7637-3. - DOI - PubMed

[8] Piccolo L, et al. Multiple sclerosis in Japan appears to be a milder disease compared to the UK. J. Neurol. 2015;262:831–836. doi: 10.1007/s00415-015-7637-3. - DOI - PubMed

[9] Nakamura Y, et al. A comparison of brain magnetic resonance imaging lesions in multiple sclerosis by race with reference to disability progression. J. Neuroinflamm. 2018;15:255. doi: 10.1186/s12974-018-1295-1. - DOI - PMC - PubMed

[10] Nakamura Y, et al. A comparison of brain magnetic resonance imaging lesions in multiple sclerosis by race with reference to disability progression. J. Neuroinflamm. 2018;15:255. doi: 10.1186/s12974-018-1295-1. - DOI - PMC - PubMed

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HLA genotype-clinical phenotype correlations in multiple sclerosis and neuromyelitis optica spectrum disorders based on Japan MS/NMOSD Biobank data

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HLA genotype-clinical phenotype correlations in multiple sclerosis and neuromyelitis optica spectrum disorders based on Japan MS/NMOSD Biobank data

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