Parent-of-origin effect in multiple sclerosis susceptibility

• Project/Area Number: 18K07529
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Kyushu University
• Principal Investigator: Isobe Noriko 九州大学, 医学研究院, 特任准教授 (60452752)
• Co-Investigator(Kenkyū-buntansha): 松下 拓也 九州大学, 大学病院, 講師 (00533001) ; 吉良 潤一 九州大学, 医学研究院, 教授 (40183305)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
• Keywords: 多発性硬化症 / 片親起源効果 / 遺伝的凝集度 / 関連解析 / エピジェネティクス / 遺伝的刷り込み / SNP / 遺伝子解析

Outline of Final Research Achievements

Multiple sclerosis is a complex disease which both genetic and environmental factors play roles in its pathogenesis. Parent-of-origin effect means that the phenotypic effect of an allele depends on whether the allele is inherited from an individual's mother side or father side. We aimed to clarify whether parent-of-origin effect plays any roles in the pathomechanism of the established MS risk-associated regions and whether analysis which cares parent-of-origin effect can contribute for finding novel MS-associated loci. As a result, we found out that one of the established MS loci, the EVI5 locus on chromosome 1 possessed a MS susceptibility region where maternal allele contributed to MS Risk and another region where paternal allele contributed to MS risk. In conclusion, the analysis on parent-of-origin effect could help understanding of MS susceptibility through epigenetic mechanism.

Academic Significance and Societal Importance of the Research Achievements

本研究は、神経難病の1つである、多発性硬化症について、その発症の仕組みを明らかにするための研究である。多発性硬化症の発症には、遺伝的発症リスクと環境由来のリスク因子の両方とが組み合わさっているが、遺伝的リスクにおいても、その遺伝的リスクアリルが父親由来であるのか、母親由来であるのか、によって、影響が異なる可能性を見いだした。
本研究によって、これまでの多発性硬化症の発症メカニズムに対し、エピジェネティックな要因を加えて検討することで、多発性硬化症の発症メカニズムをより深く解明することができた。

Research Products

• [Int'l Joint Research] University of California San Francisco(米国)
• [Int'l Joint Research] University of California San Francisco(米国)
• [Int'l Joint Research] University of California San Francisco(米国)
• [Journal Article] HLA genotype-clinical phenotype correlations in multiple sclerosis and neuromyelitis optica spectrum disorders based on Japan MS/NMOSD Biobank data (2021)
  • Author(s): Watanabe M. Nakamura Y. Sato S. Niino M. Fukaura H. Tanaka M. Ochi H. et al
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 607-607
  • DOI: 10.1038/s41598-020-79833-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A new clustering method identifies multiple sclerosis‐specific T‐cell receptors (2021)
  • Author(s): Hayashi Fumie、Isobe Noriko、Glanville Jacob、Matsushita Takuya、Maimaitijiang Guzailiayi、Fukumoto Shoko、Watanabe Mitsuru、Masaki Katsuhisa、Kira Jun‐ichi
  • Journal Title: Annals of Clinical and Translational Neurology Volume: 8 Issue: 1 Pages: 163-176
  • DOI: 10.1002/acn3.51264
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genetic factors for susceptibility to and manifestations of neuromyelitis optica (2020)
  • Author(s): Matsushita Takuya、Masaki Katsuhisa、Isobe Noriko、Sato Shinya、Yamamoto Ken、Nakamura Yuri、Watanabe Mitsuru、Suenaga Toshihiko、Kira Jun‐ichi、the Japan Multiple Sclerosis Genetic Consortium
  • Journal Title: Annals of Clinical and Translational Neurology Volume: 7 Issue: 11 Pages: 2082-2093
  • DOI: 10.1002/acn3.51147
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Two genetic variants explain the association of European ancestry with multiple sclerosis risk in African-Americans (2020)
  • Author(s): Nakatsuka Nathan、Patterson Nick、Patsopoulos Nikolaos A.、Altemose Nicolas、Tandon Arti、Beecham Ashley H.、McCauley Jacob L.、Isobe Noriko、Hauser Stephen、De Jager Philip L.、Hafler David A.、Oksenberg Jorge R.、Reich David
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 16902-16902
  • DOI: 10.1038/s41598-020-74035-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Painful trigeminal neuropathy associated with anti-Plexin D1 antibody (2020)
  • Author(s): Fujii Takayuki、Yamasaki Ryo、Miyachi Yukino、Iinuma Kyoko、Hashimoto Yu、Isobe Noriko、Matsushita Takuya、Kira Jun-ichi
  • Journal Title: Neurology - Neuroimmunology Neuroinflammation Volume: 7 Issue: 5
  • DOI: 10.1212/nxi.0000000000000819
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Contribution of cortical lesions to cognitive impairment in Japanese patients with multiple sclerosis. (2020)
  • Author(s): Shinoda K, Matsushita T, Nakamura Y, Masaki K, Sakai S, Nomiyama H, Togao O, Hiwatashi A, Niino M, Isobe N, Kira J.
  • Journal Title: Scientific Reports Volume: 10 Pages: 5228-5228
  • Peer Reviewed / Open Access
• [Journal Article] Risk HLA-DRB1 alleles differentially influence brain and lesion volumes in Japanese patients with multiple sclerosis (2020)
  • Author(s): Fukumoto S, Nakamura Y, Watanabe M, Isobe N, Matsushita T, Sakoda A, Hiwatashi A, Shinoda K, Yamasaki R, Tsujino A, Kira J.
  • Journal Title: Journal of the Neurological Sciences Volume: 413 Pages: 116768-116768
  • DOI: 10.1016/j.jns.2020.116768
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Unique HLA haplotype associations in IgG4 anti-neurofascin 155 antibody-positive chronic inflammatory demyelinating polyneuropathy (2020)
  • Author(s): Ogata H, Isobe N, Zhang X, Yamasaki R, Fujii T, Machida A, Morimoto N, Kaida K, Masuda T, Ando Y, Kuwahara M, Kusunoki S, Nakamura Y, Matsushita T, Kira J.
  • Journal Title: Journal of Neuroimmunology Volume: 339 Pages: 577139-577139
  • DOI: 10.1016/j.jneuroim.2019.577139
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Central nervous system-specific antinuclear antibodies in patients with multiple sclerosis (2020)
  • Author(s): Fujii T, Yamasaki R, Miyachi Y, Nagata S, Maimaitijiang G, Nakamura Y, Shinoda K, Matsushita T, Isobe N, Kira J.
  • Journal Title: Journal of the Neurological Sciences Volume: 409 Pages: 116619-116619
  • DOI: 10.1016/j.jns.2019.116619
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Environmental risk factors for multiple sclerosis in Japanese people (2020)
  • Author(s): Sakoda A, Matsushita T, Nakamura Y, Watanabe M, Shinoda K, Masaki K, Isobe N, Yamasaki R, Kira J.
  • Journal Title: Multiple Sclerosis and Related Disorders Volume: 38 Pages: 101872-101872
  • DOI: 10.1016/j.msard.2019.101872
  • Peer Reviewed
• [Journal Article] Oligodendroglial connexin 47 regulates neuroinflammation upon autoimmune demyelination in a novel mouse model of multiple sclerosis (2020)
  • Author(s): Zhao Y, Yamasaki R, Yamaguchi H, Nagata S, Une H, Cui Y, Masaki K, Nakamuta Y, Iinuma K, Watanabe M, Matsushita T, Isobe N, Kira J.
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 117 Issue: 4 Pages: 2160-2169
  • DOI: 10.1073/pnas.1901294117
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Spinal cord involvement by atrophy and associations with disability are different between multiple sclerosis and neuromyelitis optica spectrum disorder (2019)
  • Author(s): Nakamura Y, Liu Z, Fukumoto S, Shinoda K, Sakoda A, Matsushita T, Hayashida S, Isobe N, Watanabe M, Hiwatashi A, Yamasaki R, Kira J.
  • Journal Title: European Journal of Neurology Volume: 27 Issue: 1 Pages: 92-99
  • DOI: 10.1111/ene.14038
  • Peer Reviewed / Open Access
• [Journal Article] Intrathecal cytokine profile in neuropathy with anti‐neurofascin 155 antibody (2019)
  • Author(s): Ogata H, Zhang X, Yamasaki R, Fujii T, Machida A, Morimoto N, Kaida K, Masuda T, Ando Y, Kuwahara M, Kusunoki S, Nakamura Y, Matsushita T, Isobe N, Kira J.
  • Journal Title: Annals of Clinical and Translational Neurology Volume: 6 Issue: 11 Pages: 2304-2316
  • DOI: 10.1002/acn3.50931
  • Peer Reviewed / Open Access
• [Journal Article] Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility (2019)
  • Author(s): International Multiple Sclerosis Genetics Consortium.
  • Journal Title: Science Volume: 365 Issue: 6460 Pages: 6460-6460
  • DOI: 10.1126/science.aav7188
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Serum GFAP and neurofilament light as biomarkers of disease activity and disability in NMOSD (2019)
  • Author(s): Watanabe M, Nakamura Y, Michalak Z, Isobe N, Barro C, Leppert D, Matsushita T, Hayashi F, Yamasaki R, Kuhle J, Kira J.
  • Journal Title: Neurology Volume: 93 Issue: 13
  • DOI: 10.1212/wnl.0000000000008160
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Long-term use of interferon-β in multiple sclerosis increases Vδ1(-)Vδ2(-)Vγ9(-) γδ T cells that are associated with a better outcome (2019)
  • Author(s): Maimaitijiang G, Watanabe M, Shinoda K, Isobe N, Nakamura Y, Masaki K, Matsushita T, Yoshikai Y, Kira J.
  • Journal Title: Journal of Neuroinflammation Volume: 16 Issue: 1 Pages: 179-179
  • DOI: 10.1186/s12974-019-1574-5
  • Peer Reviewed / Open Access
• [Journal Article] The genetic diversity of multiple sclerosis risk among Hispanic and African American populations living in the United States (2019)
  • Author(s): Beecham AH, Amezcua L, Chinea A, Manrique CP, Rubi C, Isobe N, Lund BT, Santaniello A, Beecham GW, Burchard EG, Comabella M, Patsopoulos N, Fitzgerald K, Calabresi PA, De Jager P, Conti DV, Delgado SR, Oksenberg J, McCauley JL.
  • Journal Title: Multiple Sclerosis Journal Volume: in press Issue: 11 Pages: 1329-1339
  • DOI: 10.1177/1352458519863764
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Sex-specific Tau methylation patterns and synaptic transcriptional alterations are associated with neural vulnerability during chronic neuroinflammation (2019)
  • Author(s): Didonna A, Canto E, Shams H, Isobe N, Zhao C, Caillier S, Condello C, Yamate-Morgan H, Tiwari-Woodruff SK, Mofrad MRK, Hauser SL, Oksenberg JR.
  • Journal Title: Journal of Autoimmunity Volume: 101 Pages: 56-69
  • DOI: 10.1016/j.jaut.2019.04.003
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Discriminative clinical and neuroimaging features of motor-predominant hereditary diffuse leukoencephalopathy with axonal spheroids and primary progressive multiple sclerosis: A preliminary cross-sectional study (2019)
  • Author(s): Saitoh B, Yamasaki R, Hiwatashi A, Matsushita T, Hayashi S, Mitsunaga Y, Maeda Y, Isobe N, Yoshida K, Ikeda S, Kira J.
  • Journal Title: Multiple Sclerosis and Related Disorders Volume: 31 Pages: 22-31
  • DOI: 10.1016/j.msard.2019.03.008
  • Peer Reviewed
• [Journal Article] A systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis (2019)
  • Author(s): International Multiple Sclerosis Genetics Consortium.
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 2236-2236
  • DOI: 10.1038/s41467-019-09773-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cerebrospinal fluid cytokine/chemokine/growth factor profiles in idiopathic hypertrophic pachymeningitis. (2019)
  • Author(s): Zhang X, et al
  • Journal Title: J Neuroimmunol. Volume: 330 Pages: 38-43
  • DOI: 10.1016/j.jneuroim.2019.01.010
  • Peer Reviewed
• [Presentation] 第5回全国調査が示す多発性硬化症・視神経脊髄炎総患者数の増加． (2020)
  • Author(s): 磯部紀子、新野正明、松下拓也、中村優理、中島一郎、渡邉充、酒井康成、迫田礼子、中原仁、河内泉、越智博文、中辻裕司、福元尚子、林史恵、中村好一、中村幸志、坂田清美、嶋田莉奈子、松井真、吉良潤一．
  • Organizer: 第32回日本神経免疫学会学術集会
• [Presentation] 免疫介在性疾患の病因追究手段としてのHLAその他の遺伝子解析手法の原理と臨床的意義づけ (2020)
  • Author(s): 磯部紀子
  • Organizer: 第32回日本神経免疫学会学術集会
  • Invited
• [Presentation] Increase of Mycobacterium avium subsp. Paratuberculosis (MAP) antibody in multiple sclerosis (2019)
  • Author(s): Isobe N, Hayashi F, Cossu D, Yokoyama K, Maimatijiang G, Nakamura Y, Matsushita T, Kira JI.
  • Organizer: 60th Annual Meeting of The Japanese Society of Neurology
• [Presentation] Disease-characteristic TCRs recognize CMV in Japanese MS with HLA-DRB1*04:05; a novel approach with GLIPH. (2019)
  • Author(s): Hayashi F, Isobe N, Glanville J, Matsushita T, Kira J.
  • Organizer: 60th Annual Meeting of The Japanese Society of Neurology
• [Presentation] Progressive multifocal leukoencephalopathy in the era of disease-modifying therapies. Genetic backgrounds of Japanese MS and JC virus antibody. (2019)
  • Author(s): Isobe N.
  • Organizer: 60th Annual Meeting of The Japanese Society of Neurology
• [Presentation] T cell receptor repertoire in a monozygotic triplet discordant for multiple Sclerosis. (2019)
  • Author(s): Isobe N, Hayashi F, Matsushita T, Okamoto K, Kira JI.
  • Organizer: 35th Congress of The European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS)
  • Int'l Joint Research
• [Presentation] HLA-DRB1*04:05陽性MS患者におけるサイトメガロウイルス（CMV）関連T細胞受容体の同定． (2019)
  • Author(s): 林史恵、磯部紀子、Jacob Glanville、松下拓也、吉良潤一．
  • Organizer: 第31回日本神経免疫学会学術集会
• [Presentation] 表現型不一致の一卵性品胎における多発性硬化症関連Ｔ細胞受容体レパトア解析． (2019)
  • Author(s): 磯部紀子、林史恵、渡邉充、松下拓也、岡本幸市、吉良潤一．
  • Organizer: 第31回日本神経免疫学会学術集会
• [Presentation] Genetic approach for disease heterogeneity of multiple sclerosis: for the era of precision medicine. Perspectives on Personalized Medicine for Multiple Sclerosis. (2019)
  • Author(s): Isobe N.
  • Organizer: 12th Congress of the Pan-Asian Committee for Treatment and Research in Multiple Sclerosis (PACTRIMS)
  • Int'l Joint Research
• [Presentation] Increase of EBV lytic infection in Japanese patients with multple sclerosis. (2019)
  • Author(s): Isobe N, Dilek HF, Sakoda A, Hayashi F, Watanabe M, Matsushita T, Kira JI.
  • Organizer: The 12th Congress of the PACTRIMS
  • Int'l Joint Research
• [Presentation] Parent-of-origin effects in multiple sclerosis (2018)
  • Author(s): Isobe N, Tsai A, Caillier SJ, Santaniello A, Kira J, Hauser SL, Oksenberg JR.
  • Organizer: 第59回日本神経学会学術大会
• [Presentation] Multiple sclerosis: from genetics to epigenetics. (2018)
  • Author(s): Isobe N.
  • Organizer: The 6th LingNan-Internatinoal Neurology and Neuroimmunology Meeting (LINIM, 2018)
  • Int'l Joint Research / Invited
• [Presentation] 片親起源効果を用いた新規多発性硬化症リスク遺伝子の探索 (2018)
  • Author(s): 磯部紀子、Andy Tsai、Stacy J Caillier、Adam Santaniello、松下拓也、吉良潤一、Stephen L. Hauser、Jorge R. Oksenberg．
  • Organizer: 第30回日本神経免疫学会学術集会
• [Presentation] Parent-of-origin genetic effects in multiple sclerosis. (2018)
  • Author(s): Isobe N, Tsai A, Caillier SJ, Santaniello A, Kira JI, Hauser SL, Oksenberg JR.
  • Organizer: 34th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS)
  • Int'l Joint Research