Copy number variations in multiple sclerosis and neuromyelitis optica

Shinya Sato, Ken Yamamoto, Takuya Matsushita, Noriko Isobe, Yuji Kawano, Kyoko Iinuma, Masaaki Niino, Toshiyuki Fukazawa, yuri nakamura, mitsuru watanabe, Tomomi Yonekawa, Katsuhisa Masaki, Satoshi Yoshimura, Hiroyuki Murai, Ryo Yamasaki, Jun-Ichi Kira

Research output: Contribution to journalArticle

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Abstract

Objective To clarify the potential association of copy number variations (CNVs) with multiple sclerosis (MS) and neuromyelitis optica (NMO) in Japanese cases. Methods Genome-wide association analyses of CNVs among 277 MS patients, 135 NMO/NMO spectrum disorder (NMOSD) patients, and 288 healthy individuals as a discovery cohort, and among 296 MS patients, 76 NMO/NMOSD patients, and 790 healthy individuals as a replication cohort were performed using high-density single nucleotide polymorphism microarrays. Results A series of discovery and replication studies revealed that most identified CNVs were 5 to 50kb deletions at particular T cell receptor (TCR) gamma and alpha loci regions. Among these CNVs, a TCR gamma locus deletion was found in 16.40% of MS patients (p = 2.44E-40, odds ratio [OR] = 52.6), and deletion at the TCR alpha locus was found in 17.28% of MS patients (p = 1.70E-31, OR = 13.0) and 13.27% of NMO/NMOSD patients (p = 5.79E-20, OR = 54.6). These CNVs were observed in peripheral blood T-cell subsets only, suggesting the CNVs were somatically acquired. NMO/NMOSD patients carrying the CNV tended to be seronegative for anti-aquaporin-4 antibody or had significantly lower titers than those without CNV. Interpretation Deletion-type CNVs at specific TCR loci regions contribute to MS and NMO susceptibility.

Original languageEnglish
Pages (from-to)762-774
Number of pages13
JournalAnnals of Neurology
Volume78
Issue number5
DOIs
Publication statusPublished - Nov 1 2015

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Neuromyelitis Optica
Multiple Sclerosis
T-Cell Antigen Receptor
Odds Ratio
Aquaporin 4
Genome-Wide Association Study
T-Lymphocyte Subsets
Single Nucleotide Polymorphism
Blood Cells

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology

Cite this

Copy number variations in multiple sclerosis and neuromyelitis optica. / Sato, Shinya; Yamamoto, Ken; Matsushita, Takuya; Isobe, Noriko; Kawano, Yuji; Iinuma, Kyoko; Niino, Masaaki; Fukazawa, Toshiyuki; nakamura, yuri; watanabe, mitsuru; Yonekawa, Tomomi; Masaki, Katsuhisa; Yoshimura, Satoshi; Murai, Hiroyuki; Yamasaki, Ryo; Kira, Jun-Ichi.

In: Annals of Neurology, Vol. 78, No. 5, 01.11.2015, p. 762-774.

Research output: Contribution to journalArticle

Sato, S, Yamamoto, K, Matsushita, T, Isobe, N, Kawano, Y, Iinuma, K, Niino, M, Fukazawa, T, nakamura, Y, watanabe, M, Yonekawa, T, Masaki, K, Yoshimura, S, Murai, H, Yamasaki, R & Kira, J-I 2015, 'Copy number variations in multiple sclerosis and neuromyelitis optica', Annals of Neurology, vol. 78, no. 5, pp. 762-774. https://doi.org/10.1002/ana.24511
Sato, Shinya ; Yamamoto, Ken ; Matsushita, Takuya ; Isobe, Noriko ; Kawano, Yuji ; Iinuma, Kyoko ; Niino, Masaaki ; Fukazawa, Toshiyuki ; nakamura, yuri ; watanabe, mitsuru ; Yonekawa, Tomomi ; Masaki, Katsuhisa ; Yoshimura, Satoshi ; Murai, Hiroyuki ; Yamasaki, Ryo ; Kira, Jun-Ichi. / Copy number variations in multiple sclerosis and neuromyelitis optica. In: Annals of Neurology. 2015 ; Vol. 78, No. 5. pp. 762-774.
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AU - Sato, Shinya

AU - Yamamoto, Ken

AU - Matsushita, Takuya

AU - Isobe, Noriko

AU - Kawano, Yuji

AU - Iinuma, Kyoko

AU - Niino, Masaaki

AU - Fukazawa, Toshiyuki

AU - nakamura, yuri

AU - watanabe, mitsuru

AU - Yonekawa, Tomomi

AU - Masaki, Katsuhisa

AU - Yoshimura, Satoshi

AU - Murai, Hiroyuki

AU - Yamasaki, Ryo

AU - Kira, Jun-Ichi

PY - 2015/11/1

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N2 - Objective To clarify the potential association of copy number variations (CNVs) with multiple sclerosis (MS) and neuromyelitis optica (NMO) in Japanese cases. Methods Genome-wide association analyses of CNVs among 277 MS patients, 135 NMO/NMO spectrum disorder (NMOSD) patients, and 288 healthy individuals as a discovery cohort, and among 296 MS patients, 76 NMO/NMOSD patients, and 790 healthy individuals as a replication cohort were performed using high-density single nucleotide polymorphism microarrays. Results A series of discovery and replication studies revealed that most identified CNVs were 5 to 50kb deletions at particular T cell receptor (TCR) gamma and alpha loci regions. Among these CNVs, a TCR gamma locus deletion was found in 16.40% of MS patients (p = 2.44E-40, odds ratio [OR] = 52.6), and deletion at the TCR alpha locus was found in 17.28% of MS patients (p = 1.70E-31, OR = 13.0) and 13.27% of NMO/NMOSD patients (p = 5.79E-20, OR = 54.6). These CNVs were observed in peripheral blood T-cell subsets only, suggesting the CNVs were somatically acquired. NMO/NMOSD patients carrying the CNV tended to be seronegative for anti-aquaporin-4 antibody or had significantly lower titers than those without CNV. Interpretation Deletion-type CNVs at specific TCR loci regions contribute to MS and NMO susceptibility.

AB - Objective To clarify the potential association of copy number variations (CNVs) with multiple sclerosis (MS) and neuromyelitis optica (NMO) in Japanese cases. Methods Genome-wide association analyses of CNVs among 277 MS patients, 135 NMO/NMO spectrum disorder (NMOSD) patients, and 288 healthy individuals as a discovery cohort, and among 296 MS patients, 76 NMO/NMOSD patients, and 790 healthy individuals as a replication cohort were performed using high-density single nucleotide polymorphism microarrays. Results A series of discovery and replication studies revealed that most identified CNVs were 5 to 50kb deletions at particular T cell receptor (TCR) gamma and alpha loci regions. Among these CNVs, a TCR gamma locus deletion was found in 16.40% of MS patients (p = 2.44E-40, odds ratio [OR] = 52.6), and deletion at the TCR alpha locus was found in 17.28% of MS patients (p = 1.70E-31, OR = 13.0) and 13.27% of NMO/NMOSD patients (p = 5.79E-20, OR = 54.6). These CNVs were observed in peripheral blood T-cell subsets only, suggesting the CNVs were somatically acquired. NMO/NMOSD patients carrying the CNV tended to be seronegative for anti-aquaporin-4 antibody or had significantly lower titers than those without CNV. Interpretation Deletion-type CNVs at specific TCR loci regions contribute to MS and NMO susceptibility.

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