Premium
Copy number variations in multiple sclerosis and neuromyelitis optica
Author(s) -
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 Junichi
Publication year - 2015
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.24511
Subject(s) - multiple sclerosis , copy number variation , neuromyelitis optica , locus (genetics) , single nucleotide polymorphism , t cell receptor , genetics , genome wide association study , biology , medicine , immunology , genotype , t cell , gene , genome , immune system
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. Ann Neurol 2015;78:Ann Neurol 2015;78:679–696