Annals of neurology · 2015
Copy number variations in multiple sclerosis and neuromyelitis optica.
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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, Japan Multiple Sclerosis Genetics Consortium
Аннотация
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.
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.
Предметные рубрики MeSH
AdolescentAdultAquaporin 4Asian PeopleChromosomesCohort StudiesDNA Copy Number VariationsFemaleGene DeletionGenetic LociGenome-Wide Association StudyHumansMaleMultiple SclerosisNeuromyelitis OpticaPolymerase Chain ReactionPolymorphism, Single NucleotideReceptors, Antigen, T-Cell, alpha-betaReceptors, Antigen, T-Cell, gamma-deltaReproducibility of ResultsRisk FactorsT-Lymphocyte Subsets