TY - JOUR
T1 - Genetic factors for susceptibility to and manifestations of neuromyelitis optica
AU - Matsushita, Takuya
AU - Masaki, Katsuhisa
AU - Isobe, Noriko
AU - Sato, Shinya
AU - Yamamoto, Ken
AU - Nakamura, Yuri
AU - Watanabe, Mitsuru
AU - Suenaga, Toshihiko
AU - Kira, Jun ichi
AU - the Japan Multiple Sclerosis Genetic Consortium
N1 - Funding Information:
The authors would like to thank Dr. Satoshi O. Suzuki and Professor Toru Iwaki (Department of Neuropathology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University) for advice and support for the histopathological investigations. We thank Professor Jorge Oksenberg for advice and support for the genetic analyses. We thank Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript. This study was funded by ?Strategic Young Researcher Overseas Visits Program for Accelerating Brain Circulation? from the Japan Society for the Promotion of Science (JSPS) (G2320), grants from JSPS KAKENHI (Grant Nos. 17K16124, 19H01045, 19H05562), the ?Practical Research Project for Rare/Intractable Diseases? from the Japan Agency for Medical Research and Development, AMED, Japan (JP16ek0109039, JP19ek0109308h0002), and a Health and Labor Sciences Research Grant on Intractable Diseases (H29-Nanchitou (Nan)-Ippan-043) from the Ministry of Health, Labor and Welfare, Japan.
PY - 2020/11
Y1 - 2020/11
N2 - Objective: To identify genetic factors associated with susceptibility to and clinical features of neuromyelitis optica spectrum disorders (NMOSD). Methods: Genome-wide single nucleotide polymorphism (SNP) genotyping was conducted in 211 Japanese patients with NMOSD fulfilling the 2006 criteria with or without anti-aquaporin-4 (AQP4) antibody and 1,919 Japanese healthy controls (HCs). HLA-DRB1 and HLA-DPB1 alleles were genotyped in 184 NMOSD cases and 317 HCs. Multiple sclerosis (MS) risk alleles outside the major histocompatibility complex (MHC) region were tested in NMOSD and MS genetic burden (MSGB) scores were compared between HCs and NMOSD. Results: A SNP (rs1964995) in the MHC region was associated with NMOSD susceptibility (odds ratio (OR) = 2.33, P = 4.07 × 10−11). HLA-DRB1*08:02 (OR = 2.86, P = 3.03 × 10−4) and HLA-DRB1*16:02 (OR = 8.39, P = 1.92 × 10−3) were risk alleles for NMOSD susceptibility whereas HLA-DRB1*09:01 was protective (OR = 0.27, P = 1.06 × 10−5). Three MS risk variants were associated with susceptibility and MSGB scores were significantly higher in NMOSD than in HCs (P = 0.0095). A SNP in the KCNMA1 (potassium calcium-activated channel subfamily M alpha 1) gene was associated with disability score with genome-wide significance (rs1516512, P = 2.33 × 10−8) and transverse myelitis (OR = 1.77, P = 0.011). KCNMA1 was immunohistochemically detected in the perivascular endfeet of astrocytes and its immunoreactivity was markedly diminished in active spinal cord lesions in NMOSD. Interpretation: Specific HLA-DRB1 alleles confer NMOSD susceptibility and KCNMA1 is associated with disability and transverse myelitis in NMOSD.
AB - Objective: To identify genetic factors associated with susceptibility to and clinical features of neuromyelitis optica spectrum disorders (NMOSD). Methods: Genome-wide single nucleotide polymorphism (SNP) genotyping was conducted in 211 Japanese patients with NMOSD fulfilling the 2006 criteria with or without anti-aquaporin-4 (AQP4) antibody and 1,919 Japanese healthy controls (HCs). HLA-DRB1 and HLA-DPB1 alleles were genotyped in 184 NMOSD cases and 317 HCs. Multiple sclerosis (MS) risk alleles outside the major histocompatibility complex (MHC) region were tested in NMOSD and MS genetic burden (MSGB) scores were compared between HCs and NMOSD. Results: A SNP (rs1964995) in the MHC region was associated with NMOSD susceptibility (odds ratio (OR) = 2.33, P = 4.07 × 10−11). HLA-DRB1*08:02 (OR = 2.86, P = 3.03 × 10−4) and HLA-DRB1*16:02 (OR = 8.39, P = 1.92 × 10−3) were risk alleles for NMOSD susceptibility whereas HLA-DRB1*09:01 was protective (OR = 0.27, P = 1.06 × 10−5). Three MS risk variants were associated with susceptibility and MSGB scores were significantly higher in NMOSD than in HCs (P = 0.0095). A SNP in the KCNMA1 (potassium calcium-activated channel subfamily M alpha 1) gene was associated with disability score with genome-wide significance (rs1516512, P = 2.33 × 10−8) and transverse myelitis (OR = 1.77, P = 0.011). KCNMA1 was immunohistochemically detected in the perivascular endfeet of astrocytes and its immunoreactivity was markedly diminished in active spinal cord lesions in NMOSD. Interpretation: Specific HLA-DRB1 alleles confer NMOSD susceptibility and KCNMA1 is associated with disability and transverse myelitis in NMOSD.
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U2 - 10.1002/acn3.51147
DO - 10.1002/acn3.51147
M3 - Article
C2 - 32979043
AN - SCOPUS:85091406018
VL - 7
SP - 2082
EP - 2093
JO - Annals of Clinical and Translational Neurology
JF - Annals of Clinical and Translational Neurology
SN - 2328-9503
IS - 11
ER -