Genetic factors for susceptibility to and manifestations of neuromyelitis optica

Takuya Matsushita; Katsuhisa Masaki; Noriko Isobe; Shinya Sato; Ken Yamamoto; Yuri Nakamura; Mitsuru Watanabe; Toshihiko Suenaga; Jun-Ichi Kira; Japan Multiple Sclerosis Genetic Consortium

doi:10.1002/acn3.51147

Genetic factors for susceptibility to and manifestations of neuromyelitis optica

Ann Clin Transl Neurol. 2020 Nov;7(11):2082-2093. doi: 10.1002/acn3.51147. Epub 2020 Sep 26.

Authors

Takuya Matsushita¹, Katsuhisa Masaki¹, Noriko Isobe², Shinya Sato¹, Ken Yamamoto³, Yuri Nakamura¹, Mitsuru Watanabe¹, Toshihiko Suenaga⁴, Jun-Ichi Kira¹; Japan Multiple Sclerosis Genetic Consortium

Affiliations

¹ Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
² Department of Neurological Therapeutics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
³ Department of Medical Chemistry, Kurume University School of Medicine, Kurume, Japan.
⁴ Department of Neurology, Tenri Hospital, Tenri, Japan.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Aged, 80 and over
Female
Genetic Predisposition to Disease / genetics*
Genome-Wide Association Study
HLA-DRB1 Chains / genetics*
Humans
Japan
Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / genetics*
Male
Middle Aged
Multiple Sclerosis / genetics*
Neuromyelitis Optica / genetics*
Neuromyelitis Optica / pathology
Polymorphism, Single Nucleotide
Protective Factors
Risk Factors

Substances

HLA-DRB1 Chains
KCNMA1 protein, human
Large-Conductance Calcium-Activated Potassium Channel alpha Subunits

Grants and funding

This work was funded by Japan Agency for Medical Research and Development grants JP16ek0109039 and JP19ek0109308h0002; Ministry of Health, Labour and Welfare grant H29‐Nanchitou (Nan)‐Ippan‐043; Japan Society for the Promotion of Science grants 17K16124, 19H01045, 19H05562, and G2320.