Abstract
HLA genotype-clinical phenotype correlations are not established for multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). We studied HLA-DRB1/DPB1 genotype–phenotype correlations in 528 MS and 165 NMOSD cases using Japan MS/NMOSD Biobank materials. HLA-DRB1*04:05, DRB1*15:01 and DPB1*03:01 correlated with MS susceptibility and DRB1*01:01, DRB1*09:01, DRB1*13:02 and DPB1*04:01 were protective against MS. HLA-DRB1*15:01 was associated with increased optic neuritis and cerebellar involvement and worsened visual and pyramidal functional scale (FS) scores, resulting in higher progression index values. HLA-DRB1*04:05 was associated with younger onset age, high visual FS scores, and a high tendency to develop optic neuritis. HLA-DPB1*03:01 increased brainstem and cerebellar FS scores. By contrast, HLA-DRB1*01:01 decreased spinal cord involvement and sensory FS scores, HLA-DRB1*09:01 decreased annualized relapse rate, brainstem involvement and bowel and bladder FS scores, and HLA-DRB1*13:02 decreased spinal cord and brainstem involvement. In NMOSD, HLA-DRB1*08:02 and DPB1*05:01 were associated with susceptibility and DRB1*09:01 was protective. Multivariable analysis revealed old onset age, long disease duration, and many relapses as independent disability risks in both MS and NMOSD, and HLA-DRB1*15:01 as an independent risk only in MS. Therefore, both susceptibility and protective alleles can influence the clinical manifestations in MS, while such genotype–phenotype correlations are unclear in NMOSD.
Highlights
human leukocyte antigen (HLA) genotype-clinical phenotype correlations are not established for multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD)
Clinical information and genotypes of HLA-DRB1 and -DPB1 alleles were available from 528 MS and 183 NMO/ NMOSD patients based on the 2010 revised McDonald c riteria[25] and NMO and NMOSD criteria advocated by Wingerchuk in 2006 and 2 00726,27, respectively
Co-existing autoimmune diseases and/or autoantibodies, especially Sjögren syndrome, anti-nuclear antibody (ANA), and anti-SS-A/SS-B antibodies, were more frequent in NMOSD patients compared with MS patients, while frequencies of co-existing thyroid disease and/or thyroid-related antibodies did not differ between the two groups
Summary
HLA genotype-clinical phenotype correlations are not established for multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). Multivariable analysis revealed old onset age, long disease duration, and many relapses as independent disability risks in both MS and NMOSD, and HLA-DRB1*15:01 as an independent risk only in MS. Both susceptibility and protective alleles can influence the clinical manifestations in MS, while such genotype–phenotype correlations are unclear in NMOSD. Abbreviations ANA Anti-nuclear antibody AQP4 Aquaporin 4 ARR Annualized relapse rate CI Confidence interval CNS Central nervous system CSF Cerebrospinal fluid DMD Disease-modifying drug EDSS Expanded disability status scale FS Functional system HLA Human leukocyte antigen LESCL Longitudinally extensive spinal cord lesion MOG Myelin oligodendrocyte glycoprotein MS Multiple sclerosis MSSS Multiple sclerosis severity score NMO Neuromyelitis optica NMOSD Neuromyelitis optica spectrum disorders OCBs Oligoclonal IgG bands OR Odds ratio PI Progression Index PPMS Primary progressive multiple sclerosis RRMS Relapsing–remitting multiple sclerosis SPMS Secondary progressive multiple sclerosis. Information and biological samples, such as DNA, as a part of the Rare Disease Bank at the National Institutes of Biomedical Innovation, Health and Nutrition in Japan[16]
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