HLA genotype-clinical phenotype correlations in multiple sclerosis and neuromyelitis optica spectrum disorders based on Japan MS/NMOSD Biobank data

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.

Human Leukocyte Antigen Association Study Reveals DRB1*04:02 Effects Additional to DRB1*07:01 in Anti-LGI1 Encephalitis

“…A notable finding was a strong independent protective effect of DPA1*01:02∼DPB1*03:01, a finding distinct from previously reported DPA1*02:01∼DPB1*11:01 predisposing effects. 16 Of interest, DPB1*03:01 is a high-expression allele 35 and has been involved in susceptibility (not protection) to a number of other autoimmune diseases, such as multiple sclerosis, 36-38 severe aplastic anemia, 39 primary biliary cholangitis, 40 and B27 negative ankylosing spondylitis. 41 By contrast, although HLA class I alleles known to be associated with DRB1*07:01, such as B*57:01, B*44:03, C*06:02, and C*16:01, were increased in the sample uncorrected for DRB1*07:01 (data not shown) as previously reported, 16 all HLA class I association disappeared after controlling for the main DR7 association (data not shown).…”

Evaluation of Month of Birth in Neuromyelitis Optica Spectrum Disorders (NMSOD) and Multiple Sclerosis (MS)

“…Our findings suggest a possible association between month of birth and risk of NMOSD; however, the evidence is still insufficient to draw a certain conclusion. Because of differences between NMOSD and MS in environmental and genetic risk factors [ 46 , 48 ], it is impossible to apply the suggested seasonal factors to the NMOSD population. Further studies are recommended to elucidate the relation between month of birth and disease development of NMOSD and its seasonal factors.…”

Neuromyelitis Optica Spectrum Disorder: From Basic Research to Clinical Perspectives

“…Furthermore, HLA-DQA1*102, HLA-DQA1*501, HLA-DQB1*0201, and HLA-DRB1*03 alleles were significantly associated with NMOSD [ 96 , 98 ]. In Japan, Ogawa et al found that HLA-DQA1*05:03 was significantly associated with NMOSD, whereas Watanabe et al reported that HLA-DRB1*08:02 and HLA-DPB1*05:01 were associated with susceptibility to NMOSD and that HLA-DRB1*09:01 was protective against NMOSD [ 99 , 100 , 101 ]. In addition, distinct genetic and infectious profiles in Japanese patients with NMOSD demonstrated that the HLA-DRB1*1602 and HLA-DPB1*0501 alleles as well as infection with Helicobacter pylori and Chlamydia pneumonia were associated with higher susceptibility to AQP4-IgG-seropositive NMOSD [ 102 ].…”