Abstract
BackgroundHigher latitude and human leukocyte antigen (HLA)-DRB1*04:05 increase susceptibility to multiple sclerosis (MS) in the Japanese population, but their effects on disease severity are unknown. We aimed to clarify the effects of latitude and the HLA-DRB1 and HLA-DPB1 genes on disease severity in Japanese patients with MS.MethodsWe enrolled 247 MS patients and 159 healthy controls (HCs) from the northernmost main island of Japan, Hokkaido Island (42–45° north), and 187 MS patients and 235 HCs from the southern half (33–35° north) of the Japanese archipelago (33–45° north). We genotyped HLA-DRB1 and HLA-DPB1 alleles, compared demographic features, and analyzed factors contributing to differences in clinical and laboratory findings between MS patients from southern and northern Japan. The Multiple Sclerosis Severity Score (MSSS), which adjusts the Kurtzke’s Expanded Disability Status Scale score according to disease duration, was used to estimate disease severity.ResultsThe HLA-DRB1*04:05 and DRB1*15:01 alleles conferred susceptibility to MS in our Japanese population (pcorr = 0.0004 and pcorr = 0.0019, respectively). Southern patients had higher MSSS scores than northern patients (p = 0.003). Northern patients had higher frequencies of brain lesions meeting the Barkhof criteria (Barkhof brain lesions) and cerebrospinal fluid (CSF) IgG abnormalities than southern patients (p = 0.0012 and p < 0.0001, respectively). DRB1*04:05-positive MS patients had lower MSSS scores and lower frequencies of Barkhof brain lesions and CSF IgG abnormalities than DRB1*04:05-negative MS patients (p = 0.0415, p = 0.0026, and p < 0.0001, respectively). Multivariate analyses revealed that latitude and DRB1*04:05 were independently associated with the lowest quartile of MSSS and that latitude was positively associated with Barkhof brain lesions and CSF IgG abnormalities. DRB1*04:05 was negatively associated with these parameters. MSSS was decreased by 0.57 per DRB1*04:05 allele (p = 0.0198).ConclusionsLiving at a higher latitude and carrying the DRB1*04:05 allele independently lessens MS symptom severity as defined by MSSS. However, these factors influence the frequency of Barkhof brain lesions and CSF IgG abnormalities in opposite ways; higher latitude increases the frequency of Barkhof brain lesions and CSF IgG abnormalities, whereas DRB1*04:05 decreases them.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0695-3) contains supplementary material, which is available to authorized users.
Highlights
Higher latitude and human leukocyte antigen (HLA)-DRB1*04:05 increase susceptibility to multiple sclerosis (MS) in the Japanese population, but their effects on disease severity are unknown
Frequencies of the HLA-DRB1 and HLA-DPB1 alleles As shown in Table 2, the phenotypic frequencies of the DRB1*04:05 and DRB1*15:01 alleles were significantly higher in MS patients than healthy controls (HCs)
We examined the association of Multiple Sclerosis Severity Score (MSSS) with Barkhof brain lesions and cerebrospinal fluid (CSF) IgG abnormalities and found that neither was associated with MSSS in the total population nor in the northern or southern MS patient populations (Additional file 2: Table S8)
Summary
Higher latitude and human leukocyte antigen (HLA)-DRB1*04:05 increase susceptibility to multiple sclerosis (MS) in the Japanese population, but their effects on disease severity are unknown. We aimed to clarify the effects of latitude and the HLA-DRB1 and HLA-DPB1 genes on disease severity in Japanese patients with MS. MS susceptibility and phenotypes result from complex interactions between multiple genetic and environmental factors [2]. We previously reported that the HLA-DRB1*04:05 allele is the strongest genetic risk factor for MS in the southern Japanese population. The clinical phenotypes of patients with the HLA-DRB1*04:05 allele include a milder clinical course, younger age at disease onset, slower disease progression, fewer brain lesions, and rare cerebrospinal fluid (CSF) IgG abnormalities compared with patients lacking the HLA-DRB1*04:05 allele [6]. We have reported that latitude independently affects the emergence of CSF IgG abnormalities in Japanese patients with MS [13]
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