Latitude and HLA-DRB1*04:05 independently influence disease severity in Japanese multiple sclerosis: a cross-sectional study

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.

Case of central nervous system inflammatory disease in late pregnancy

“…However, there were some conflicting findings for this diagnosis. 6,7 Therefore, there was a reasonable probability that the present patient might have neuro-Behҫet's disease because of the presence of these HLA alleles. Each disease shows a different tendency of disease activity during pregnancy and puerperium.…”

“…5 This effect size is much larger than the risk for MS with HLA-DRB1*15:01 or HLA-DRB1*04:05, which the present patient also possessed. 6,7 Therefore, there was a reasonable probability that the present patient might have neuro-Behҫet's disease because of the presence of these HLA alleles.…”

Long‐standing patchy alopecia areata along the hairline, a variety of alopecia areata mimicking frontal fibrosing alopecia and other cases of hair loss: case series of 11 patients

“…2d), both compatible with MS. 3,4 Cerebrospinal fluid was positive in oligoclonal band. Human leucocyte antigen typing revealed the presence of DRB1*04:05, which is the susceptible allele for MS. 5 Collectively, we concluded that these CNS lesions are indicative of MS. After two courses of high-dose intravenous methylprednisolone (1 g/day for three consecutive days), the lesions enhanced by gadolinium significantly diminished. However, a new small T2WI-high/diffusion weighted image-high/apparent diffusion coefficient mapping-low lesion was found in his hippocampus ( Fig.…”

Statistical genetics and its application to neuroimmunology

“…19 In African Americans, HLA-DRB1 is known as the highest-risk HLA allele; however, HLA-DRB1*15:01 is present in just 6.6% of those suffering from MS. 30 HLA-DRB1*15:03 has also been reported to be associated with MS in African Americans. 30 Furthermore, in Japan, HLA-DRB1*04:05 is associated with MS. 31 The heterogeneity of the MS risk of these HLA alleles between populations might contribute to the different rates of prevalence of MS. In some studies, protective effects of HLA against MS have also been reported.…”

“…HLA‐DRB1*15:03 has also been reported to be associated with MS in African Americans . Furthermore, in Japan, HLA‐DRB1*04:05 is associated with MS . The heterogeneity of the MS risk of these HLA alleles between populations might contribute to the different rates of prevalence of MS.…”