Genetic and Infectious Profiles of Japanese Multiple Sclerosis Patients

Abstract

BackgroundNationwide surveys conducted in Japan over the past thirty years have revealed a four-fold increase in the estimated number of multiple sclerosis (MS) patients, a decrease in the age at onset, and successive increases in patients with conventional MS, which shows an involvement of multiple sites in the central nervous system, including the cerebrum and cerebellum. We aimed to clarify whether genetic and infectious backgrounds correlate to distinct disease phenotypes of MS in Japanese patients.Methodology/Principal FindingsWe analyzed HLA-DRB1 and -DPB1 alleles, and IgG antibodies specific for Helicobacter pylori, Chlamydia pneumoniae, varicella zoster virus, and Epstein-Barr virus nuclear antigen (EBNA) in 145 MS patients and 367 healthy controls (HCs). Frequencies of DRB1*0405 and DPB1*0301 were significantly higher, and DRB1*0901 and DPB1*0401 significantly lower, in MS patients as compared with HCs. MS patients with DRB1*0405 had a significantly earlier age of onset and lower Progression Index than patients without this allele. The proportion and absolute number of patients with DRB1*0405 successively increased with advancing year of birth. In MS patients without DRB1*0405, the frequency of the DRB1*1501 allele was significantly higher, while the DRB1*0901 allele was significantly lower, compared with HCs. Furthermore, DRB1*0405-negative MS patients were significantly more likely to be positive for EBNA antibodies compared with HCs.ConclusionsOur study suggests that MS patients harboring DRB1*0405, a genetic risk factor for MS in the Japanese population, have a younger age at onset and a relatively benign disease course, while DRB1*0405-negative MS patients have features similar to Western-type MS in terms of association with Epstein-Barr virus infection and DRB1*1501. The recent increase of MS in young Japanese people may be caused, in part, by an increase in DRB1*0405-positive MS patients.

The immunogenetics of neurological disease

“…48 This observation has been strengthened by a study in a population from Martinique with African ancestry. 49 Non-European studies suggested a correlation of DRB1*15 and DRB1*04:05 with MS in Japanese 50 and Asian populations, respectively. 50,51 The same studies have reported the association of DRB1*04:05 with a clinically 54 populations provided a coherent model for DR4 with MS aetiology.…”

“…49 Non-European studies suggested a correlation of DRB1*15 and DRB1*04:05 with MS in Japanese 50 and Asian populations, respectively. 50,51 The same studies have reported the association of DRB1*04:05 with a clinically 54 populations provided a coherent model for DR4 with MS aetiology. Additionally, the correlation of DRB1*03:01 and DRB1*13:03 was first detected in Sardinian 55 and Israeli Ashkenazi and non-Ashkenazi Jewish MS 41 patients, respectively, but this allele is extremely common throughout Europe, Africa and Asia.…”

Multiple Sclerosis: Etiology and Mechanism, with Special Reference to Asians

“…In Japanese cases, Barkhof(À)/LESCL(À) MS is associated with HLA-DRB1*0405 [50], suggesting that certain HLA alleles are influential on MRI features. After completely excluding cases with NMO/NMO spectrum disorder (NMOSD), based on an anti-AQP4 antibody assay, we also found that the frequencies of DRB1*0405 and DPB1*0301 were significantly higher, and those of DRB1*0901 and DPB1*0401 significantly lower, in non-NMO/NMOSD MS patients compared with healthy controls [51]. Thus, DRB1*0405 and DPB1*0301 are susceptibility alleles for non-NMOSD MS, while DRB1*0901 and DPB1*0401 are resistance alleles.…”

The Role of HLA in MS Susceptibility and Phenotype

“…It is likely that some of the studies did not have sufficient power to detect any correlations other than for DRB1*15:01, due to the lower frequency of the other alleles in the MS population in general. In a study from Japan, the presence of DRB1*04:05, which is found significantly more frequently in MS patients than in controls, correlated with an earlier age of onset of MS (27.2 ± 1.3 years in DRB1*04:05 positive vs 34.8 ± 1.5 years in DRB1*04:05 negative patients) (Yoshimura et al 2012). …”

“…Using an extremes of outcome design, in which only patients from the extremes of distribution of long-term outcome are considered, DRB1*01 was found to be underrepresented in malignant vs benign cases of MS (DeLuca et al 2007). In Japanese populations, the presence of DRB1*04:05 correlates with more benign MS (Yoshimura et al 2012). In African-Americans, who have a higher proportion of DRB5*null alleles than do Caucasians, DRB5 attenuated MS severity, and DRB5*null patients were at greater risk of developing SP-MS (Caillier et al 2008).…”