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



We 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.



The HLA-DRB1*04:05 and DRB1*15:01 alleles conferred susceptibility to MS in our Japanese population (p (corr) = 0.0004 and p (corr) = 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).



Living 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.
Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Yuri
Y
Nakamura
Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Takuya
T
Matsushita
Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Shinya
S
Sato
Department of Clinical Research, Hokkaido Medical Center, Yamanote 5-jo 7-chome, Nishi-ku, Sapporo, 063-0005, Japan.
Masaaki
M
Niino
Sapporo Neurology Clinic, 21-2-1, Kita 21-jo Higashi, Higashi-ku, Sapporo, 065-0021, Japan.
Toshiyuki
T
Fukazawa
Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Satoshi
S
Yoshimura
Department of Neurology, School of Medicine, Sapporo Medical University, South 1 West 16, Chuo-ku, Sapporo, 060-8543, Japan.
Shin
S
Hisahara
Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Noriko
N
Isobe
Department of Neurology, School of Medicine, Sapporo Medical University, South 1 West 16, Chuo-ku, Sapporo, 060-8543, Japan.
Shun
S
Shimohama
Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Mitsuru
M
Watanabe
Department of Neurology, Asahikawa Red Cross Hospital, 1-1-1, Akebono 1-jo, Asahikawa, 070-8530, Japan.
Kazuto
K
Yoshida
Department of Neurology, Obihiro Kosei General Hospital, 8-1, Nishi 6-jo Minami, Obihiro, 080-0016, Japan.
Hideki
H
Houzen
Department of Clinical Research, Hokkaido Medical Center, Yamanote 5-jo 7-chome, Nishi-ku, Sapporo, 063-0005, Japan.|Department of Neurology, Hokkaido Medical Center, Yamanote 5-jo 7-chome, Nishi-ku, Sapporo, 063-0005, Japan.
Yusei
Y
Miyazaki
Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Ryo
R
Yamasaki
Department of Neurology, Hokkaido Medical Center, Yamanote 5-jo 7-chome, Nishi-ku, Sapporo, 063-0005, Japan.
Seiji
S
Kikuchi
Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. kira@neuro.med.kyushu-u.ac.jp.
Jun-Ichi
J
Kira
D000328:Adult; D000483:Alleles; D000531:Altitude; D003430:Cross-Sectional Studies; D004185:Disability Evaluation; D004198:Disease Susceptibility / Q000209:etiology*; D005260:Female; D005787:Gene Frequency; D059647:Gene-Environment Interaction; D005838:Genotype; D059868:HLA-DP beta-Chains / Q000235:genetics; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006801:Humans; D007564:Japan / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000453:epidemiology / Q000209:etiology* / Q000235:genetics*; D012044:Regression Analysis; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric
D059868:HLA-DP beta-Chains; C071170:HLA-DPB1 antigen; D059811:HLA-DRB1 Chains; C493960:HLA-DRB1*04:05 antigen
HLA; Latitude; Magnetic resonance imaging; Multiple sclerosis; Oligoclonal IgG bands