TY - JOUR
T1 - Latitude and HLA-DRB1*04:05 independently influence disease severity in Japanese multiple sclerosis
T2 - A cross-sectional study
AU - Nakamura, Yuri
AU - Matsushita, Takuya
AU - Sato, Shinya
AU - Niino, Masaaki
AU - Fukazawa, Toshiyuki
AU - Yoshimura, Satoshi
AU - Hisahara, Shin
AU - Isobe, Noriko
AU - Shimohama, Shun
AU - Watanabe, Mitsuru
AU - Yoshida, Kazuto
AU - Houzen, Hideki
AU - Miyazaki, Yusei
AU - Yamasaki, Ryo
AU - Kikuchi, Seiji
AU - Kira, Jun ichi
N1 - Funding Information:
TM received a grant and payment from Bayer Schering Pharma and Takeda Pharmaceutical Company for the development of educational presentations and has also received speaker honoraria from Mitsubishi Tanabe Pharma, Bayer Schering Pharma, and Biogen. MN has received funding for travel and/or speaker honoraria from Biogen Idec, Bayer Schering Pharma, Mitsubishi, and Tanabe Pharma Corporation; is part of the scientific advisory board for Biogen Idec; and has received research support from Grants-in-Aid for Scientific Research from the Ministry of Health, Labour and Welfare of Japan. TF serves/ has served on scientific advisory boards for Bayer Pharma, Biogen Idec, Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Company, and Novartis Pharma and has received funding for travel and speaker honoraria from Bayer Pharma, Biogen Idec, Mitsubishi Tanabe Pharma Corporation, and Novartis Pharma. SSh has received speaker honoraria from Novartis Pharma, Boehringer Ingelheim, Kyowa Hakko Kirin, Dainippon Sumitomo Pharma, Takeda Pharmaceutical Company, Daiichi Sankyo Pharma, Jansen Pharma, Eisai Pharma, Biogen Idec, and Mitsubishi Tanabe Pharma Corporation and has received research support from Grants-in-Aid for Scientific Research from the Ministry of Health, Labour and Welfare of Japan and the Smoking Research Foundation. HH serves on scientific advisory boards for Biogen Idec, Novartis Pharma, and Mitsubishi Tanabe Pharma Corporation. JK is a consultant for Biogen Idec Japan and Medical Review; has received honoraria from Bayer Healthcare, Mitsubishi Tanabe Pharma, Nobelpharma, Otsuka Pharmaceutical, and Medical Review; and is funded by a research grant for Nervous and Mental Disorders from the Ministry of Health, Labour and Welfare, Japan, and grants from the Japan Science and Technology Agency and the Ministry of Education, Culture, Sports, Science and Technology, Japan. These sponsors had no control over the interpretation, writing, or publication of this work. YN, SSa, SY, SH, NI, MW, KY, YM, RY, and SK have nothing to declare.
Funding Information:
This study was supported in part by a Health and Labour Sciences Research Grant on Intractable Diseases (H26-Nanchitou (Nan)-Ippan-074) from the Ministry of Health, Labour, and Welfare, Japan; by the “Practical Research Project for Rare/Intractable Diseases” from Japan Agency for Medical Research and Development, AMED, Japan; and by a Grant-in-Aid for Scientific Research A (MEXT KAKENHI Grant No. 16H02657), a Grant-in-Aid for Scientific Research C (No. 15K09341), a Grant-in-Aid for Exploratory Research (MEXT KAKENHI Grant No. 15K15341), a Grant-in-Aid for Scientific Research on Innovative Areas (No. 25117012), and a “Glial Assembly” Grant-in Aid for Scientific Research on Innovative Areas (JSPS KAKENHI Grant No. 25117001) from the Japan Society for the Promotion of Science, Japan. None of the funding bodies played any role in the study design, data collection and analysis, data interpretation, or writing the manuscript.
Publisher Copyright:
© 2016 The Author(s).
PY - 2016/9/6
Y1 - 2016/9/6
N2 - Background: 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. Methods: 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. Results: 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). Conclusions: 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.
AB - Background: 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. Methods: 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. Results: 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). Conclusions: 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.
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U2 - 10.1186/s12974-016-0695-3
DO - 10.1186/s12974-016-0695-3
M3 - Article
C2 - 27599848
AN - SCOPUS:84985998576
VL - 13
JO - Journal of Neuroinflammation
JF - Journal of Neuroinflammation
SN - 1742-2094
IS - 1
M1 - 239
ER -