PMID- 27599848 OWN - NLM STAT- MEDLINE DCOM- 20171010 LR - 20181113 IS - 1742-2094 (Electronic) IS - 1742-2094 (Linking) VI - 13 IP - 1 DP - 2016 Sep 6 TI - Latitude and HLA-DRB1*04:05 independently influence disease severity in Japanese multiple sclerosis: a cross-sectional study. PG - 239 LID - 10.1186/s12974-016-0695-3 [doi] LID - 239 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 degrees north), and 187 MS patients and 235 HCs from the southern half (33-35 degrees north) of the Japanese archipelago (33-45 degrees 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. FAU - Nakamura, Yuri AU - Nakamura Y AD - Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. FAU - Matsushita, Takuya AU - Matsushita T AD - Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. FAU - Sato, Shinya AU - Sato S AD - Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. FAU - Niino, Masaaki AU - Niino M AD - Department of Clinical Research, Hokkaido Medical Center, Yamanote 5-jo 7-chome, Nishi-ku, Sapporo, 063-0005, Japan. FAU - Fukazawa, Toshiyuki AU - Fukazawa T AD - Sapporo Neurology Clinic, 21-2-1, Kita 21-jo Higashi, Higashi-ku, Sapporo, 065-0021, Japan. FAU - Yoshimura, Satoshi AU - Yoshimura S AD - Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. FAU - Hisahara, Shin AU - Hisahara S AD - Department of Neurology, School of Medicine, Sapporo Medical University, South 1 West 16, Chuo-ku, Sapporo, 060-8543, Japan. FAU - Isobe, Noriko AU - Isobe N AD - Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. FAU - Shimohama, Shun AU - Shimohama S AD - Department of Neurology, School of Medicine, Sapporo Medical University, South 1 West 16, Chuo-ku, Sapporo, 060-8543, Japan. FAU - Watanabe, Mitsuru AU - Watanabe M AD - Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. FAU - Yoshida, Kazuto AU - Yoshida K AD - Department of Neurology, Asahikawa Red Cross Hospital, 1-1-1, Akebono 1-jo, Asahikawa, 070-8530, Japan. FAU - Houzen, Hideki AU - Houzen H AD - Department of Neurology, Obihiro Kosei General Hospital, 8-1, Nishi 6-jo Minami, Obihiro, 080-0016, Japan. FAU - Miyazaki, Yusei AU - Miyazaki Y AD - Department of Clinical Research, Hokkaido Medical Center, Yamanote 5-jo 7-chome, Nishi-ku, Sapporo, 063-0005, Japan. AD - Department of Neurology, Hokkaido Medical Center, Yamanote 5-jo 7-chome, Nishi-ku, Sapporo, 063-0005, Japan. FAU - Yamasaki, Ryo AU - Yamasaki R AD - Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. FAU - Kikuchi, Seiji AU - Kikuchi S AD - Department of Neurology, Hokkaido Medical Center, Yamanote 5-jo 7-chome, Nishi-ku, Sapporo, 063-0005, Japan. FAU - Kira, Jun-Ichi AU - Kira J AD - 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. CN - Japan Multiple Sclerosis Genetics Consortium LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160906 PL - England TA - J Neuroinflammation JT - Journal of neuroinflammation JID - 101222974 RN - 0 (HLA-DP beta-Chains) RN - 0 (HLA-DPB1 antigen) RN - 0 (HLA-DRB1 Chains) RN - 0 (HLA-DRB1*04:05 antigen) SB - IM MH - Adult MH - Alleles MH - *Altitude MH - Cross-Sectional Studies MH - Disability Evaluation MH - Disease Susceptibility/*etiology MH - Female MH - Gene Frequency MH - Gene-Environment Interaction MH - Genotype MH - HLA-DP beta-Chains/genetics MH - HLA-DRB1 Chains/*genetics MH - Humans MH - Japan/epidemiology MH - Male MH - Middle Aged MH - Multiple Sclerosis/epidemiology/*etiology/*genetics MH - Regression Analysis MH - Severity of Illness Index MH - Statistics, Nonparametric PMC - PMC5013608 OTO - NOTNLM OT - HLA OT - Latitude OT - Magnetic resonance imaging OT - Multiple sclerosis OT - Oligoclonal IgG bands EDAT- 2016/09/08 06:00 MHDA- 2017/10/11 06:00 PMCR- 2016/09/06 CRDT- 2016/09/08 06:00 PHST- 2016/01/13 00:00 [received] PHST- 2016/08/20 00:00 [accepted] PHST- 2016/09/08 06:00 [entrez] PHST- 2016/09/08 06:00 [pubmed] PHST- 2017/10/11 06:00 [medline] PHST- 2016/09/06 00:00 [pmc-release] AID - 10.1186/s12974-016-0695-3 [pii] AID - 695 [pii] AID - 10.1186/s12974-016-0695-3 [doi] PST - epublish SO - J Neuroinflammation. 2016 Sep 6;13(1):239. doi: 10.1186/s12974-016-0695-3.