title: A NOTCH4 missense mutation confers resistance to multiple sclerosis in Japanese.
abstract: BACKGROUND
  The G allele of NOTCH4 rs422951 is protective against demyelinating disease in Japanese.
  
  
  OBJECTIVE
  The purpose of this study was to assess the relation of the G allele to neuromyelitis optica (NMO)/NMO spectrum disorder (NMOSD) and multiple sclerosis (MS) and the interaction between the G allele and HLA-DRB1 alleles, and to clarify any association of the G allele with clinical features.
  
  
  METHODS
  DNA sequencing was used to genotype 106 NMO/NMOSD patients, 118 MS patients and 152 healthy controls (HCs) for rs422951.
  
  
  RESULTS
  G allele frequency in MS patients, but not that in NMO/NMOSD patients, was lower than that in HCs (8.9% vs 21.7%, p<0.0001, odds ratio (OR)=0.35). HLA-DRB1*0405 was positively associated with MS (OR=2.22, p(corr) =0.0380) while DRB1*0901 was negatively associated (OR=0.32, p(corr) =0.0114). Logistic regression analyses revealed that, after adjusting for gender and either HLA-DRB1*0405 or DRB1*0901, rs422951 was associated with MS in the dominant model (OR=0.37, 95% confidence interval (CI)= 0.20-0.66, p=0.0012). Haplotype analyses identified two susceptible and three resistant haplotypes formed from rs422951 and either HLA-DRB1*0405 or DRB1*0901. There were no statistically significant differences in clinical features between G allele carriers and non-G allele carriers.
  
  
  CONCLUSIONS
  This NOTCH4 missense mutation decreased the risk for developing MS in Japanese, but did not affect clinical features of those who had already developed the disease.
authors.affiliation: Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yoshimura
authors.forename: Noriko
authors.initials: N
authors.lastname: Isobe
authors.forename: Takuya
authors.initials: T
authors.lastname: Matsushita
authors.forename: Tomomi
authors.initials: T
authors.lastname: Yonekawa
authors.forename: Shinya
authors.initials: S
authors.lastname: Sato
authors.forename: Ryo
authors.initials: R
authors.lastname: Yamasaki
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Kira
mesh_terms: D000483:Alleles; D051401:Aquaporin 4 / Q000235:genetics / Q000276:immunology; D016001:Confidence Intervals; D004247:DNA / Q000235:genetics; D060467:Disease Resistance / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D059811:HLA-DRB1 Chains / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D007564:Japan / Q000453:epidemiology; D015810:Linkage Disequilibrium; D016015:Logistic Models; D008297:Male; D009103:Multiple Sclerosis / Q000453:epidemiology / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics*; D009471:Neuromyelitis Optica / Q000453:epidemiology / Q000235:genetics; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D000074562:Receptor, Notch4; D017447:Receptors, Dopamine D1 / Q000235:genetics; D051880:Receptors, Notch / Q000235:genetics*
chemical_list: D051401:Aquaporin 4; D059811:HLA-DRB1 Chains; C493960:HLA-DRB1*04:05 antigen; C106075:NOTCH4 protein, human; D011518:Proto-Oncogene Proteins; D000074562:Receptor, Notch4; D017447:Receptors, Dopamine D1; D051880:Receptors, Notch; D004247:DNA
keywords:     NOTCH4; Multiple sclerosis; genetics; human leukocyte antigen; polymorphism