Huang J, Yoshimura S, Isobe N, Matsushita T, Yonekawa T, Sato S, Yamasaki R, Kira JI; the South Japan Multiple Sclerosis Genetics Consortium. A NOTCH4 missense mutation confers resistance to multiple sclerosis in Japanese. Mult Scler. 2013 Apr. [Epub ahead of print]
BACKGROUND: The G allele of NOTCH4 rs422951 is protective against demyelinating disease in Japanese.
OBJECTIVES: 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, pcorr=0.0380) while DRB1*0901 was negatively associated (OR=0.32, pcorr =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.
CONCLUSION: 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.
Notch family members play a role in a variety of developmental processes by controlling cell fate decisions. Neurogenic locus notch homolog protein 4 is a protein that in humans is encoded by the NOTCH4 gene may play a role in vascular, renal, and hepatic development. This gene may be associated with susceptibility to schizophrenia in a small portion of cases and variant has been found to be associated with not developing MS, but this did not seem to influence MS if you had it. A different major histocompatibility type was associated with MS i.e. HLADRB1*0405 compared to the HLARB1*1501 type often found in European Msers. Further highlighting that there are more than one genetic route to developing MS.
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