Genetic analysis of the aquaporin-4 gene for anti-AQP4 antibody-positive neuromyelitis optica in a Japanese population

Abstract

Purpose: Neuromyelitis optica (NMO) is an inflammatory demyelinating disorder that generally affects the optic nerve and spinal cord. The etiology of this disease is still uncertain, but autoantibodies to aquaporin-4 (AQP4) are specific and pathogenic for NMO. Recent studies show that AQP4 gene variants are associated with NMO. In this study, we assessed the contribution of AQP4 genetic variants to susceptibility to anti-AQP4 antibody (AQP4-Ab)-positive NMO in a Japanese population. Methods: The subjects were 16 patients with AQP4-Ab-positive NMO (13 sporadic cases, and 3 familial cases from 2 families) and 255 healthy controls. All coding exons of AQP4 were sequenced and five tag single-nucleotide polymorphisms (SNPs) in AQP4 were genotyped. We also performed an imputation analysis to evaluate the potential association of un-genotyped SNPs in AQP4. Results: Known or novel mutations were not detected in any coding exon regions. The T allele frequency of polymorphism (−810 bp (C/T): rs2075575) of the promoter region in patients with AQP4-Ab-positive NMO was significantly higher than that in controls (50.0 vs 25.7 %, P = 0.0036, Pc = 0.018 odds ratio = 2.89). No other tag or imputed SNPs were significant. Conclusions: These findings suggest that the T allele of rs2075575 is a risk for AQP4-Ab-positive NMO. However, the results are the opposite of a previous study in the southern Han Chinese population, and therefore further genetic studies are needed to determine the possible contribution of the AQP4 region to development of NMO.