Dai Yuyang, Ni Siyang, Wu Feng, Guo Shaojie, Zhao Xiuli, Wang Jiawei
National Institute for Drug Clinical Trial, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
Department of Neurology, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
J Clin Pharm Ther. 2022 Sep;47(9):1379-1387. doi: 10.1111/jcpt.13675. Epub 2022 Apr 29.
Patients with optic neuritis (ON) have significant individual differences in their response to high-dose intravenous methylprednisolone (HIMP) therapy. This study aims to evaluate the association between gene polymorphisms and the efficacy of HIMP therapy in Chinese Han patients with ON mediated by aquaporin-4 immunoglobulin G antibody (AQP4-IgG) -positive neuromyelitis optica spectrum disorder (NMOSD) or multiple sclerosis (MS).
Chinese Han patients with AQP4-IgG NMOSD-ON or MS-ON were genotyped for four candidate genes: ABCB1 (rs1045642, rs1128503, rs2032582), NR3C1 (rs41423247), TBX21 (rs9910408, rs16947078) and VDR (rs731236, rs1544410, rs7975232, rs2228570). Patients were divided into glucocorticoid resistance (GR) and glucocorticoid sensitivity (GS) groups based on vision acuity (VA) improvement after HIMP treatment. Intergroup comparisons were performed on clinical characteristics, allele and genotype frequencies and haplotype distributions.
A total of 267 patients completed the follow-up, including 120 patients with AQP4-IgG NMOSD-ON and 147 patients with MS-ON. We observed a significant association between the ABCB1 G2677T/A (rs2032582) polymorphism and glucocorticoid response in AQP4-IgG NMOSD-ON patients. Changes in VA scores in patients with the GG genotype were significantly lower than those in patients with the T/A T/A genotype (1.07 ± 1.20 vs. 1.77 ± 1.31, p = 0.026). In the GS group, the G allele had a lower frequency than the T/A allele (32.03% vs. 60.16%, p = 0.001). Logistic regression analysis showed that the G2677T/A GG and G T/A genotypes could increase the GR risk 3.53 and 2.67 times compared with the T/A T/A genotype, respectively (OR = 3.534, 95% CI: 1.186-10.527, p = 0.023; OR = 2.675, 95% CI: 1.005-7.123, p = 0.049). In addition, haplotype analysis showed that AQP4-IgG NMOSD-ON patients with the TAT/TTT haplotype (ABCB1 C3435T-G2677T/A-C1236T) were only 0.54 times more likely to develop GR than those with other haplotypes (OR = 0.542, 95% CI: 0.315-0.932, p = 0.026). However, we did not observe intergroup differences in the MS-ON population.
Our findings suggest that the G > T/A polymorphism of ABCB1 G2677T/A and the TAT/TTT haplotype played a protective role in HIMP treatment of AQP4-IgG NMOSD-ON but not MS-ON.
视神经炎（ON）患者对大剂量静脉注射甲基强的松龙（HIMP）治疗的反应存在显著个体差异。本研究旨在评估基因多态性与HIMP治疗在中国汉族AQP4水通道蛋白4免疫球蛋白G抗体（AQP4-IgG）阳性视神经脊髓炎谱系障碍（NMOSD）或多发性硬化症（MS）介导的ON患者中的疗效之间的关联。
对中国汉族AQP4-IgG NMOSD-ON或MS-ON患者的四个候选基因进行基因分型：ABCB1（rs1045642、rs1128503、rs2032582）、NR3C1（rs41423247）、TBX21（rs9910408、rs16947078）和VDR（rs731236、rs1544410、rs7975232、rs2228570）。根据HIMP治疗后视力（VA）改善情况将患者分为糖皮质激素抵抗（GR）组和糖皮质激素敏感（GS）组。对临床特征、等位基因和基因型频率以及单倍型分布进行组间比较。
共有267例患者完成随访，其中AQP4-IgG NMOSD-ON患者120例，MS-ON患者147例。我们观察到ABCB1 G2677T/A（rs2032582）多态性与AQP4-IgG NMOSD-ON患者的糖皮质激素反应之间存在显著关联。GG基因型患者的VA评分变化显著低于T/A T/A基因型患者（1.07±1.20 vs. 1.77±1.31，p = 0.026）。在GS组中，G等位基因频率低于T/A等位基因（32.03% vs. 60.16%，p = 0.001）。逻辑回归分析显示，与T/A T/A基因型相比，G2677T/A GG和G T/A基因型分别使GR风险增加3.53倍和2.67倍（OR = 3.534，95%CI：1.186 - 10.527，p = 0.023；OR = 2.675，95%CI：1.005 - 7.123，p = 0.049）。此外，单倍型分析显示，具有TAT/TTT单倍型（ABCB1 C3435T - G2677T/A - C1236T）的AQP4-IgG NMOSD-ON患者发生GR的可能性仅为其他单倍型患者的0.54倍（OR = 0.542，95%CI：0.315 - 0.932，p = 0.026）。然而，我们在MS-ON人群中未观察到组间差异。
我们的研究结果表明，ABCB1 G2677T/A的G>T/A多态性和TAT/TTT单倍型在HIMP治疗AQP4-IgG NMOSD-ON中起保护作用，但在MS-ON中不起作用。
