Department of Neurology, The Second Hospital of Hebei Medical University, City Shijiazhuang, Province Hebei, China.
Key Laboratory of Neurology of Hebei Province, City Shijiazhuang, Province Hebei, China.
CNS Neurosci Ther. 2021 Dec;27(12):1549-1560. doi: 10.1111/cns.13738. Epub 2021 Oct 12.
This study aimed to determine the correlation between B-lymphoid tyrosine kinase (BLK) polymorphism, mRNA gene expression of BLK, and NMOSD in a Chinese Han population.
B-lymphoid tyrosine kinase gene expressed mainly in B cells plays a key role in various autoimmune disorders. However, no studies have investigated the association of BLK polymorphisms with neuromyelitis optica spectrum disorder (NMOSD).
Han Chinese population of 310 subjects were recruited to analyze three single nucleotide polymorphisms (rs13277113, rs4840568, and rs2248932) under allele, genotype, and haplotype frequencies, followed by clinical characteristics stratified analysis. Real-time PCR was used to analyze mRNA expression levels of BLK in the peripheral blood mononuclear cells of 64 subjects.
Patients with NMOSD showed lower frequencies of the minor allele G of rs2248932 than healthy controls (odds ratio (OR) =0.57, 95% confidence intervals (CI) 0.39-0.83, p = 0.003). The association between minor allele G of rs2248932 and reduced NMOSD susceptibility was found by applying genetic models of inheritance (codominant, dominant, and recessive) and haplotypes analysis. Subsequently, by stratification analysis for AQP4-positivity, the minor allele G frequencies of rs2248932 in AQP4-positive subgroup were significantly lower than in the healthy controls (OR =0.46, 95% CI 0.30-0.72, p = 0.001). Notably, the genotype GG of rs2248932 was more frequent in AQP4-negative subgroup (n = 14) than in AQP4-positive subgroup (n = 93) (p = 0.003, OR =0.05, 95% CI =0.01-0.57). BLK mRNA expression levels in the NMOSD patients (n = 36) were lower than in healthy controls (n = 28) (p < 0.05). However, the acute non-treatment (n = 7), who were untreated patients in the acute phase from the NMOSD group, showed BLK mRNA expression levels 1.8-fold higher than healthy controls (n = 8) (p < 0.05).
This study evaluated that the minor allele G of rs2248932 in BLK is associated with reduced susceptibility to NMOSD and protected the risk of AQP4-positive. BLK mRNA expression in NMOSD was lower as compared to healthy controls while significantly increased in acute-untreated patients.
本研究旨在探讨 B 淋巴细胞酪氨酸激酶（BLK）多态性、BLK mRNA 基因表达与中国汉族人群 NMOSD 的相关性。
B 淋巴细胞酪氨酸激酶基因主要在 B 细胞中表达，在各种自身免疫性疾病中发挥关键作用。然而，目前尚无研究探讨 BLK 多态性与视神经脊髓炎谱系疾病（NMOSD）之间的关系。
本研究纳入了 310 名汉族受试者，分析了三个单核苷酸多态性（rs13277113、rs4840568 和 rs2248932）在等位基因、基因型和单倍型频率下的分布情况，并进行了临床特征分层分析。采用实时 PCR 法分析了 64 例 NMOSD 患者和 28 例健康对照者外周血单个核细胞中 BLK 的 mRNA 表达水平。
NMOSD 患者中 rs2248932 次要等位基因 G 的频率低于健康对照组（比值比（OR）=0.57，95%置信区间（CI）0.39-0.83，p=0.003）。通过遗传模型（共显性、显性和隐性）和单倍型分析发现，rs2248932 次要等位基因 G 与 NMOSD 易感性降低有关。随后，通过对 AQP4 阳性的分层分析，rs2248932 的次要等位基因 G 在 AQP4 阳性亚组中的频率明显低于健康对照组（OR=0.46，95%CI 0.30-0.72，p=0.001）。值得注意的是，rs2248932 的 GG 基因型在 AQP4 阴性亚组（n=14）中比 AQP4 阳性亚组（n=93）更为常见（p=0.003，OR=0.05，95%CI 0.01-0.57）。NMOSD 患者（n=36）的 BLK mRNA 表达水平低于健康对照组（n=28）（p<0.05）。然而，NMOSD 组的急性未治疗患者（n=7）在急性阶段未接受治疗，其 BLK mRNA 表达水平较健康对照组（n=8）高 1.8 倍（p<0.05）。
本研究评估了 BLK 中 rs2248932 的次要等位基因 G 与 NMOSD 易感性降低有关，并保护了 AQP4 阳性的风险。NMOSD 患者的 BLK mRNA 表达水平低于健康对照组，而急性未治疗患者的 BLK mRNA 表达水平显著升高。
