Whole-exome sequencing reveals the major genetic factors contributing to neuromyelitis optica spectrum disorder in Chinese patients with aquaporin 4-IgG seropositivity
Whole-exome sequencing reveals the major genetic factors contributing to neuromyelitis optica spectrum disorder in Chinese patients with aquaporin 4-IgG seropositivity
复制标题
全外显子组测序揭示水通道蛋白4-IgG血清阳性中国患者视神经脊髓炎谱系障碍的主要遗传因素
DOI：
10.1111/ene.14771
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Qiu W.
中科院分区：
文献类型：
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作者：
Zhong X;Chen C;Sun X;Wang J;Li R;Chang Y;Fan P;Wang Y;Wu Y;Peng L;Lu Z;Qiu W.
背景与目的视神经脊髓炎性谱系障碍(NMOSD)是一种自身免疫性疾病。虽然遗传因素参与了其发病机制，但这方面的证据有限。方法对广州地区228例AQP4-Ig G阳性的NMOSD患者和1400例健康体检者进行外显子组测序，并进行人类白细胞抗原(人类白细胞抗原)测序。结果DQB1、DQA2和DQA1在6号染色体上有显著差异，DQB1、DQA2和DQA1变异较大，经DNA测序证实最显著的等位基因为HLADQB1*05：02(P<；P<0.01，优势比[OR]3.73)。基因模型分析显示，在加性效应模型和显性效应模型中，HLADQB1*05：02与NMOSD显著相关(P<；P<0.05)。NMOSD组单倍型“HLADQB1*05：02-DRB1*15：01”的比例显著高于对照组，分别为8.42%和1.23%(P<0.001，OR=7.39)。基因负荷分析显示NOP16功能缺失突变在NMOSD组(11.84%)明显高于对照组(5.71%；P<；0.001，OR=2.22)。IgG1-G390R变异在NMOSD中更为常见，T等位基因频率在NMOSD患者中为0.605，在对照组中为0.345(P<；0.01OR=2.92)。结论人类白细胞抗原性与NMOSD高度相关，NOP16和IgG1-G390R在疾病易感性中起重要作用。
Background and objectiveNeuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease. Although genetic factors are involved in its pathogenesis, limited evidence is available in this area. The aim of the present study was to identify the major genetic factors contributing to NMOSD in Chinese patients with aquaporin 4 (AQP4)‐IgG seropositivity.MethodsWhole‐exome sequencing (WES) was performed on 228 Chinese NMOSD patients seropositive for AQP4‐IgG and 1400 healthy controls in Guangzhou, South China.Human leukocyte antigen(HLA) sequencing was also utilized. Genotype model and haplotype, gene burden, and enrichment analyses were conducted.ResultsA significant region of theHLAcomposition is on chromosome 6, and great variation was observed inDQB1, DQA2andDQA1.HLAsequencing confirmed that the most significant allele wasHLA‐DQB1*05:02(p< 0.01, odds ratio [OR] 3.73). The genotype model analysis revealed thatHLA‐DQB1*05:02was significantly associated with NMOSD in the additive effect model and dominant effect model (p< 0.05). The proportion of haplotype “HLA‐DQB1*05:02‐DRB1*15:01” was significantly greater in the NMOSD patients than the controls, at 8.42% and 1.23%, respectively (p< 0.001, OR 7.39). The gene burden analysis demonstrated that loss‐of‐function mutations inNOP16were more common in the NMOSD patients (11.84%) than the controls (5.71%;p< 0.001, OR 2.22). TheIgG1‐G390Rvariant was significantly more common in NMOSD, and the rate of the T allele was 0.605 in patients and 0.345 in the controls (p< 0.01, OR 2.92). The enrichment analysis indicated that most of the genetic factors were mainly correlated with nervous and immune processes.ConclusionsHuman leukocyte antigenis highly correlated with NMOSD.NOP16andIgG1‐G390Rplay important roles in disease susceptibility.