基因变异与英夫利昔单抗抗体产生之间的关联：一项针对中国克罗恩病患者的横断面研究。
Association between genetic variants and development of antibodies to infliximab: A cross-sectional study in Chinese patients with Crohn's disease.
作者信息
Zhu Kouzhu, Ding Xiaoliang, Chen Zhiyao, Xi Qinhua, Pang Xueqin, Chen Weichang, Miao Liyan
机构信息
Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, China.
College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
出版信息
Front Pharmacol. 2023 Jan 16;14:1096816. doi: 10.3389/fphar.2023.1096816. eCollection 2023.
Genetic variants increase the susceptibility to anti-drug antibodies (ADA) in response to anti-TNF therapy in chronic inflammatory diseases. However, little is known about genetic variants in Chinese populations. This study aimed to identify genetic variants contributing to the risk of the development of antibodies to infliximab (ATI) in Chinese patients with Crohn's disease (CD). CD patients (n = 104) treated with infliximab (IFX) during the maintenance therapy were enrolled in this cross-sectional study. ATI was assessed by an in-house developed drug-tolerant ELISA method. ATI titers of 1:20 and ≥1:60 were considered a low titer and a high titer, respectively. Thirteen types of single nucleotide polymorphisms (SNPs) within 13 genes involved in the immune process, the susceptibility to chronic inflammatory diseases, cytokines and apoptosis pathways were investigated. The median trough levels of infliximab (TLI) in patients with clinical remission (CR) were higher than those in patients without CR (3.80 vs. 1.50 μg/mL, < .001). The median TLI in patients with high-titer ATI was significantly lower than that in ATI-negative patients (1.15 vs. 4.48 μg/mL, .001) or those with low-titer ATI (1.15 vs. 2.95 μg/mL, = .03). The rs2097432 GG and GA genotypes were more frequent in patients with ATI (GG and AG vs. AA, 27/38 = 71.05% vs. 29/66 = 43.94%, OR 2.94, 95% CI 1.19-7.30, = .02). Patients carrying the CC and AC genotypes of rs396991 in were associated with a higher frequency of ATI formation (CC and AC vs. AA, 37/57 = 64.91% vs. 19/47 = 40.43%, OR 2.94, 95% CI 1.24-6.96, = .01). According to the number of variants in rs2097432 and rs393991, patients with two variants had a higher proportion of producing ATI (two variants vs. no variant, 17/21 = 80.95% vs. 9/30 = 30.00%, OR 9.92, 95% CI 2.59-37.87, = .001; single variant vs. no variant, 30/53 = 56.60% vs. 9/30 = 30.00%, OR 3.04, 95% CI 1.18-7.88, = .02). No association was found between other SNPs and ATI production. Rs2097432 in and rs396991 in are associated with ATI production in Chinese patients with CD. A pharmacogenomic strategy could help with the clinical management of CD.
基因变异会增加慢性炎症性疾病患者在接受抗TNF治疗时产生抗药物抗体（ADA）的易感性。然而，对于中国人群中的基因变异情况知之甚少。本研究旨在确定中国克罗恩病（CD）患者中导致产生英夫利昔单抗抗体（ATI）风险增加的基因变异。本横断面研究纳入了104例在维持治疗期间接受英夫利昔单抗（IFX）治疗的CD患者。采用自行研发的耐药物酶联免疫吸附测定法评估ATI。ATI滴度为1:20及≥1:60分别被视为低滴度和高滴度。研究了参与免疫过程、慢性炎症性疾病易感性、细胞因子和凋亡途径的13个基因中的13种单核苷酸多态性（SNP）。临床缓解（CR）患者的英夫利昔单抗谷浓度中位数（TLI）高于未缓解患者（3.80 vs. 1.50μg/mL，P<0.001）。高滴度ATI患者的TLI中位数显著低于ATI阴性患者（1.15 vs. 4.48μg/mL，P = 0.001）或低滴度ATI患者（1.15 vs. 2.95μg/mL，P = 0.03）。rs2097432的GG和GA基因型在ATI患者中更为常见（GG和AG vs. AA，27/38 = 71.05% vs. 29/66 = 43.94%，OR 2.94，95%CI 1.19 - 7.30，P = 0.02）。携带rs396991的CC和AC基因型的患者ATI形成频率较高（CC和AC vs. AA，37/57 = 64.91% vs. 19/47 = 40.43%，OR 2.94，95%CI 1.24 - 6.96，P = 0.01）。根据rs2097432和rs393991中的变异数量，有两个变异的患者产生ATI的比例更高（两个变异vs.无变异，17/21 = 80.95% vs. 9/30 = 30.00%，OR 9.92，95%CI 2.59 - 37.87，P = 0.001；单个变异vs.无变异，30/53 = 56.60% vs. 9/30 = 30.00%，OR 3.04，95%CI 1.18 - 7.88，P = 0.02）。未发现其他SNP与ATI产生之间存在关联。rs2097432和rs396991与中国CD患者的ATI产生相关。药物基因组学策略有助于CD的临床管理。
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