Association between genetic variants and development of antibodies to infliximab: A cross-sectional study in Chinese patients with Crohn's disease

Kouzhu Zhu; Xiaoliang Ding; Zhiyao Chen; Qinhua Xi; Xueqin Pang; Weichang Chen; Liyan Miao

doi:10.3389/fphar.2023.1096816

Association between genetic variants and development of antibodies to infliximab: A cross-sectional study in Chinese patients with Crohn's disease

Front Pharmacol. 2023 Jan 16:14:1096816. doi: 10.3389/fphar.2023.1096816. eCollection 2023.

Authors

Kouzhu Zhu^{1

2}, Xiaoliang Ding^{1

3}, Zhiyao Chen¹, Qinhua Xi⁴, Xueqin Pang⁴, Weichang Chen⁴, Liyan Miao^{1

2

3

5}

Affiliations

¹ Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, China.
² College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
³ Institute for Interdisciplinary Drug Research and Translational Sciences, Soochow University, Suzhou, China.
⁴ Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China.
⁵ National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, Suzhou, China.

Abstract

Aims: 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). Methods: 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. Results: 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, p < .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, p < .001) or those with low-titer ATI (1.15 vs. 2.95 μg/mL, p = .03). The HLA-DQA1*05 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, p = .02). Patients carrying the CC and AC genotypes of rs396991 in FCGR3A 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, p = .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, p = .001; single variant vs. no variant, 30/53 = 56.60% vs. 9/30 = 30.00%, OR 3.04, 95% CI 1.18-7.88, p = .02). No association was found between other SNPs and ATI production. Conclusion: Rs2097432 in HLA-DQA1*05 and rs396991 in FCGR3A are associated with ATI production in Chinese patients with CD. A pharmacogenomic strategy could help with the clinical management of CD.

Keywords: Crohn’s disease; anti-drug antibodies; drug-tolerant enzyme immunoassay; genetic variants; infliximab.

Grants and funding

This study was financed by the Suzhou Health Leading Talent (No. GSWS2019001), Key R&D Program of Jiangsu Province (BE2021644), the National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University (2020WSC07) and the Priority Academic Program Development of the Jiangsu Higher Education Institutes (PAPD).