携带新生儿 Fc 受体可变数目串联重复多态性或 HLA-DQA1*05G>A 基因型的炎症性肠病患者中，英夫利昔单抗浓度降低。

Decreased Infliximab Concentrations in Patients With Inflammatory Bowel Disease Who Carry a Variable Number Tandem Repeat Polymorphism in the Neonatal Fc Receptor or Variant HLADQA1*05G>A Genotype.

机构信息

Department of Physiology & Pharmacology, Western University, Medical Sciences Building, Rm 216, London, ON, N6A 5C1, Canada.

Division of Gastroenterology, Department of Medicine, Western University, 339 Windermere Rd, London, ON, N6A 5A5, Canada.

出版信息

Inflamm Bowel Dis. 2023 Mar 1;29(3):437-443. doi: 10.1093/ibd/izac188.

DOI:10.1093/ibd/izac188

PMID:36112504

Abstract

BACKGROUND

Multiple variables contribute to variation in patient exposure and response to tumor necrosis factor alpha antagonist biologics such as infliximab. This study aimed to assess the association between maintenance-phase infliximab concentrations and genetic variation in HLADQA1*05G>A and fragment crystallisable (Fc) fragment of IgG receptor and transporter (FCGRT) among patients with inflammatory bowel disease.

METHODS

A cross-sectional study was carried out in participants with inflammatory bowel disease prescribed infliximab who were in the maintenance phase of treatment. Participants were genotyped for the presence of the FCGRT variable number tandem repeat (VNTR) and HLADQA1*05G>A (rs74291249). A point estimate of the infliximab trough concentration during the maintenance phase was determined using a standard enzyme-linked immunosorbent assay for each patient. Other variables associated with infliximab pharmacokinetics were collected.

RESULTS

A total of 156 participants with inflammatory bowel disease were included from 2 tertiary care centers affiliated with Western University, London, Canada. Median infliximab trough concentrations were lower in participants who carried the FCGRT VNTR 2/3 or 2/2 (4.14 µg/mL; interquartile range [IQR], 6.48 µg/mL) vs wild type individuals (7.00 µg/mL; IQR, 7.66; P = .0027). Median infliximab trough concentrations were significantly lower in participants who were HLADQA105G>A variant carriers (4.73µg/mL; IQR, 4.79) vs wild type individuals (7.85µg/mL; IQR, 7.44; P = .0006). A significant decrease in infliximab trough concentrations was seen in individuals who were dual carriers of variant polymorphisms in HLADQA105G>A and FCGRT VNTR (no variants, 8.96µg/mL; IQR, 6.84 vs one variant, 4.96 µg/mL; IQR, 4.95 vs dual variants, 0.86µg/mL; IQR, 5.82).

CONCLUSION

FCGRT VNTR and HLADQA1*05G>A are associated with lower maintenance-phase infliximab concentrations, particularly among patients who carry both variants.

摘要

背景

多种因素导致肿瘤坏死因子 α 拮抗剂生物制剂（如英夫利昔单抗）在患者中的暴露和反应存在差异。本研究旨在评估炎症性肠病患者维持期英夫利昔单抗浓度与 HLA-DQA1*05G>A 和免疫球蛋白 G 受体和转运体（FCGRT）片段结晶区（Fc）多态性之间的相关性。

方法

对正在接受英夫利昔单抗治疗且处于维持期的炎症性肠病患者进行了一项横断面研究。对患者的 FCGRT 可变数目串联重复（VNTR）和 HLA-DQA1*05G>A(rs74291249)进行基因分型。使用标准酶联免疫吸附试验（ELISA）为每位患者确定维持期的英夫利昔单抗谷浓度的点估计值。收集了与英夫利昔单抗药代动力学相关的其他变量。

结果

共纳入来自加拿大西安大略大学附属 2 家三级保健中心的 156 名炎症性肠病患者。携带 FCGRT VNTR 2/3 或 2/2（4.14μg/ml；四分位距[IQR]，6.48μg/ml）的患者的英夫利昔单抗谷浓度中位数较低（7.00μg/ml；IQR，7.66；P=0.0027）。与野生型个体相比，HLA-DQA105G>A 变异携带者的英夫利昔单抗谷浓度中位数显著降低（4.73μg/ml；IQR，4.79）（P=0.0006）。在 HLA-DQA105G>A 和 FCGRT VNTR 双重变异携带者中，英夫利昔单抗谷浓度明显降低（无变异，8.96μg/ml；IQR，6.84 vs 单一变异，4.96μg/ml；IQR，4.95 vs 双重变异，0.86μg/ml；IQR，5.82）。