Center for Pharmacogenomics and Translational Research, Nemours Children's Health System, Jacksonville, Florida.
College of Pharmacy, University of Florida, Jacksonville, Florida.
Clin Gastroenterol Hepatol. 2021 Oct;19(10):2046-2053.e2. doi: 10.1016/j.cgh.2020.08.020. Epub 2020 Aug 13.
BACKGROUND & AIMS: Based on histologic features, variants in STAT6 are associated with a poor initial response to proton pump inhibitor (PPI) therapy in pediatric patients with eosinophilic esophagitis (EoE). We investigated whether these genetic variants are associated with a poor long-term response in children with EoE who initially responded to PPI therapy.
We performed a prospective longitudinal cohort study of children ages 2 to 16 years who met the diagnostic criteria for EoE (≥15 eosinophils/high-power field [eos/hpf]), responded to 8 weeks of treatment with 2 mg/kg/d PPI (<15 eos/hpf), and whose dose then was reduced to 1 mg/kg/d PPI (maintenance therapy) for 1 year, at which point biopsy specimens were collected by endoscopy. Genomic DNA was isolated from formalin-fixed paraffin-embedded biopsy tissue and was genotyped for variants of STAT6. Remission of inflammation was assessed at eos/hpf thresholds of <15 and ≤5.
Among 73 patients who received 1 mg/kg/d PPI maintenance therapy for 1 year, 13 patients (18%) had 6 to 14 eos/hpf, 36 patients (49%) had 5 or fewer eos/hpf, and 24 patients (33%) relapsed to EoE (≥15 eos/hpf). Carriage of any of 3 STAT6 variants in linkage disequilibrium (r ≥0.8; rs324011, rs167769, or rs12368672) was associated with a 2.3- to 2.8-fold increase in the odds of EoE relapse, and with a 2.8- to 4.1-fold increase in the odds of having 6 to 14 eos/hpf. For rs324011, the odds ratio [95% CI] for relapse was 2.77 [1.11, 6.92]; P = .029, and the odds ratio [95% CI] for having 6 to 14 eos/hpf was 3.06 [1.27, 7.36]; P = .012.
Pediatric EoE patients who initially respond to PPI therapy and carry STAT6 variants rs324011, rs167769, or rs12368672 are at increased risk of relapse after 1 year of PPI maintenance therapy.
基于组织学特征，STAT6 变异与质子泵抑制剂（PPI）治疗儿童嗜酸性食管炎（EoE）初始反应不佳相关。我们研究了这些遗传变异是否与接受 PPI 治疗后初始反应良好的 EoE 儿童的长期反应不佳有关。
我们对年龄在 2 至 16 岁之间的符合 EoE 诊断标准（≥15 个嗜酸性粒细胞/高倍视野 [eos/hpf]）的儿童进行了前瞻性纵向队列研究，这些儿童接受了 8 周 2mg/kg/d PPI（<15 eos/hpf）治疗，然后将剂量减少至 1mg/kg/d PPI（维持治疗）1 年，此时通过内镜收集活检标本。从福尔马林固定石蜡包埋的活检组织中提取基因组 DNA，并对 STAT6 变异进行基因分型。采用 eos/hpf 阈值<15 和≤5 评估炎症缓解情况。
在接受 1mg/kg/d PPI 维持治疗 1 年的 73 例患者中，13 例（18%）患者 eos/hpf 为 6 至 14，36 例（49%）患者 eos/hpf 为 5 个或更少，24 例（33%）患者复发 EoE（≥15 eos/hpf）。携带连锁不平衡（r ≥0.8；rs324011、rs167769 或 rs12368672）中任何 3 种 STAT6 变异的患者，EoE 复发的几率增加 2.3 至 2.8 倍，6 至 14 eos/hpf 的几率增加 2.8 至 4.1 倍。对于 rs324011，复发的比值比[95%CI]为 2.77[1.11,6.92]；P=0.029，6 至 14 eos/hpf 的比值比[95%CI]为 3.06[1.27,7.36]；P=0.012。
最初对 PPI 治疗有反应且携带 STAT6 rs324011、rs167769 或 rs12368672 变异的儿科 EoE 患者在接受 PPI 维持治疗 1 年后复发的风险增加。
