Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan.
Pharmacogenomics J. 2023 Nov;23(6):141-148. doi: 10.1038/s41397-023-00312-z. Epub 2023 Jul 17.
Recently, the HLA-DQA1*05 (rs2097432) genetic variation has been reported to be linked to early infliximab (IFX) treatment failure in the Caucasian Crohn's disease (CD) population, but that evidence is scarce in the Asian population. This study aimed to investigate the relationship between rs2097432 and the cumulative discontinuation-free time of IFX (IFX persistence) in 189 Japanese biologics-naive CD patients. We also performed a genome-wide association study (GWAS) to discover novel genetic predictors for IFX persistence. The C allele of rs2097432 significantly increased the risk of early discontinuation of IFX [Hazard ratio (HR) = 2.23 and P-value = 0.026]. In GWAS, one locus tagged by rs73277969, located upstream of PPARGC1B which attenuates macrophage-mediated inflammation, reached genome-wide significance (HR = 6.04 and P-value = 7.93E-9). Pathway analysis suggested association of signaling by PDGF and FCGR activation signaling with IFX persistence (P-value = 8.56E-5 and 5.80E-4, respectively).
最近，有人报道 HLA-DQA1*05(rs2097432) 基因变异与高加索人群克罗恩病（CD）患者早期英夫利昔单抗（IFX）治疗失败有关，但亚洲人群的证据很少。本研究旨在探讨 rs2097432 与 189 例日本生物制剂初治 CD 患者 IFX 累积停药无失败时间（IFX 持续时间）之间的关系。我们还进行了全基因组关联研究（GWAS），以发现 IFX 持续时间的新遗传预测因子。rs2097432 的 C 等位基因显著增加了 IFX 早期停药的风险[风险比（HR）=2.23，P 值=0.026]。在 GWAS 中，一个由 rs73277969 标记的位于 PPARGC1B 上游的位点与巨噬细胞介导的炎症减弱有关，达到了全基因组显著性（HR=6.04，P 值=7.93E-9）。通路分析表明，PDGF 信号和 FCGR 激活信号与 IFX 持续时间有关（P 值分别为 8.56E-5 和 5.80E-4）。
