HLA-DQA105 and upstream variants of PPARGC1B are associated with infliximab persistence in Japanese Crohn's disease patients

• Published in: The pharmacogenomics journal Vol. 23; no. 6; pp. 141 - 148
• Main Authors: Shimoda, Fumiko, Naito, Takeo, Kakuta, Yoichi, Kawai, Yosuke, Tokunaga, Katsushi, Shimoyama, Yusuke, Moroi, Rintaro, Shiga, Hisashi, Nagasaki, Masao, Kinouchi, Yoshitaka, Masamune, Atsushi
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.11.2023
• Subjects: Asian people; Biobanks; Biological products; Body mass index; Clinical medicine; Crohn's disease; Crohns disease; DQA1 protein; Endoscopy; Fc receptors; Fistula; Genetic diversity; Genome-wide association studies; Genomes; Histocompatibility antigen HLA; Inflammatory bowel disease; Infliximab; Macrophages; Medical prognosis; Medicine; Monoclonal antibodies; Polymorphism; Population studies; Remission (Medicine); Survival analysis; Tumor necrosis factor-TNF; Tumor necrosis factor-α; White people
• ISSN: 1470-269X; 1473-1150
• DOI: 10.1038/s41397-023-00312-z

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).