HLA-DQA1*05 and upstream variants of PPARGC1B are associated with infliximab persistence in Japanese Crohn’s disease patients

Abstract

Recently, the HLA-DQA1*05 (rs2097432) genetic variation has been reported to be linked to early In iximab (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 IFX-naiveCD patients. We also performed a genome-wide association study (GWAS) to discover novel genetic predictors for IFX persistence. The rs2097432 signi cantly increased the risk of early discontinuation of IFX even after being adjusted by other clinical parameters [Hazard ratio (HR) = 2.13 and P-value = 0.038]. In GWAS, one locus tagged by rs73277969, located upstream of PPARGC1B, reached genome-wide signi cance (HR = 6.04 and P-value = 7.93E-9). We con rmed the robust association of rs2097432 with IFX persistence regardless of the population. A novel genetic factor for IFX persistence was also identi ed using GWAS.In addition, unbiased genome-wide association research (GWAS) has revealed relationships between genetic backgrounds and clinical response to several drugs, such as rs2097432. Recent pharmacogenomics research in Asian patients with IBD showed a link between a genetic polymorphism of the Nudix hydrolase 15 (NUDT15) and the severe adverse effect of thiopurines [16]. Before these ndings, NUDT15's role in thiopurine metabolism was unknown, suggesting the usefulness of the unbiased approaches in this eld. Performing GWAS to identify novel predictors for IFX failure in Japanese patients, which has never been found before, is also an urgent issue.This study primarily aimed to explore the association between rs2097432 and cumulative IFX discontinuationfree rates in Japanese patients with CD. Furthermore, we conducted an unbiased genome-wide survival analysis to identify the novel genetic factors associated with cumulative IFX discontinuation-free rates. Materials And Methods Study designThis was a single-center retrospective, observational cohort study. The study protocol was reviewed and approved by the Tohoku University Hospital Ethics Committee (2020-1-608). All the patients provided written informed consent. The research followed the Japanese Ministry of Health, Labor, and Welfare ethical guidelines for medical and health studies in humans. SubjectsFrom August 2002 to December 2020, we enrolled consecutive, self-reported Japanese CD patients who had a history of treatment with IFX (Remicade®, Mitsubishi-Tanabe Pharma, Tokyo, Japan) at Tohoku University Hospital. We excluded patients who did not receive the scheduled maintenance treatment within 8 weeks due to either primary non-response or intolerance to the agents. Primary non-response was de ned as a case where IFX was stopped in the induction phase ( rst three administrations) due to a lack of or unsatisfactory agent response. Intolerance was de ned as a case where IFX was stopped because of an adverse event.CD was diagnosed based on endoscopic, radiological, and/or his...