Introduction: To achieve the goal of personalized medicine in inflammatory bowel disease (IBD), it is relevant to identify genetic variant involved in pharmacogenes pathways to predict response to anti-tumor necrosis factor (TNF) therapy in IBD patients.
Methods: The Mayo Clinic RIGHT pharmacogenes protocol, derived from the source institutional project Mayo Clinic Biobank, since 2012 has recruited more than 10,000 study subjects who are adult community volunteers consented to donate biological specimens, provided risk factor data, and allowed access to EHR data for research. Seventy-seven selected pharmacogenes, including loci CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, DPYD, SLCO1B1, TPMT, UGT1A1, VKORC1, HLA-A and HLA-B, were sequenced using lymphocyte-derived DNA by PGRN-Seq assay. Adult patients (≥18 years old) with confirmed IBD validated by medical record review were eligible. The primary outcome of response to anti-(tumor necrosis factor) TNF therapy was defined by the clinical response to anti-TNF drug (e.g. infliximab/IFX or adalimumab/ADA). Quality control measures: call rates ≥95%, Hardy-Weinberg equilibrium (P >10E−3).
Results: Among 169 IBD cases of European ancestry, 80 were male (47%), 70 Crohn’s disease (CD)(41%), age at diagnosis (mean: 39, SD 17.5), disease duration (mean 22 years, SD 15), ever smoke 68 (40%), PSC 17 (16 in UC 16%, 1 in CD 1%), IBD surgery (CD: 58%, UC: 31%). Among 34 IBD treated with IFX, clinical response rate was 85% in CD, 36% in UC; pharmacogenetic association analysis showed carrying CYP1A2*1F polymorphism (1A/1F, 1F/1F, rs762551) is associated with lower IFX response rate (63%, 17 out of 27) compared with wild type (1A/1A)(100%, 5 out of 5)(P=0.04). In CYP2C9 gene, poor metabolizer *2 (R144C) and *3 (I359L) are reduced metabolizers. A suggestive association was found between carrying *2 or *3 and higher IFX clinical response rate (84%, 11 out of 13) compared with wild type (*1/*1)(57%, 11 out of 19)(P=0.09).
Among 17 IBD treated with ADA, clinical response rate was 36% in CD, 66% in UC, no association was found between ADA response and CYP1A2*1F polymorphism. However, a suggestive association was found between genotype CYP2C9*1/*2 and higher ADA response (71%, 5 out of 7) compared with wild type CYP2C9*1/*1 (33%, 3 out of 10)(P =0.10).
Discussion: We identified suggestive evidence of pharmacogenes CYP1A2 and possibly CYP2C9 associated with anti-TNF clinical response. This work warrants further replication in an independent large cohort.
Ming-Hsi Wang indicated no relevant financial relationships.
Lawrence Timmons indicated no relevant financial relationships.
Andree Koop indicated no relevant financial relationships.
William Tremaine indicated no relevant financial relationships.
Ming-Hsi Wang, MD, PhD1, Lawrence Timmons, 2, Andree Koop, MD3, William Tremaine, MD2. P2686 - Pharmacogene CYP1A2*1F Polymorphism Lowers Anti-TNF (infliximab) Response in Inflammatory Bowel Disease Patients, ACG 2021 Annual Scientific Meeting Abstracts. Las Vegas, Nevada: American College of Gastroenterology.