# TPMT and HLA-DQ Allelic Variants in Relation to Drug Response, Safety and Need for Therapy Optimization in Pediatric Inflammatory Bowel Disease

## TL;DR

This study explores how genetic variants in TPMT and HLA-DQ affect drug response and safety in children with inflammatory bowel disease.

## Contribution

The study identifies specific TPMT and HLA-DQ allelic variants that influence treatment optimization in pediatric IBD patients.

## Key findings

- TPMT mutations were rare, but HLA-DQA105 was linked to anti-drug antibodies against anti-TNF therapy.
- HLA-DQA101 was more common in children on optimized therapy regimens.
- TPMT genotyping is recommended before azathioprine therapy to prevent adverse effects.

## Abstract

What are the main findings?
Pharmacogenetic variants shape treatment response to azathioprine and anti-TNF agents in pediatric IBD.Genetic differences influence both efficacy and risk of adverse events.Evidence remains limited and heterogeneous.

Pharmacogenetic variants shape treatment response to azathioprine and anti-TNF agents in pediatric IBD.

Genetic differences influence both efficacy and risk of adverse events.

Evidence remains limited and heterogeneous.

What is the implication of the main finding?
Pharmacogenetics paves the way for personalized IBD therapy in children, but further clinical validation is still required.

Pharmacogenetics paves the way for personalized IBD therapy in children, but further clinical validation is still required.

Background/Objectives: Pharmacogenetics examines genome variability and its influence on drug efficacy and toxicity, forming the foundation for personalized medicine. Patients with inflammatory bowel disease (IBD) treated with azathioprine with thiopurine S-methyltransferase (TPMT) deficiency are at an increased risk of drug-related toxic effects. Variability in the HLA-DQA1 and DQB1 alleles may lead to an inadequate therapeutic response. This study aimed to determine the significance of TPMT and HLA-DQ Allelic Variants in therapy optimization planning. Methods: A retrospective study was conducted to determine TPMT gene polymorphism and the presence of HLA-DQA1 and HLA-DQB1 alleles in children diagnosed with IBD and treated at the Institute for Child and Youth Health Care of Vojvodina in May 2023. Results: The study included 104 children with a mean age of 13.71 ± 3.1 years, with a balanced gender distribution. A TPMT mutation was identified in only one child. The most common HLA-DQA1 alleles were *01 (49%) and *05 (28.8%), while the most frequent allele at the HLA-DQB1 locus was 03 (15.4%). The presence of the HLA-DQA105 allele was associated with the development of anti-drug antibodies against anti-TNF therapy (RR: 1.23; 95% CI: 1.03–1.50), while the presence of HLA-DQA101 was significantly more frequent in children on optimized therapeutic regimens (RR: 1.63; 95% CI: 1.13–2.10). Conclusions: Prior to the initiation of azathioprine therapy, TPMT genotyping should be performed to prevent adverse effects and ensure optimal drug dosing. Identification of the HLA-DQA105 and HLA-DQA101 alleles plays an important role in the planning of biological therapy regimens, including decisions on dose escalation or interval shortening.