Genetic Determinants of Azathioprine Efficacy

Azathioprine (AZA) is among the most widely prescribed immunosuppressive agents of the past five decades. It finds its application in organ transplantation therapy, autoimmune disorders, and various inflammatory conditions. However, its therapeutic efficacy is often marred by unwanted side effects or adverse drug reactions (ADRs). Polymorphism in genes like thiopurine methyltransferase (TPMT), inosine triphosphate pyrophosphatase (ITPA), nudix hydrolase 15 (NUDT15), and subsequent influences on enzymatic activity play a crucial role in modulating AZA's response and toxicity. Additionally, racial and ethnic factors further complicate the metabolic outcome of this drug. These changes can lead to undesirable outcomes like myelotoxicity, hematopoietic toxicity, neutropenia, and leukocytopenia. Due to the unpredictability of AZA outcome, elicited by genetic variations, the Food and Drug Administration (FDA) has recommended genetic screening prior to AZA therapy initiation, highlighting the move towards precision medicine. While pharmacogenetic screening is recommended, accessibility, cost, and ethical consideration remain a hurdle in its implementation. This review article will delve deep into the studies and literature available, reporting the intricate interaction between SNPs and the resulting impact on AZA efficacy. The article will also recommend how to effectively use the pharmacogenetic tools for optimizing its usage. By incorporating genetic information in treatment plans involving AZA, a patient-centered approach can be achieved, potentially optimizing efficacy, safety, and cost-effectiveness of AZA therapy.