Pharmacogenetics and Predictive Testing of Drug Hypersensitivity Reactions

Abstract

Adverse drug reactions adverse drug reaction (ADR) occur in approximately 17% of patients. Avoiding ADR is thus mandatory from both an ethical and an economic point of view. Whereas, pharmacogenetics changes of the pharmacokinetics may contribute to the explanation of some type A reactions, strong relationships of genetic markers has also been shown for drug hypersensitivity belonging to type B reactions. We present the classifications of ADR, discuss genetic influences and focus on delayed-onset hypersensitivity reactions, i.e., drug-induced liver injury, drug-induced agranulocytosis, and severe cutaneous ADR. A guidance how to read and interpret the contingency table is provided as well as an algorithm whether and how a test for a pharmacogenetic biomarker should be conducted.

Keywords: adverse drug reactions (ADRs); drug hypersensitivity reactions; drug-induced agranulocytosis (DIA); drug-induced liver injury (DILI); drug-induced severe cutaneous adverse reactions (SCARs).

FIGURE 1

Overview of different ADR types, examples for drugs and reactions and influencing biomarkers or patients’ conditions.

FIGURE 2

Stimuli for degranulation of mast cells and basophils and interplay/overlap with type II-IV reactions. Beside the canonical IgE-mediated true allergic pathway, activation of the complement system and the direct interaction with IgE-receptor can lead to degranulation. Changes in the the metabolism and signaling of various arachidonic acid-derivatives, e.g., cysteinyl leukotrienes, or in the histaminergic system, as well as changes to the kallikrein-kinine-system are believed to aggravate any reactions. Light red: proteins/genes involved in hypersensitivity with known genetic associations; Dark red: example of drugs leading to primarily non-allergic hypersensitivity ADR. ACEi, angiotensin-converting-enzyme inhibitor; ALOX5, 5′-lipoxygenase; ASA, acetylsalicylic acid (USAN: aspirin); C3a/C5a, activated components 3 and 5 of the complement system; DAO, diaminooxidase; Fc𝜀R, IgE-receptor; HLA, human leukocyte antigen; HRH, histamine receptor; LTC4S, cysteinyl leukotriene synthetase; NAT, N-acetyl transferase; NSAID, non-steroidal anti-inflammatory drugs; RCM, radio contrast media; TBXAS1, thromboxane synthetase; TCR, T-cell receptor; TXA2R, thromboxane receptor; XPNPEP2, aminopeptidase P.