(UGT1A1)N-Acetyltransferase 2 (NAT2), and glutathionS-transferase (GST) have
been demonstrated to be of great importance for clinical practice.^20 ,^21
Genetic variation also plays a crucial role in drug–drug interactions. Presence of
a second drug may induce (enhance) or inhibit the metabolic activity of a certain
enzyme responsible for drug metabolism. Such unwanted drug–drug interactions
can influence the activity of the enzyme and reduce bioavailability of the primary
drug being taken. If this occurs in a patient with low initial level of enzyme activity
due to genetic variation, drug–drug interaction can result in poor efficacy and
dangerous side effects.^22
Pharmacogenomics promote the development of targeted therapies. There are
very good examples of important applications of pharmacogenomics for cancer
therapy like cetuximab/panitumumab andKRAS, vemurafenib andBRAF, gefitinib/
erlotinib andEGFR, crizotinib andEML4-ALK, imatinib andKIT (c-KIT).^23
Drug hypersensitivity remains an important clinical issue. It is consisted of a
variety of phenotypes, mainly the cutaneous adverse reactions that range from
milder skin reactions (e.g., exanthem, urticaria, and angioedema) to severe cutane-
ous adverse reactions (SCARs). SCARs are life threatening, including Stevens-
Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with
eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity
syndrome (DIHS). Associations between human leukocyte antigen (HLA) alleles
and specific drug hypersensitivity syndromes such as abacavir hypersensitivity
have accelerated the widespread use of a pharmacogenetic test in clinical practice
to prevent the development of specific life-threatening drug toxicity.^24
Genetic predisposition to drug-induced liver injury (DILI) may be due to
variation in both pharmacokinetic and pharmacodynamic pathways. GWAS have
identified, in the HLA alleles, strong genetic factors that predispose to liver injury
on exposure to any of several drugs.^25
A clear role in drug toxicity and efficacy has been established for some gene–
drug combinations, yet the implementation of pharmacogenomic tests in clinical
practice lags behind this knowledge. It is partly due to the lack of specific guidelines
on how to adjust medications on the basis of genetic test results. To overcome this
problem, in recent years, the Pharmacogenetics Implementation Consortia were
established. The main goal of the Consortia is to provide peer-reviewed, updated,
evidence-based, freely accessible guidelines for gene/drug pairs (http://www.
pharmgkb.org). These guidelines will facilitate the translation of pharmacogenomic
knowledge from bench to bedside (Table 4 ).^26 ,^27
(^20) Sim et al. ( 2013 ).
(^21) Stingl et al. ( 2014 ).
(^22) Cascorbi and Tyndale ( 2014 ).
(^23) Ong et al. ( 2012 ).
(^24) Kaniwa and Saito ( 2013 ).
(^25) Alfirevic and Pirmohamed ( 2012 ).
(^26) Caudle et al. ( 2014 ).
(^27) Swen et al. ( 2011 ).
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