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association study on lumiracoxib-treated patients with liver injury and matched
lumiracoxib-treated patients without liver injury (controls) identifi es risk SNPs in
the major histocompatibility complex (MHC) class II region in patients with
lumiracoxib- related liver injury (Singer et al. 2010 ). Fine mapping identifi ed a
strong association to a common HLA haplotype (HLA-DRB11501-HLA-
DQB10602-HLA-DRB50101-HLA-DQA10102). The mapping of the genetic
association to the MHC class II region suggests a possible immunological mecha-
nism for lumiracoxib-related hepatotoxicity as previous studies have also linked
MHC genes to other adverse drug effects such as hypersensitivity to the HIV drug
abacavir and liver injury associated with the antibiotic fl ucloxacillin. These results
offer the potential to improve the safety profi le of lumiracoxib by identifying indi-
viduals at elevated risk for liver injury and excluding them from lumiracoxib
treatment.
Pharmacogenetic Basis of Thiopurine Toxicity
Thiopurine S-methyltransferase (TPMT) catalyzes the S-methylation of thiopurine
drugs. TPMT genetic polymorphisms represent a striking example of the potential
clinical value of pharmacogenetics. Subjects homozygous for TPMT3A (an allele
that encodes a protein with two changes in amino acid sequence), which is the most
common variant allele for low activity, are at greatly increased risk for life-
threatening toxicity when treated with standard doses of thiopurines. These subjects
have virtually undetectable levels of TPMT protein. TPMT3A results in protein
misfolding and aggregation in vitro. Results of studies on this topic provide an
insight into a unique pharmacogenetic mechanism by which common polymor-
phisms affect TPMT protein function and, as a result, alter therapeutic response to
thiopurine drugs.
TPMT testing prior to the prescription of azathioprine in autoimmune diseases is
one of the few examples of a pharmacogenetic test that has made the transition from
research into clinical practice. TPMT testing could lead to improved prescribing of
azathioprine resulting in a reduction in ADRs as well as an improvement in effec-
tiveness. A prospective economic evaluation was conducted in the UK alongside the
TARGET (TPMT: Azathioprine Response to Genotype and Enzyme Testing) study,
a pragmatic controlled trial that randomized (1:1) patients to undergo TPMT geno-
typing before azathioprine or current practice (Thompson et al. 2014 ). The study
concluded that TPMT genotyping potentially offers a less expensive alternative
than current practice, but it may also have a small but negative effect on health sta-
tus. These fi ndings are associated with signifi cant uncertainty, and the causal effect
of TPMT genotyping on changes in health status and health care resource use
remains uncertain. The results from this study therefore pose a diffi cult challenge to
decision makers.
4 Pharmacogenetics