Human Leukocyte Antigen (HLA) Pharmacogenomic Tests: Potential and Pitfalls
Ann K. Daly
Affiliation: Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
Keywords: Abacavir, carbamazepine, drug-induced liver injury, human leukocyte antigen, hypersensitivity, B*57:01, B*15:02.
Adverse drug reactions involving a range of prescribed drugs and affecting the skin, liver and other organs show strong associations
with particular HLA alleles. For some reactions, HLA typing prior to prescription, so that those positive for the risk allele are
not given the drug associated with the reaction, shows high positive and negative predictive values. The best example of clinical
implementation relates to the hypersensitivity reaction induced by the anti-HIV drug abacavir. When this reaction is phenotyped
accurately, 100% of those who develop it are positive for HLA-B*57:01. Drug regulators worldwide now recommend genotyping for
HLA-B*57:01 before abacavir is prescribed. Serious skin rashes including Stevens-Johnson syndrome and toxic epidermal necrosis can
be induced by carbamazepine and other anticonvulsant drugs. In certain East Asians, these reactions are significantly associated with
HLA-B*15:02, and typing for this allele is now recommended prior to carbamazepine prescription in these populations. Other HLA
associations have been described for skin rash induced by carbamazepine, allopurinol and nevirapine and for liver injury induced by
flucloxacillin, amoxicillin-clavulanate, lapatanib, lumiracoxib and ticlopidine. However, the predictive values for typing HLA alleles
associated with these adverse reactions are lower. Clinical implementation therefore seems unlikely. Performing HLA typing is relatively
complex compared with genotyping assays for single nucleotide polymorphisms. With emphasis on HLA-B*57:01, the approaches used
commonly, including use of sequence-specific oligonucleotide PCR primers and DNA sequencing are considered, together with their
successful implementation. Genotyping single nucleotide polymorphisms tagging HLA alleles is a simpler alternative to HLA typing but
appears insufficiently accurate for clinical use.
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