HLA-B*5801 Genotype, Allopurinol Hypersensitivity, Blood
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
The human leukocyte antigen (HLA) genes help the immune system recognize and respond to foreign substances (such as viruses and bacteria). The HLA-B gene encodes a class 1 HLA molecule in the major histocompatibility complex (MHC), which acts by presenting peptides to immune cells. There are more than 1,500 different HLA-B alleles identified, one of which is the HLA-B*58:01 allele. Frequency of the HLA-B*58:01 allele varies with ethnicity, with a frequency of 6% to 7% in Asian populations, and 1% in Caucasian populations.
Allopurinol is a drug widely used for hyperuricemia-related diseases such as gout, Lesch-Nyhan syndrome, and recurrent urate kidney stones. However, this drug is one of the most common causes of severe cutaneous adverse reactions (SCAR), an umbrella term encompassing drug hypersensitivity syndrome, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). These reactions have a reported mortality rate of 20% to 25%. For individuals taking allopurinol, the presence of the HLA-B*58:01 allele has been strongly associated with allopurinol-induced SCAR.
Guidelines from the Clinical Pharmacogenomics Implementation Consortium (CPIC) recommend HLA-B*58:01 genotyping be performed when considering prescribing allopurinol, and that allopurinol should not be prescribed to patients who test positive for the allele due to the increased risk of SCAR.(1) In addition, guidelines developed by the 2012 American College of Rheumatology for Management of Gout recommend that HLA-B*58:01 testing should be considered in select patient subpopulations at an elevated risk for allopurinol-induced SCAR. Those of Korean descent, especially those with stage 3 or higher chronic kidney disease, or of Han Chinese or Thai descent, irrespective of renal function, should be tested.(2)
Identifying individuals with an increased risk of severe cutaneous adverse reactions to allopurinol based on the presence of the human leukocyte antigen HLA-B*58:01 allele
Positivity for HLA-B*58:01 confers increased risk for hypersensitivity to allopurinol.
For additional information regarding pharmacogenomic genes and their associated drugs, see the Pharmacogenomic Associations Tables in Special Instructions. This resource also includes information regarding enzyme inhibitors and inducers, as well as potential alternate drug choices.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
Samples may contain donor DNA if obtained from patients who received heterologous blood transfusions or allogeneic blood or marrow transplantation. Results from samples obtained under these circumstances may not accurately reflect the recipient’s genotype. For individuals who have received blood transfusions, the genotype usually reverts to that of the recipient within 6 weeks. The impact of blood or marrow transplantation on risk of severe cutaneous adverse reactions with allopurinol is not defined in the literature.
Rare or novel variants may be present that could lead to false-negative or false-positive results. This assay also detects closely related rare alleles including HLA-B*57:05, *58:04, *58:05, *58:09, *58:10, *58:11, *58:12, *58:13, *58:15, *58:17, *58:19, *58:21, *58:22, *58:23, *58:24, and *58:28. There are currently no data indicating whether these or any other alleles or subtypes are associated with allopurinol-induced severe cutaneous adverse reactions.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
An interpretive report will be provided.
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Saito Y, Stamp L, Caudle K, et al: Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for human leukocyte antigen B (HLA-B) genotype and allopurinol dosing: 2015 update. Clin Pharmacol Ther 2015 June;doi: 10.1002/cpt.161
2. Khanna D, Fitzgerald J, Khanna P, et al: 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res 2012;64:1431-1446
3. Hershfield MS, Callaghan JT, Tassaneeyakul W, et al: Clinical Pharmacogenetics Implementation Consortium guidelines for human leukocyte antigen-B genotype and allopurinol dosing. Clin Pharmacol Ther 2013 Feb;93(2):153-158
4. Chung WH, Hung SI, Chen YT: Human leukocyte antigens and drug hypersensitivity. Curr Opin Allergy Clin Immunol 2007;7:317-323