HLA-B*58:01 Genotyping, Allopurinol Hypersensitivity

HLA-B*58:01 Genotyping, Allopurinol Hypersensitivity 3001393
Method: Polymerase Chain Reaction/Sequence Specific Oligonucleotide Probe Hybridization

HLA-B*58:01 genotyping can be used to identify patients who are at increased risk for developing severe cutaneous adverse reactions (SCAR) after treatment with allopurinol, based on the presence of the HLA-B*58:01 allele. SCAR, also known as allopurinol hypersensitivity reaction, includes Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).

DISEASE OVERVIEW

The presence of the HLA-B*58:01 allele shows strong association with allopurinol-induced SCAR, including SJS and TEN.

Prevalence and/or Incidence

HLA-B*58:01 allele frequency varies by ethnicity. The highest frequencies are found in Asian populations: up to 20% in Taiwan, Singapore, and among Han Chinese; 15.4% in India; 14.2% in Hong Kong; 12% in China and Korea; and 11% in Indonesia.

HLA-B*58:01 Allele Frequency in U.S. Population
Ethnicity Allele Frequency (%)

Asians

5.3

African Americans

3.8

Native Hawaiians or Pacific Islanders

1.45

Hispanics

1.35

American Indians or Alaska Natives

1.19

Caucasians

0.8

Symptoms

  • Allopurinol is a major cause of SCAR, with an estimated risk of 0.1-0.4%.
  • SCAR is manifested by SJS, TEN, or a drug reaction with eosinophilia, and systemic symptoms.
  • Symptoms include rash combined with eosinophilia, leukocytosis, fever, hepatitis, and progressive kidney failure.
  • Allopurinol-induced SCAR typically develops within weeks or a few months after initiation of treatment, and can be serious, with up to 25% mortality.

Diagnostic Issues

  • In addition to SCAR, a mild skin rash not associated with systemic symptoms or organ damage may develop in patients taking allopurinol.
    • These less severe rashes may occur in 2-3% of patients, and cannot be predicted by HLA-B*58:01 allele status.
  • FDA guidelines recommend discontinuing allopurinol if a rash develops, regardless of allele status.

Screening/Detection

  • Allopurinol is the most commonly used drug to treat hyperuricemia and gout. It inhibits xanthine oxidase, a key enzyme involved in uric acid formation.
  • Due to the severity of allopurinol-induced SCAR, guidelines from the Clinical Pharmacogenomics Implementation Consortium (CPIC) recommend testing for the HLA-B*58:01 allele prior to initiation of therapy.

GENETICS

Gene 

HLA-B*58:01 allele

Inheritance

Codominant

Structure/Function

  • The HLA-B*58:01 allele is located in the Class I HLA region, on human chromosome 6 (6p21.1-6p21.3).
  • HLA-B58 encoded by the HLA-B*58:01 allele is expressed on the surface of all nucleated cells and has important immunological role in antigen presentation to T lymphocytes.

TEST INTERPRETATION

Sensitivity/Specificity

  • Overall 50-60% sensitivity and ~90% specificity in pooled populations.
    • Higher in populations with increased HLA-B*58:01 allele frequency
      • 90-100% sensitivity in Korean, Thai, Sardinia Italian, and Han Chinese populations.
  • Low positive-predictive value (~1.5%), and high negative-predictive value for the HLA-B*58:01 allele, especially in patients of Asian descent (>99%).
  • Analytical sensitivity/specificity is >99%.

Results

Positive

  • HLA-B*58:01, heterozygous or homozygous, is detected.
  • The presence of this allele increases risk for allopurinol-induced SCAR, including SJS or TEN.
    • Allopurinol treatment is contraindicated.
    • Alternative medication should be used as first-line therapy.
  • Therapy should be discontinued immediately if symptoms of SJS or TEN develop.

Negative

  • HLA-B*58:01 is not detected.
  • The patient is not at risk for allopurinol-induced SCAR, including SJS or TEN.
    • Allopurinol can be used per standard dosing guidelines.
  • Testing negative for HLA-B*58:01 does not totally eliminate the possibility of developing SCAR, especially in the Caucasian population with low-risk allele frequency.
  • Allopurinol therapy should be discontinued in all patients if symptoms of SJS or TEN develop, regardless of HLA-B*58:01 status.

Limitations

  • Copy number of HLA-B*58:01 will not be reported.
  • Negative result for HLA-B*58:01 does not replace the need for therapeutic drug monitoring or other clinical testing.
  • Other genetic and nongenetic factors that influence allopurinol-related adverse reactions are not evaluated.
  • Diagnostic errors can occur due to rare sequence variations, or the presence of rare and undocumented alleles.
References 

Hershfield MS, Callaghan JT, Tassaneeyakul W, Mushiroda T, Thorn CF, Klein TE, Lee MT. Clinical Pharmacogenetics Implementation Consortium guidelines for human leukocyte antigen-B genotype and allopurinol dosing. Clin Pharmacol Ther. 2013; 93(2): 153-8. PubMed

Saito Y, Stamp LK, Caudle KE, Hershfield MS, McDonagh EM, Callaghan JT, Tassaneeyakul W, Mushiroda T, Kamatani N, Goldspiel BR, Phillips EJ, Klein TE, Lee MT, Clinical Pharmacogenetics Implementation Consortium. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for human leukocyte antigen B (HLA-B) genotype and allopurinol dosing: 2015 update. Clin Pharmacol Ther. 2016; 99(1): 36-7. PubMed

Yu K, Yu C, Fang Y. Diagnostic utility of HLA-B*5801 screening in severe allopurinol hypersensitivity syndrome: an updated systematic review and meta-analysis. Int J Rheum Dis. 2017; 20(9): 1057-1071. PubMed

Last Update: February 2019