HLA-B*58:01 Genotyping, Allopurinol Hypersensitivity

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.