Pharmacogenetic Biomarker

Thiopurine methyltransferase (TPMT) variants

Selected Variants (Mutant Allele, Enzyme Activity)

TPMT*2 (238G>C, ↓);

TPMT*3A (460G>A and 719A>G, ↓↓);

TPMT*3B (460G>A, ↓);

TPMT*3C (719A>G, ↓)

Allele Frequency

About 10–12% of whites and blacks have reduced enzyme activity because they are heterozygous for one of the mutant alleles. About 1 in 300 whites is homozygous for a mutant allele.

Drugs

Azathioprine (AZA), 6-mercaptopurine (6-MP)

Clinical Relevance

AZA is a prodrug that is metabolized to 6-MP, which is then further metabolized to active 6-thioguanine (6-TG) and inactive 6-methylmercaptopurine (6-MMP) by hypoxanthine phosphoribosyltransferase and TPMT, respectively. Variation in the TPMT gene can result in functional inactivation of the enzyme and an increased risk of life-threatening 6-TG–associated myelosuppression. TPMT genotyping before instituting AZA or 6-MP can help prevent toxicity by identifying individuals with low or absent TPMT enzyme activity. Patients with homozygous or compound heterozygous mutant alleles (“poor metabolizers”) should not be given AZA or 6-MP, whereas heterozygotes with a single mutant allele should be treated with lower doses.