Thiopurine methyltransferase (TPMT) variants

Pharmacogenetic Biomarker

Pharmacogenetic Biomarker

Pharmacogenetic Biomarker

Thiopurine methyltransferase (TPMT) variants

Selected Variants (Mutant Allele, Enzyme Activity)

Selected Variants (Mutant Allele, Enzyme Activity)

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

Allele Frequency

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

Drugs

Drugs

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

Clinical Relevance

Clinical Relevance

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.

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