TPMT3A

TPMT3A is a pharmacogenetic haplotype of the TPMT gene, which encodes the enzyme thiopurine S-methyltransferase. This enzyme inactivates thiopurine drugs such as azathioprine, 6-mercaptopurine, and 6-thioguanine, and TPMT activity influences patient response and toxicity to these medications.

Genetic basis and structure: TPMT3A comprises two coding-region single-nucleotide polymorphisms in the TPMT gene, rs1800460 (G460A) and rs1142345 (A719G). These variants commonly co-occur on the same chromosome, forming the TPMT*3A haplotype and resulting in reduced enzymatic activity.

Clinical significance: Individuals carrying TPMT*3A typically have lower TPMT activity, leading to intermediate or poor metabolizer phenotypes. When given standard thiopurine doses, these patients face an increased risk of myelosuppression and cytopenias. Pre-treatment testing and subsequent dose adjustments or therapy modifications are therefore recommended to minimize toxicity.

Population relevance and management: TPMT*3A is among the most common TPMT variants associated with reduced activity in people of European descent. Testing can be performed by TPMT genotyping for the rs1800460 and rs1142345 variants or by phenotyping TPMT activity. Clinical guidelines advocate tailoring thiopurine dosing based on TPMT phenotype or genotype, with dose reductions and closer blood monitoring for heterozygotes and poor metabolizers.

Related alleles and interpretation: Other TPMT variants, such as TPMT*3B and TPMT*3C, also reduce activity. A comprehensive assessment may involve haplotype analysis to capture multiple contributing alleles.