rs1800460 — TPMT *3B

TPMT*3B — Half of the TPMT*3A Haplotype That Causes Thiopurine Toxicity in Europeans

TPMT (thiopurine S-methyltransferase) is the enzyme your body uses to inactivate thiopurine drugs¹¹ inactivate thiopurine drugs
Azathioprine, 6-mercaptopurine, and thioguanine — used for inflammatory bowel disease, autoimmune diseases, organ transplantation, and childhood leukemia by methylating them into harmless metabolites. When TPMT activity is reduced, these drugs shunt into an alternative pathway that generates toxic thioguanine nucleotides, which incorporate into DNA and can cause life-threatening bone marrow suppression at standard doses. The TPMT*3B variant (rs1800460) is the decreased-function star allele that, almost always, travels on the same chromosome as TPMT*3C (rs1142345) — and that pair-in-cis is what clinical labs call TPMT*3A, the most common TPMT deficiency haplotype in people of European ancestry.

The Mechanism

TPMT*3B is a single-nucleotide substitution in exon 7 (coding-strand c.460G>A, plus-strand C>T at chr6:18138997 because TPMT is on the minus strand) that changes alanine 154 to threonine (p.Ala154Thr), in a region critical for substrate binding and protein stability. On its own, the 3B substitution moderately reduces enzyme activity by destabilising the folded protein. What makes *3B clinically important is that it is almost always inherited together with *3C (p.Tyr240Cys) on the same chromosome — a configuration called **TPMT*3A*. The two amino acid changes together accelerate proteolysis of the enzyme²² accelerate proteolysis of the enzyme
Tai et al. PNAS 1997 showed TPMT*3A protein has a half-life roughly 15-fold shorter than wild-type, with near-complete degradation via the ubiquitin-proteasome pathway, leaving carriers with essentially no functional TPMT from the *3A allele. When TPMT cannot methylate thiopurine drugs, these medications are diverted almost entirely into pathways that generate toxic thioguanine nucleotides (TGNs), which incorporate into DNA and cause cytotoxicity — normally kept in check by TPMT methylation to the inactive 6-methylmercaptopurine metabolite — producing profound myelosuppression.

The Evidence

TPMT is one of the oldest and best-documented pharmacogenes. The CPIC guideline for thiopurine dosing³³ CPIC guideline for thiopurine dosing
Clinical Pharmacogenetics Implementation Consortium — Level A evidence, the highest tier for clinical implementation was first published in 2011 and has been updated multiple times since, recommending pre-treatment TPMT genotyping for all patients starting azathioprine, 6-mercaptopurine, or thioguanine. The original 2011 CPIC guideline⁴⁴ original 2011 CPIC guideline
Relling MV et al. Clin Pharmacol Ther 2011 named TPMT*2, *3A, *3B, and *3C as the four clinically relevant no-function alleles, and the 2018 update⁵⁵ 2018 update
Relling MV et al. Clin Pharmacol Ther 2019 extended the framework to NUDT15. The original molecular characterisation of TPMT*3A/*3B/*3C by Otterness et al.⁶⁶ Otterness et al.
Human thiopurine methyltransferase pharmacogenetics: gene sequence polymorphisms. Clin Pharmacol Ther 1997 found TPMT*3A (the *3B + *3C cis haplotype) in roughly 3.2-5.7% of Caucasian populations and in over 80% of Caucasian patients with deficient TPMT activity. A more recent genome-wide association study of TPMT enzyme activity⁷⁷ genome-wide association study of TPMT enzyme activity
Liu et al. Genomewide approach validates thiopurine methyltransferase activity as a monogenic pharmacogenomic trait. Clin Pharmacol Ther 2017 in 1,026 leukemia patients confirmed rs1800460 and rs1142345 as the two SNPs reaching genome-wide significance for TPMT activity, with TPMT being the only gene to reach that threshold. The FDA includes TPMT status in its pharmacogenomic biomarker table⁸⁸ pharmacogenomic biomarker table for azathioprine, mercaptopurine, and thioguanine, and the package inserts explicitly recommend genotyping or phenotyping before treatment.

Practical Implications

If you carry one or two copies of TPMT*3B, you are at risk for severe thiopurine-induced bone marrow suppression at standard doses. European populations carry the *3B variant at roughly 3.6% allele frequency, meaning about 7% of Europeans are heterozygotes (one functional TPMT allele) and roughly 1 in 800 are homozygous for *3B or compound heterozygous with another TPMT variant. The CPIC 2025 guideline recommends starting at 30-80% of the standard dose for intermediate metabolizers (one variant copy) and 10% of the standard dose or an alternative medication for poor metabolizers (two variant copies). Because TPMT deficiency classification depends on all variant alleles in combination, anyone with a *3B variant should also be checked for TPMT*3C, TPMT*2, and NUDT15 variants — especially if they have East Asian or admixed ancestry where NUDT15 is the dominant thiopurine safety gene.

Interactions

The dominant interaction for TPMT*3B is cis-haplotype configuration with TPMT*3C (rs1142345). In the overwhelming majority of Caucasian carriers, *3B and *3C are found on the same chromosome, forming the TPMT*3A haplotype⁹⁹ TPMT*3A haplotype
Otterness et al. found *3A accounted for ~84% of variant alleles in deficient Caucasians; *3B alone and *3C alone are each rare in isolation in this population. If your genome file shows you carry both rs1800460(T) and rs1142345(C), you most likely have TPMT*3A (both variants in cis on one chromosome) rather than two independent decreased-function alleles in trans. Clinical labs distinguish these configurations through phase determination, which requires long-read sequencing, family studies, or extended phenotyping — most SNP-array platforms cannot resolve cis vs trans without additional testing. This matters because *3A in cis behaves as a single deficient allele (heterozygote phenotype when one chromosome carries both variants), whereas *3B and *3C in trans (on separate chromosomes) would behave as compound heterozygous — two functional-null alleles — and produce the rare, severe poor-metabolizer phenotype.

A second critical interaction is with NUDT15 (rs116855232), the other thiopurine safety gene. NUDT15 loss-of-function variants are common in East Asian populations and act on a downstream step of thiopurine metabolism. Individuals carrying variants in both TPMT and NUDT15 require larger dose reductions than predicted by either gene alone, and both should be checked before thiopurine prescription. Finally, co-administration of allopurinol¹⁰¹⁰ allopurinol
Xanthine oxidase inhibitor used for gout; blocks an alternate thiopurine inactivation pathway or febuxostat with thiopurines creates a double-blockade that is particularly dangerous in TPMT variant carriers — the FDA label instructs reducing azathioprine to 25% of the standard dose when combined with allopurinol, and that reduction must be applied on top of any TPMT-based dose reduction.