rs1142345 — TPMT *3C

TPMT*3C — The Most Common Thiopurine Deficiency Allele in East Asian and African Populations

TPMT (thiopurine S-methyltransferase) is the primary enzyme responsible for inactivating thiopurine drugs¹¹ inactivating thiopurine drugs
These immunosuppressants include azathioprine, 6-mercaptopurine, and thioguanine, used to treat leukemia, inflammatory bowel disease, rheumatoid arthritis, and prevent organ transplant rejection. The TPMT*3C variant (rs1142345) is a no-function allele²² no-function allele
Produces an unstable enzyme with negligible activity that accounts for over 95% of TPMT deficiency cases in East Asian populations and is the predominant variant in individuals of African descent. This variant is one of three genetic markers covered by FDA labeling requirements³³ FDA labeling requirements
The FDA mandates that azathioprine drug labels include information about TPMT genetic testing for thiopurine drugs.

The Mechanism

The TPMT*3C allele results from an A-to-G substitution at position 719 in exon 10 of the TPMT gene, causing a tyrosine-to-cysteine amino acid change at position 240⁴⁴ tyrosine-to-cysteine amino acid change at position 240
p.Tyr240Cys disrupts protein folding (p.Tyr240Cys). This missense mutation produces a structurally unstable enzyme⁵⁵ structurally unstable enzyme
The mutant protein undergoes enhanced degradation via the ubiquitin-proteasome pathway with drastically reduced cellular protein levels and virtually no enzymatic activity. When TPMT cannot inactivate thiopurine drugs through methylation, these medications are shunted into pathways that generate toxic thioguanine nucleotides (TGNs)⁶⁶ thioguanine nucleotides (TGNs)
TGNs incorporate into DNA causing cell death; normally kept in check by TPMT methylation, leading to life-threatening bone marrow suppression.

The Evidence

A genome-wide association study of 1,026 children with leukemia⁷⁷ genome-wide association study of 1,026 children with leukemia
Liu et al. Genomewide approach validates thiopurine methyltransferase activity is a monogenic pharmacogenomic trait. Clin Pharmacol Ther. 2017 identified rs1142345 as the top hit (P = 8.6 × 10⁻⁶¹) for TPMT enzyme activity, with TPMT being the only gene to reach genome-wide significance. The Clinical Pharmacogenetics Implementation Consortium (CPIC)⁸⁸ Clinical Pharmacogenetics Implementation Consortium (CPIC)
Level A evidence - highest tier for clinical implementation has designated TPMT testing as having the strongest evidence for clinical utility, with specific dosing guidelines updated in 2025. Population studies reveal striking ethnic variation: TPMT*3C accounts for 100% of variant alleles in Chinese populations⁹⁹ 100% of variant alleles in Chinese populations
Collie-Duguid et al. found 4.7% of Chinese individuals carried TPMT*3C vs 0.5% in Caucasians. Pharmacogenetics 1999, 7.6% of alleles in Ghanaians, and 52.2% of variant alleles in African Americans, but only 0.17-0.3% in European populations.

Practical Implications

If you carry one or two copies of TPMT*3C, you are at risk for severe, potentially fatal bone marrow toxicity if given standard doses of thiopurine medications. Patients homozygous for TPMT deficiency alleles¹⁰¹⁰ Patients homozygous for TPMT deficiency alleles
About 0.3% of most populations, but varies by ancestry experience life-threatening myelosuppression on standard doses, while heterozygotes have intermediate risk. The CPIC guideline recommends 30-70% dose reduction for intermediate metabolizers (one variant allele) and 90% dose reduction or alternative therapy for poor metabolizers (two variant alleles). Critically, these recommendations are supported by the FDA, which includes TPMT status in drug labeling for azathioprine, mercaptopurine, and thioguanine.

Genetic testing before starting thiopurine therapy is considered essential for drug safety¹¹¹¹ considered essential for drug safety
Dutch Pharmacogenetics Working Group (DPWG) designates pre-treatment genotyping as essential by multiple international guidelines. If you require immunosuppression or chemotherapy, knowing your TPMT genotype allows your physician to either prescribe alternative medications (such as mycophenolate for transplant patients or methotrexate for inflammatory bowel disease) or adjust the dose appropriately with close monitoring.

Interactions

TPMT*3C commonly occurs together with TPMT*3B (rs1800460) to form the TPMT*3A compound allele, which is the most common variant in Caucasian populations. If you carry both rs1142345(G) and rs1800460(A), you likely have TPMT*3A rather than *3C alone, though this requires haplotype phasing¹²¹² haplotype phasing
Most clinical labs cannot distinguish whether variants are on the same chromosome (cis) or different chromosomes (trans) to confirm. The related gene NUDT15 (particularly rs116855232) also affects thiopurine metabolism and is more common in East Asians; individuals with variants in both TPMT and NUDT15 require even more substantial dose reductions.

A critical interaction occurs with xanthine oxidase inhibitors like allopurinol (used for gout). Since allopurinol blocks one pathway for inactivating thiopurines, combining it with reduced TPMT activity creates a double-blockade effect¹³¹³ double-blockade effect
FDA warns against allopurinol-azathioprine combination; if necessary, reduce azathioprine to 25% of standard dose that requires azathioprine dose reduction to 25% of normal or avoidance of the combination entirely.