NUDT15 rs36056065: Thiopurine Response and Risk

What each genotype means

Genetic Identity and Molecular Nature of rs36056065

The variant rs36056065 represents an insertion polymorphism in the coding region of the NUDT15 gene, which resides on the short arm of chromosome 13 (13q14.2). At the molecular level, it involves an in-frame insertion of six nucleotides (c.55_56insGAGTCG), resulting in the addition of two amino acids (p.Gly18_Val19insGlyVal) within the encoded nudix hydrolase 15 enzyme. In pharmacogenetic nomenclature standardized by the Pharmacogene Variation Consortium (PharmVar), this insertion defines the core marker for the NUDT15*6 star allele. Unlike single-nucleotide missense substitutions that alter a single amino acid, this structural addition directly alters the polypeptide chain near the enzyme's catalytic core. Research cataloged in pharmacogenomic resources such as the [Clinical Pharmacogenetics Implementation Consortium (CPIC)](https://cpicpgx.org) and [PharmGKB](https://www.pharmgkb.org/gene/PA166156543) classifies the *6 haplotype as an intermediate-function or reduced-function allele, distinct from full loss-of-function variants like NUDT15*3 but still biologically impactful.

The Biological Role of NUDT15 in Drug Detoxification

NUDT15 encodes a nudix hydrolase family enzyme responsible for sanitizing oxidized or modified nucleotide pools. In clinical pharmacogenomics, its most significant known function is the detoxification of thiopurine antimetabolites, including azathioprine, 6-mercaptopurine, and 6-thioguanine. These medications are widely prescribed for conditions such as inflammatory bowel disease, autoimmune disorders, and acute lymphoblastic leukemia. During cellular metabolism, thiopurines convert into active thioguanine triphosphates (TGTP and TdGTP), which insert into cellular RNA and DNA, halting rapid replication. NUDT15 acts as a cellular brake by hydrolyzing TGTP and TdGTP back to monophosphates, preventing excessive incorporation into the genome. When variants such as rs36056065 impair normal NUDT15 function, toxic metabolites accumulate rapidly in hematopoietic tissues. This molecular overload leads directly to premature leukocyte death, resulting in clinically dangerous cytopenias.

Clinical Evidence and Association with Myelosuppression

Historically, early clinical guidelines focused exclusively on TPMT testing to avoid thiopurine toxicities, but studies in non-European cohorts revealed that NUDT15 variants account for a substantial portion of hematologic adverse reactions, as detailed in reviews on [thiopurine therapy and NUDT15](https://www.mdpi.com/2076-3271/13/3/112). Observational studies and systematic reviews indexed in [PubMed](https://pubmed.ncbi.nlm.nih.gov/?term=NUDT15+rs36056065) demonstrate that individuals harboring NUDT15 reduced-function alleles face significantly increased odds of early-onset leukopenia, neutropenia, and alopecia. The rs36056065 insertion specifically results in an intermediate-activity phenotype. When combined with a standard normal-function allele (*1/*6), patients exhibit decreased drug tolerance compared to the wild-type population, though the myelotoxic risk is generally less pronounced than that seen with homozygous null alleles like *3/*3. Because empirical data on rs36056065 is drawn from smaller cohorts relative to the primary *3 variant, professional bodies categorize its direct evidence strength as limited to moderate.

Ancestral Diversity and Allele Distribution

The frequency of rs36056065 exhibits notable population-specific stratification. In East Asian populations and individuals of admixed American (Hispanic) and Indigenous American ancestry, the minor allele frequency (MAF) is observed at approximately 1% to 2% (0.01–0.02). Conversely, large-scale genomic databases like [gnomAD](https://gnomad.broadinstitute.org) demonstrate that this specific insertion is exceedingly rare or virtually absent in individuals of unadmixed European and African ancestries. This stark divergence explains why NUDT15 testing has emerged as a cornerstone of personalized prescribing protocols in East Asia and parts of the Americas, whereas European clinical practice historically relied primarily on TPMT screening. Comprehensive multi-ethnic clinical panels have since recognized this distribution, leading expert groups to recommend broader inclusion of diverse NUDT15 alleles to ensure equitable safety assessments across all genetic backgrounds.

Clinical Utility and Next Steps for Patients

Genetic knowledge of rs36056065 is an informative risk factor rather than a medical diagnosis. A genotype report indicating the presence of this insertion does not guarantee that severe adverse drug reactions will occur, nor does an absence of the variant eliminate all potential side effects. Clinical pharmacogenetics implementation guidelines, such as those published by CPIC and the Association for Molecular Pathology, suggest that patients identified as intermediate or poor metabolizers may benefit from proactive dose reductions of thiopurine medications or consideration of alternate immunosuppressants. However, genotype results should never prompt self-directed changes in medication regimens. Any patient prescribed azathioprine or mercaptopurine who has questions regarding their NUDT15 status should review their laboratory findings directly with a treating physician, oncologist, or specialized pharmacogenomics pharmacist.

Frequently asked questions

Sources & further reading

Related variants in NUDT15