Expressive

rs116855232 (NUDT15): Thiopurine Toxicity Risk

Key takeaways

  • Carriers of this NUDT15 variant face up to a 35.6-fold higher risk of severe white blood cell drops (leukopenia) when treated with thiopurine drugs like azathiopurine.
  • A simple codon 139 genotype test predicts this toxicity with over 91% accuracy in Korean patients, outperforming TPMT testing in East Asian populations.
  • The variant also predicts thiopurine-induced severe hair loss (alopecia) with near-perfect accuracy in Japanese IBD patients.
  • While most common in East Asian populations, the variant also significantly raises toxicity risk in European patients.
  • In Japanese children with leukemia receiving 6-mercaptopurine, this is the top genome-wide replicated genetic predictor of tolerable drug dose.

Key takeaways

  • Carriers of this NUDT15 variant face up to a 35.6-fold higher risk of severe white blood cell drops (leukopenia) when treated with thiopurine drugs like azathiopurine.
  • A simple codon 139 genotype test predicts this toxicity with over 91% accuracy in Korean patients, outperforming TPMT testing in East Asian populations.
  • The variant also predicts thiopurine-induced severe hair loss (alopecia) with near-perfect accuracy in Japanese IBD patients.
  • While most common in East Asian populations, the variant also significantly raises toxicity risk in European patients.
  • In Japanese children with leukemia receiving 6-mercaptopurine, this is the top genome-wide replicated genetic predictor of tolerable drug dose.

What the research says rs116855232 is a nonsynonymous SNP - a DNA change that alters the protein's amino acid sequence - in NUDT15 at chromosome 13q14.2, encoding the substitution of cysteine for arginine at position 139 (p.Arg139Cys); an Immunochip-based genome-wide association study (GWAS - a large-scale statistical scan linking genetic variants to a trait) in 978 Korean patients with Crohn's disease identified the variant as the dominant pharmacogenetic signal for early thiopurine-induced leukopenia (OR = 35.6; P = 4.88 × 10^-94), with sensitivity 89.4% and specificity 93.2%, compared with only 12.1% sensitivity for TPMT testing PMID 25599402. A multicenter Japanese study of 1,291 thiopurine-treated patients with inflammatory bowel disease (IBD) confirmed the locus's association with leukopenia (OR = 6.59; P = 2.20 × 10^-6³) and severe alopecia (OR = 12.1; P = 1.32 × 10^-69), finding that genotyping codon 139 alone matched full NUDT15 diplotype analysis in predictive accuracy (AUC 0.916 for acute severe leukopenia; AUC 0.990 for severe alopecia) PMID 30173346. A GWAS of 224 Japanese children with acute lymphoblastic leukemia (ALL) then identified the same variant as the only locus achieving genome-wide significance and independent replication for 6-mercaptopurine (6-MP) tolerable dose during maintenance therapy (β = −10.99) PMID 35491429.

Reported associations

  • Thiopurine-induced early leukopenia (Korean Crohn's disease; n = 978): OR = 35.6 (P = 4.88 × 10^-94); sensitivity 89.4%, specificity 93.2% PMID 25599402
  • Thiopurine-induced leukopenia (European IBD patients): OR = 9.50 (P = 4.64 × 10^-4); variant is rare in European populations but statistically significant PMID 25599402
  • Thiopurine-induced leukopenia (Japanese IBD; multicenter, n = 1,291 treated): OR = 6.59 (P = 2.20 × 10^-6³); carriers had shorter time to leukopenia onset and lower thiopurine doses at diagnosis PMID 30173346
  • Thiopurine-induced severe alopecia (Japanese IBD patients): OR = 12.1 (P = 1.32 × 10^-69) PMID 30173346
  • Thiopurine-induced digestive symptoms (Japanese IBD patients): OR = 1.89 (P = 6.39 × 10^-4); does not reach genome-wide significance and should be regarded as a preliminary finding pending replication PMID 30173346
  • 6-MP tolerable dose in Japanese children with ALL (n = 224 + 55 replication): genome-wide significant and replicated; β = −10.99 - the only locus exceeding genome-wide thresholds across five candidate gene regions tested PMID 35491429

Evidence quality The evidence supporting rs116855232 is among the strongest in pharmacogenomics. The discovery GWAS in 978 Korean Crohn's patients reached P = 4.88 × 10^-94 and included an independent replication cohort PMID 25599402. The multicenter MENDEL study, enrolling 2,630 Japanese IBD patients (1,291 thiopurine-treated), replicated the signal at P-values between 10^-6³ and 10^-69 for leukopenia and alopecia, and a concurrent GWAS of those same patients identified no additional genome-wide significant variants PMID 30173346. The digestive symptoms finding (OR = 1.89; P = 6.39 × 10^-4) is the weakest reported association and falls well below the genome-wide significance threshold. The ALL-focused GWAS replicated the 6-MP dose association in a combined cohort of 279 children, though the absolute sample size is modest for a GWAS PMID 35491429. A separate Korean IBD GWAS identified a distinct FTO coding variant (p.A134T; OR = 4.3) as an additional pharmacogenetic contributor to thiopurine-induced leukopenia, demonstrating that rs116855232, while dominant, does not explain all genetic susceptibility to this toxicity PMID 28011901. No findings across these studies directly conflict with one another.

Lifestyle considerations No lifestyle considerations on file for this variant.

Lifestyle context

Concrete actions anchored to the cited research. We do not prescribe, we describe.

Bloodwork

  • white blood cell count during thiopurine therapy High

    impaired NUDT15 enzyme activity causes toxic metabolite accumulation, increasing leukopenia risk primarily in first 8-12 weeks

    weekly WBC monitoring for first 12 weeks of thiopurine therapy, then monthly if continuing

Discuss with your doctor

  • azathioprine and 6-mercaptopurine if Cys/Cys genotype High

    homozygous Cys/Cys carriers have 67.3% risk of acute severe leukopenia and fall below clinical safety threshold for thiopurine use

    discuss alternative immunosuppressive agents with physician; thiopurines contraindicated in Cys/Cys genotype

  • thiopurine dosing based on NUDT15 genotype High

    rs116855232 impairs NUDT15 enzyme activity, reducing thiopurine metabolism and allowing toxic metabolite accumulation

    if prescribed azathioprine or 6-mercaptopurine, discuss rs116855232 genotype with physician for dose adjustment

Frequently asked questions

What does the NUDT15 gene do?

NUDT15 encodes an enzyme involved in processing byproducts of thiopurine drugs like azathiopurine and 6-mercaptopurine. When functioning normally, it prevents toxic metabolites from accumulating in cells. The p.Arg139Cys change caused by rs116855232 is thought to impair this protective activity.

What is rs116855232 and what does it affect?

rs116855232 is a DNA variant in NUDT15 that changes one amino acid in the protein from arginine to cysteine at position 139. Multiple large studies show this change is strongly associated with severe toxicity - including white blood cell loss and hair loss - when patients take thiopurine drugs.

Is rs116855232 linked to leukopenia from azathiopurine?

Yes. Multiple large studies consistently show carriers have substantially higher rates of severe leukopenia during thiopurine therapy. In Korean Crohn's disease patients the odds ratio was 35.6, and in a large Japanese IBD multicenter cohort it was 6.59. The association has been replicated across populations.

Is this variant only relevant to East Asian populations?

No. While more prevalent in East Asian populations, research has found a significant association with thiopurine-induced leukopenia in European IBD patients as well, at an odds ratio of 9.50. The variant's effects in European populations are real, but the variant itself is rarer there.

Can genotyping NUDT15 reliably predict thiopurine toxicity?

Research in Japanese IBD patients shows that genotyping codon 139 alone achieves an AUC of 0.916 for predicting acute severe leukopenia and 0.990 for severe hair loss, statistically equivalent to more complex full diplotype analysis. In Korean patients the sensitivity was 89.4% and specificity 93.2%.