Clear case for NUDT15 genetic testing in Asian patients with IBD

A study into the clinical utility of NUDT15 pharmacogenetic testing showed that NUDT15 variant carriage was associated with an increased risk of thiopurine-induced myelosuppression and severe myelosuppression. The authors made a clear case for NUDT15 testing among East and South Asian patients with inflammatory bowel disease (IBD).

Dr Chris Roberts (University of Exeter, UK) and co-investigators evaluated the utility of NUDT15 genotyping by assessing the link between NUDT15 carriage and thiopurine-induced myelosuppression [1]. The research team screened 23,081 participants of the IBD BioResource and identified 239 thiopurine-exposed individuals with NUDT15 variants and matched them with 1,570 thiopurine-exposed individuals with wildtype NUDT15 and TPMT.

East Asians (21.7%) and South Asians (13.6%) were more likely to carry any NUDT15 variants than Europeans (1.3%) or Africans (1.6%). Thiopurine-induced myelosuppression was documented in 78 (32.6%) individuals in the NUDT15 carrier group and in 115 (13.7%) individuals in the NUDT15 wildtype group (OR 3.1; 95% CI 2.2–4.3; P<0.001). “The more clinically relevant ‘severe myelosuppression’ was reported in 11.3% and 1.0% of the patients, disfavouring the NUDT15 carriers (OR 13.3; 95% CI 6.2–31.6; P<0.001),” noted Dr Roberts. “Myelosuppression-related hospitalisations were documented in 2.9% and 0.1% of the patients” (OR 7.0; 95% CI 1.0–142.6; P=0.07).

Furthermore, the number needed to genotype to prevent a single case of thiopurine-associated myelosuppression was 786 in the European population but only 29 in the South Asian population. “There is therefore a clear case for NUDT15 testing among East and South Asian individuals,” argued Dr Roberts. “Also, we recommend simultaneous NUDT15 and TPMT genotyping because of the severe myelosuppression that can be seen in patients who carry variants of both these genes.”

Dr Roberts recommended the following thiopurine dosage for NUDT15 carriers:

• In wildtype NUDT15 and TPMT: 2.0–2.5 mg/kg/day.
• In NUDT15 heterozygotes: dose reduction by 50% or alternative therapy.
• In NUDT15 homozygotes or compound heterozygotes: thiopurine avoidance.
• In NUDT15 and TPMT heterozygotes: thiopurine avoidance.

1. Roberts C, et al. Exploring the potential clinical utility of NUDT15 pharmacogenetic testing in clinical practice: a ‘focused reverse phenotyping’ study in the UK IBD Bioresource. OP11, 19^th Congress of ECCO, 21–24 February 2024, Stockholm, Sweden.

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Posted on 18 April 2024