Editorial: LAMP Lights the Way—A Pragmatic Case for NUDT15 Screening Across Diverse Populations—Authors' Reply

Résumé fourni par la source

We thank Drs. Shah and Desai for their editorial [1] discussing our study [2]. Translation of pharmacogenetic biomarkers to the clinic is complex. The burden on central laboratories of testing and the cost of current methods mandates evidence of cost-effectiveness. Critically, data on variant allele penetrance and expressivity cannot be derived from classical gene discovery studies because of recall bias inherent to phenotype-first designs. We used a reverse-phenotype, or genotype-first, retrospective case-matched cohort design to define the prevalence, penetrance and expressivity of NUDT15 variant carriage and the cost-effectiveness of an inexpensive loop-mediated isothermal amplification (LAMP) assay. The UK National Institute for Health and Care Research IBD Bioresource is a panel of recallable patients with IBD and genetic data, which enables variant screening. We showed that 1.3% of Europeans and 11.7% of South Asians carried a confirmed or suspected loss-of-function NUDT15 variant (*2, *3, *4, *5, *6, *9). Each case was then matched based on ancestry and recruiting hospital to three patients without loss-of-function NUDT15/TPMT variant alleles. Local research teams collected data on thiopurine treatment and myelosuppression outcomes. Severe myelosuppression was associated with NUDT15 variant allele carriage. Carriage of a single *3, *6 or *9 variant allele was associated with a shorter time to severe myelosuppression. The number needed to genotype to prevent severe myelosuppression in South Asians was 23 [95% CI 16–36]; in Europeans, it was 786 [95% CI 451–3045]. However, even using an inexpensive LAMP assay that could be undertaken in local hospital laboratories, NUDT15 testing was not cost-effective in either group. This reflects the relatively low prevalence and penetrance of NUDT15 variant alleles with the low thiopurine doses used in IBD clinical practice and the need for alternative, more expensive treatments in patients who carry a NUDT15 variant. This incomplete penetrance partly explains the differences between this and previous cost-effectiveness models, which assumed full NUDT15 penetrance [3, 4]. So, what is the role of NUDT15 testing in the UK? International guidelines recommend pre-treatment TPMT function or genetic testing to determine if thiopurines are safe to use and to guide initial dosing. Arguably, based on carriage rates of TPMT (9.1 vs. 3.7%) and NUDT15 (0.7 vs. 7%) in Europeans and South Asians, respectively [5], we have been testing the wrong gene in South Asian patients living in the UK for the last 20 years. For now, NUDT15 testing in Europeans should be reserved for patients with reduced TPMT activity or loss-of-function genotypes because of the potentially catastrophic consequences of thiopurine use in patients with variants in both TPMT and NUDT15 [6]. Patients of admixed ancestry will also need both NUDT15 and TPMT testing. Current guidelines recommend eight blood tests in the first year of thiopurine usage [7]. Pre-treatment testing would also allow the identification of patients at very low risk of severe myelosuppression, in whom the frequency of tests could be safely reduced. The significant additional cost savings from a reduced monitoring schedule could be used to fund pre-treatment NUDT15 and TPMT testing and increase the safety of thiopurine therapy for all. The authors' declarations of personal and financial interests are unchanged from those in the original article [2]. Chris Roberts: conceptualization, writing – original draft, writing – review and editing. James R. Goodhand: conceptualization, writing – original draft, writing – review and editing, supervision. Tariq Ahmad: writing – review and editing, conceptualization, supervision. This article is linked to Roberts et al papers. To view these articles, visit https://doi.org/10.1111/apt.70232 and https://doi.org/10.1111/apt.70260. Data sharing is not applicable to this article as no new data were created or analyzed in this study.

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