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Genetic Test Could Improve Safety of Thiopurine Treatment in IBD
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Researchers from the University of Exeter in the United Kingdom discovered a genetic variant that could potentially make thiopurine therapy safer for patients with inflammatory bowel disease.
Tariq Ahmad, DPhil, of the Exeter IBD Group and the Royal Devon and Exeter Hospital NHS Foundation Trust, and colleagues found that variations in the NUDT15 gene can help identify patients at higher risk for thiopurine-induced bone marrow suppression.
“In line with the NHS 10-year plan to increase personalized medicine, testing for this genetic abnormality prior to prescribing thiopurine drugs will reduce the risks to patients, and costs to the NHS, associated with this potentially serious drug side effect,” Ahmad said in a press release. “Working with patients and clinicians from across the U.K., we have shown the power of the NHS to deliver clinically meaningful genetic research outcomes.”
Researchers wrote that previous studies have shown that the TPMT gene predisposes patients to bone marrow suppression, which occurs in approximately 7% of patients who receive thiopurine treatment. However, not all patients who experience bone marrow suppression have the TPMT gene.
Ahmad and colleagues conducted a study comprising nearly 500 patients with IBD who experienced bone marrow suppression and 679 patients with IBD without bone marrow suppression as controls recruited from 89 international sites between 2012 and 2015 to identify other genetic variants associated with thiopurine-induced bone marrow suppression.
Researchers conducted genome-wide (311 cases, 608 controls) and exome-wide (328 cases, 633 controls) association studies to find associations.
The genome-wide analysis confirmed the association of TPMT variants with bone marrow suppression (32.4% cases vs. 16.8% controls; OR = 24; 95% CI, 1.8–3.1), while the exome-wide analysis revealed a novel association with an in-frame deletion of NUDT15 and bone marrow suppression (5.8% cases vs. 0.2% controls; OR = 38.2; 95% CI, 5.1–286.1). Investigators replicated this finding in an independent cohort (2.7% cases vs. 0.2% controls; OR = 11.8; 95% CI, 1.6–85).
Patients who had a NUDT15 variant were at increased risk independent of TPMT genotype and thiopurine dose.
Gareth Walker, MBBS, also of the Exeter IBD Group, said their findings could lead to more personalized medicine for patients with IBD.
“We hope that once a predictive test is developed, patients will be able to have a simple blood test before starting these drugs,” he said in the release. “This will allow doctors to modify treatments, either by reducing the dose or opting for different treatment altogether.” – by Alex Young
Disclosures: Ahmad reports receiving research grants, advisory board fees, speaker honorariums and support to attend international meetings from AbbVie, Celltrion, Ferring, Janssen, Merck, NAPP, Pfizer, Takeda and Tillots for unrelated topics. Walker reports consulting for AbbVie and receiving honoria from AbbVie and Falk for unrelated topics. Please see the full study for all other authors’ relevant financial disclosures.
Perspective
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Miguel Regueiro, MD
The NUDT15 genotype has been recognized as being deficient at an increased rate in the Asian population. Studies have shown that despite a normal TPMT, the NUDT15 mutation in Asians conferred a higher risk for myelosuppression when placed on thiopurines (6MP or azathioprine). This study evaluated the gene in the European population and found that in those patients with the NUDT15 mutation, there was increased risk for myelosuppression.
This is important for several reasons:
- The NUDT15 gene mutation may be found in populations other than Asians (this study showed it in Europeans);
- Even if the TPMT is normal, which is the current assay measured prior to starting thiopurines, myelosuppression may occur in the NUDT15 mutation; and
- The clinical relevance is that the NUDT15 may be incorporated into practice and along with measurement of TPMT would be a test to measure before starting 6MP or azathioprine. At this point, we do not routinely check this, but I have had patients with unexplained myelosuppression to 6MP in whom I have sent the NUDT15 and found it mutated. We usually switch away from 6MP in these patients anyway, so the question remains whether this will be commercially available as a screening test. If so, in the future we may opt not to give thiopurines (or lower doses) to the NUDT15 absent patients.
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