NUDT15 variants linked to thiopurine-induced myelosuppression

Last Updated: 2019-02-27

By Will Boggs MD

NEW YORK (Reuters Health) - Genetic variants in NUDT15, along with those previously identified in TPMT, are associated with thiopurine-induced myelosuppression (TIM) in patients with inflammatory bowel disease (IBD), according to findings from the IBD Pharmacogenetics Study Group.

"We have found that NUDT15 variants (previously thought to be important in East Asians only) predict myelosuppression to thiopurines in European populations," Dr. Tariq Ahmad from Royal Devon and Exeter Hospital, in England, told Reuters Health by email.

Genetic variation in the TPMT gene decreases TPMT enzyme activity and increases production of active methylated metabolites, predisposing patients to bone marrow suppression, but these variants are found in only 25% of patients of European ancestry affected by TIM. Studies in patients of East Asian ancestry have also identified variants in NUDT15 as risk factors for TIM.

Dr. Ahmad and colleagues investigated the association between genetic variants and TIM using genome-wide association studies (GWAS) and exome-wide association studies (EWAS) of 398 patients with IBD and TIM and 679 thiopurine-exposed patients with IBD and no history of TIM.

Nearly a third (30.5%) of affected patients had a variant in TPMT, compared with 16.4% of unaffected patients, the researchers report in the February 26 issue of JAMA.

One variant of NUDT15, a six-base-pair in-frame deletion at position 48611918 of chromosome 13 in exon 1, was present in 5.8% of the affected patients, compared with only 0.2% of unaffected patients, a highly significant difference. This represented a 74.2-fold increase in the odds of early-onset TIM and a 20.9-fold increase in the odds of late-onset TIM in patients with this variant.

The median time to TIM was significantly shorter in affected patients who carried NUDT15 variants (7.7 weeks) than in those without risk variants (20.0 weeks). This was also true of affected patients who carried double TPMT variants (6.1 weeks) relative to those without TPMT variants (20.0 weeks).

The median time to TIM was shortest in patients with both genetic variants (2.5 weeks).

Patients with variants of either gene or both genes also had more severe TIM and a greater need for granulocyte colony-stimulating factor rescue therapy.

The estimated number of patients needed to genotype to prevent one patient from developing TIM was 95 for NUDT15 and 123 for TPMT.

"In the U.K., we will implement these findings into clinical practice in 2 stages: A) We will immediately report NUDT15 genotypes to clinicians of IBD patients who already have genome sequence data, and B) Pretreatment testing of NUDT15 is likely to be commissioned by the National Health Service (NHS) and added to the NHS Genomics test directory for roll out across the U.K.," Dr. Ahmad said.

"Consider NUDT15 testing in all ethnic groups prior to starting azathioprine or mercaptopurine," he said. "Cost of genetic testing is considerably more expensive in the U.S. than in the U.K., and the cost-effectiveness may have to be considered more carefully."

Dr. Ahmad added, "Many adverse drug reactions (ADRs) are likely to have a genetic basis. Unraveling drug-gene pairs is not difficult if you have sufficient numbers of affected patients to study. Systematic recruitment of all patients with ADRs into genetic studies could help deliver the promise of personalized medicine."

SOURCE: https://bit.ly/2NzUWkw

JAMA 2019.