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New IBD Adverse Drug Response Risk Gene Identified

NEW YORK (GenomeWeb) – An international team led by investigators at the University of Exeter has uncovered genetic variants in a gene called NUDT15 that seem to coincide with treatment-related complications in individuals of European ancestry with inflammatory bowel disease (IBD).

"These findings suggest that NUDT15 genotyping may be considered prior to initiation of thiopurine therapy," first author Gareth Walker, a gastroenterology and pharmacogenetics researcher at Royal Devon and Exeter Hospital and the University of Exeter, and his colleagues wrote, though they cautioned that "further study including additional validation in independent cohorts is required."

Variants in the same nudix hydrolase 25 enzyme-coding gene have been implicated in similar conditions in individuals from East-Asian and other populations, the authors noted.

For their analysis, appearing online today in the Journal of the American Medical Association, the researchers used a genome-wide association study and an exome-wide association study to search for variants contributing to an adverse drug condition called thiopurine-induced myelosuppression in hundreds of IBD patients assessed at dozens of sites internationally from spring 2012 to November 2015 — a group that included 398 IBD patients with thiopurine-induced myelosuppression and 679 IBD patients that were tolerant to the thiopurine treatment.

Roughly 15 percent of IBD patients treated with thiopurines such as mercaptopurine experience adverse drug responses that require them to discontinue treatment, the team explained. For example, past studies suggest that genetic variants in a TPMT gene coding for a thiopurine S-methyltransferase enzyme are involved in producing methylated, less active metabolites from thiopurine drugs.

"Pre-treatment testing of TPMT is recommended by the US Food and Drug Administration to identify patient at risk of [thiopurine-induced myelosuppression]," the authors noted, though such variants turn up in just one-quarter of IBD patients with European ancestry, "suggesting the presence of other genetic and environmental determinants."

As part of an International Serious Adverse Event Consortium-funded effort, the researchers searched for such contributors using the Illumina Infinium arrays to genotype 311 IBD patients with and 608 without thiopurine-induced myelosuppression at nearly 245,200 variants. They perform an exome-wide association study in parallel, focusing on 328 thiopurine-induced myelosuppression-affected and 633-unaffected IBD patients.

Although the individuals all had European ancestry, the authors noted that they excluded IBD cases from Finland since "their unique genetic background, which has occurred as a consequence of geographical and cultural isolation, has led to the enrichment of some disease-causing gene variants and losses of others."

The team's GWAS verified a known association for a TPMT SNP and drug-induced myelosuppression, marked by a significant drop in individuals' absolute white blood cell and/or neutrophil cell counts that necessitated a lower dose or discontinuation of the thiopurine drug treatment. The EWAS, meanwhile, highlighted an association involving an in-frame NUDT15 deletion called rs746071566.

In a replication cohort that included 73 IBD patients with thiopurine-induced myelosuppression and 840 IBD patients that did not experience the adverse drug event, the investigators found that risky NUDT15 coding variants turned up in some 2.7 percent of thiopurine-induced myelosuppression-affected patients but just 0.2 percent of unaffected patients. 

"We hope that once a predictive test is developed, patients will be able to have a simple blood test before starting these drugs," Walker said in a statement. "This will allow doctors to modify treatments, either by reducing the dose or opting for different treatment altogether."

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