Mutations in the NUDT15 gene may predict predisposition to side effects of immunosuppressants — substances that change the function of the immune system — in European patients with inflammatory bowel disease (IBD), a study suggests.
The development of a test that can show whether a patient has one of the mutations might improve management of the condition.
The study, “Association of Genetic Variants in NUDT15 With Thiopurine-Induced Myelosuppression in Patients With Inflammatory Bowel Disease,” was published in the Journal of the American Medical Association (JAMA).
IBD has two main forms — Crohn’s disease and ulcerative colitis. Both are autoimmune disorders in which the body attacks its own microflora, resulting in inflammation of the digestive tract. Currently, there is no cure for these conditions; common treatments include immunomodulators and anti-inflammatory therapies.
Thiopurines, such as azathioprine and 6-mercaptopurine, are immunomodulators commonly used in the treatment of IBD and other inflammatory and autoimmune disorders.
Approximately 7% of patients develop an adverse reaction to thiopurines, called bone marrow suppression, in which the white blood cell count drops significantly, making the patient more susceptible to infections.
Mutations in the TPMT gene, which holds the instructions to produce a protein that degrades toxic products of thiopurines, are known risk factors. Currently, doctors perform genetic tests before starting treatment to avoid prescribing thiopurines to patients with mutations in the TPMT gene.
However, these mutations only account for a quarter of the patients who develop bone marrow suppression, indicating that other genes may play a role
In a NHS research collaboration, researchers recruited IBD patients of European ancestry at 89 centers in Europe, New Zealand, Australia, South Africa, and Canada to investigate genes associated with bone marrow suppression.
They analyzed the DNA of 491 IBD patients who developed thiopurine-induced bone marrow suppression and 679 IBD patients treated with thiopurines who showed no side effects and discovered an association between three variants of a gene called NUDT15 and bone marrow suppression. This association was found to be independent of TPMT variant and thiopurine dose.
Just like TPMT, NUDT15 holds the instructions to produce a protein that degrades the products of thiopurines, thus avoiding toxicity. Mutations in NUDT15 had previously been described as a risk factor, but were thought to be significant only in people of East Asian descent.
“In the largest genetic analysis into the side effects of thiopurine drugs we’ve discovered variations in a gene that can help us identify who is susceptible to thiopurine-induced bone marrow suppression,” Tariq Ahmad, PhD at England’s University of Exeter Medical School and chief investigator of the study, said in a press release.
“In line with the [National Health Service’s] 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.”
Considering potential side effects might be as important as recognizing disease symptoms during the treatment of long-lasting, complex diseases such as IBD.
“Personalizing medicine according to a person’s genetics will hopefully allow doctors to treat their patients in a safer, more effective manner,” lead author Gareth Walker, MD, of the University of Exeter, said.
“We hope that once a predictive test is developed, patients will be able to have a simple blood test before starting these drugs. This will allow doctors to modify treatments, either by reducing the dose or opting for different treatment altogether.”
Further studies considering the relevance of NUDT15 in people of various ethnicities would further validate the results of the study and improve the treatment of IBD patients.
“These findings suggest that NUDT15 genotyping may be considered prior to initiation of thiopurine therapy; however, further study including additional validation in independent cohorts is required,” the researchers said.
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