Genetic variants in NUDT15 associated with increased risk of thiopurine-induced myelosuppression

1. In this case-control study of patients of European ancestry with inflammatory bowel disease (IBD), variants in NUDT15 were associated with an increased risk of thiopurine-induced myelosuppression (TIM).

2. There were no sex-based differences in these genetic variants nor were there any differences based on IBD type.

Evidence Rating Level: 2 (Good)

Study Rundown: Thiopurine-induced myelosuppression (TIM) is an adverse drug reaction that occurs in approximately ten percent of patients who receive thiopurines for the management of inflammatory bowel disease (IBD). Currently, the FDA recommends genetic screening for the thiopurine S-methyltransferase (TPMT) gene prior to the initiation of thiopurine-based therapy. In this case-control study, IBD patients of European ancestry that had both the TPMT and the nudix hydrolase 15 (NUDT15) genes had an increased likelihood for developing TIM. For patients with the TPMT genetic variant, they were three times as likely to develop TIM while those with the NUDT15 genetic variant were thirty-eight times as likely to develop TIM. When patients had both genetic variants, they were significantly more likely to develop neutropenia, be hospitalized, and to have received granulocyte-colony stimulating factor rescue therapy. There were no sex-based differences in these genetic variants nor were there any differences based on IBD type.

While this study highlights some important applications of precision medicine, its conclusions are currently limited to patients of European ancestry. In order to more broadly apply these findings, these genetic variants should be studied in additional patient populations in order to increase the generalizability of these findings.

Click to read the study, published today in JAMA

Relevant Reading: Thiopurine-induced myleotoxicity in patients with inflammatory bowel disease: a review

In-Depth [case-control study]: In this study, patients affected (n= 491) and unaffected (n= 679) with TIM were recruited from 82 sites within the UK and from 7 sites outside the UK from March 2012 to November 2015. Genome-wide association studies (GWAS) and exome-wide association studies (EWAS) were conducted to identify genetic variants associated TIM in patients with IBD. There were no sex-based differences between affected and unaffected patients (p= 0.17). Additionally, there were no differences between the two groups based on type of IBD diagnosis (Crohn’s disease, ulcerative colitis, and IBD-unclassified; p=0.12). For patients who were affected by TIM, they tended to be significantly younger at IBD diagnosis (median 30.1 years vs. 31.6 years; p= 0.02) and had received a significantly higher weight-based dose of thiopurine-based therapy (median 2.07 mg/kg vs. 1.84 mg/kg; p= <0.001). In GWAS, patients with a thiopurine S-methyltransferase (TPMT) variant were 3.2 times more likely to develop TIM (p= 5.2 x 10^-9). The number needed to test to prevent one case of TIM for this variant is 123. In EWAS an exon mutation in nudix hydrolase 15 (NUDT15) was associated with a 38.2 times increased likelihood of developing TIM and those with early onset TIM were significantly enriched for this variant (OR 3.6; p= 0.005). The number needed to test to prevent one case of TIM for this genetic variant is 95. Overall, patients with either NUDT15 or TMPT variants were significantly more likely to develop neutropenia (p <0.001), be admitted to the hospital (p= <0.001), and to receive granulocyte colony-stimulating factor rescue therapy (p <0.001).

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