Association of Genetic Variants in NUDT15 With Thiopurine-Induced Myelosuppression in Patients With Inflammatory Bowel Disease

Abstract

IMPORTANCEUse of thiopurines may be limited by myelosuppression. TPMT pharmacogenetic testing identifies only 25% of at-risk patients of European ancestry. Among patients of East Asian ancestry, NUDT15 variants are associated with thiopurine-induced myelosuppression (TIM).OBJECTIVE To identify genetic variants associated with TIM among patients of European ancestry with inflammatory bowel disease (IBD). DESIGN, SETTING, AND PARTICIPANTSCase-control study of 491 patients affected by TIM and 679 thiopurine-tolerant unaffected patients who were recruited from 89 international sites between March 2012 and November 2015. Genome-wide association studies (GWAS) and exome-wide association studies (EWAS) were conducted in patients of European ancestry. The replication cohort comprised 73 patients affected by TIM and 840 thiopurine-tolerant unaffected patients. EXPOSURES Genetic variants associated with TIM.MAIN OUTCOMES AND MEASURES Thiopurine-induced myelosuppression, defined as a decline in absolute white blood cell count to 2.5 × 10 9 /L or less or a decline in absolute neutrophil cell count to 1.0 × 10 9 /L or less leading to a dose reduction or drug withdrawal. RESULTS Among 1077 patients (398 affected and 679 unaffected; median age at IBD diagnosis, 31.0 years [interquartile range, 21.2 to 44.1 years]; 540 [50%] women; 602 [56%] diagnosed as having Crohn disease), 919 (311 affected and 608 unaffected) were included in the GWAS analysis and 961 (328 affected and 633 unaffected) in the EWAS analysis. The GWAS analysis confirmed association of TPMT (chromosome 6, rs11969064) with TIM (30.5% [95/311] affected vs 16.4% [100/608] unaffected patients; odds ratio [OR], 2.3 [95% CI, 1.7 to 3.1], P = 5.2 × 10 −9 ). The EWAS analysis demonstrated an association with an in-frame deletion in NUDT15 (chromosome 13, rs746071566) and TIM (5.8% [19/328] affected vs 0.2% [1/633] unaffected patients; OR, 38.2 [95% CI, 5.1 to 286.1], P = 1.3 × 10 −8 ), which was replicated in a different cohort (2.7% [2/73] affected vs 0.2% [2/840] unaffected patients; OR, 11.8 [95% CI, 1.6 to 85.0], P = .03). Carriage of any of 3 coding NUDT15 variants was associated with an increased risk (OR, 27.3 [95% CI, 9.3 to 116.7], P = 1.1 × 10 −7 ) of TIM, independent of TPMT genotype and thiopurine dose.CONCLUSIONS AND RELEVANCE Among patients of European ancestry with IBD, variants in NUDT15 were associated with increased risk of TIM. 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.

Massive parallel variant characterization identifiesNUDT15alleles associated with thiopurine toxicity

“…In the crystal structure, these valine side chains strongly interact with the α1 helix to maintain the NUDIX domain conformation. In fact, a number of indel variants in this region also lead to unstable NUDT15 protein and are associated with thiopurine toxicity in patients 21,31 . Finally, we observed a significant over-representation of hotspot residues at the dimer interface of NUDT15, with 13 (30.9%) of 42 amino acid in this region extremely vulnerable to genetic variation in the abundancebased scree ( Fig.…”

“…subjects in previously published datasets 20,21,31,44,45 . The ALL cohort included US Children's 31 .…”

“…subjects in previously published datasets 20,21,31,44,45 . The ALL cohort included US Children's 31 . TPMT risk variants (e.g., rs1800462) were also genotyped as previously reported 20,21,31,44,45 , and cases carrying TPMT variants were excluded from further analysis.…”

“…The ALL cohort included US Children's 31 . TPMT risk variants (e.g., rs1800462) were also genotyped as previously reported 20,21,31,44,45 , and cases carrying TPMT variants were excluded from further analysis. This study was approved by the respective institutional review boards, and informed consent was obtained from the parents, guardians, and/or patients, as appropriate.…”

The Risk Ratio of Immune-Related Colitis, Hepatitis, and Pancreatitis in Patients With Solid Tumors Caused by PD-1/PD-L1 Inhibitors: A Systematic Review and Meta-Analysis

“…Immune-related digestive system inflammation, including colitis, hepatitis, pancreatitis, can be caused by a variety of pathogenic factors, such as genetic abnormality, autoimmune factors, immune-related drugs, viral infections, and so on (1)(2)(3)(4). PD-L1(B7-H1) is thought to be involved in the regulation of cellular and humoral immune responses through the PD-1 receptor on activated T and B cells (5,6).…”