Gene-drug interactions (data source: DGIdb)
Gene Name Entrez ID Drug Name Chembl ID Interaction Types Sources publications

Variant-drug associations (data source: PharmGKB)
Gene Name Variant Alleles Chemical Phenotype Category Significance Notes Sentence Publications Annotation ID
NUDT15 rs116855232 TT mercaptopurine dosage yes Decreased dosage was likely to be due to increased toxicity. The authors also calculated a genetic risk score based on genotype at rs1142345 and at rs116855232. Patients who were homozygous wild-type at both SNPs had the lowest genetic risk score and patients who were homozygous for the variant allele at either SNP had the highest genetic risk score. There was an inverse significant association between genetic risk score and dose reduction of mercaptopurine. Genotype TT is associated with decreased dose of mercaptopurine in children with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to genotypes CC + CT. 25624441 1444703361
NUDT15 rs116855232 CT + TT mercaptopurine dosage yes Carriers of the T allele had an increased likelihood of dose reduction as compared to those with the CC genotype. Average mercaptopurine doses during maintenance therapy were 40.7 mg/m2 for the CC genotype, 29.3 for the CT genotype and 8.8 for the TT genotype. Genotypes CT + TT is associated with decreased dose of mercaptopurine in children with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to genotype CC. 26033531 1447682626
NUDT15 rs116855232 CT + TT mercaptopurine other no No significant association was seen between the genotypes and therapy interruption. Genotypes CT + TT is not associated with discontinuation of mercaptopurine in children with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to genotype CC. 26033531 1447682637
NUDT15 rs116855232 T mercaptopurine dosage yes Children with very high-risk acute lymphoblastic leukemia (ALL) were excluded. Remaining patients had standard- or high-risk ALL. The maximal tolerable daily doses of mercaptopurine in the TT, CT and CC genotypes were 9.4, 30.7 and 44.1mg/m2, respectively. Allele T is associated with decreased dose of mercaptopurine in children with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to allele C. 26503813 1447682776
NUDT15 NUDT15*1, NUDT15*2, NUDT15*3, NUDT15*4, NUDT15*5 *1/*1 mercaptopurine dosage yes Patients were classified into three diplotypic groups: normal activity (*1/*1), intermediate activity (*1/*2, *1/*3, *1/*4, *1/*5) and low activity (*2/*3, *3/*3, *3/*5). Across three cohorts (Guatemalan, Singaporean, Japanese), and in a meta-analysis of the three cohorts, the tolerated mercaptopurine dose (mg/m2) was highest in those with normal activity, followed by intermediate activity and low activity. Note that those with the *1/*2 and *1/*3 diplotypes had similar degree of mercaptopurine tolerance, and compound-heterozygous genotypes had a similar degree of tolerance compared to homozygotes (*3/*3). NUDT15 *1/*1 (assigned as high activity phenotype) is associated with increased dose of mercaptopurine in children with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to NUDT15 *1/*2 + *1/*3 + *1/*4 + *1/*5 + *3/*3 + *3/*5 + *2/*3 (assigned as intermediate and low activity phenotype) . 26878724 1447945037
NUDT15 NUDT15*1, NUDT15*2, NUDT15*3, NUDT15*5 *1/*1 mercaptopurine metabolism/PK yes NUDT15 converts thioguanosine triphosphate (TGTP) into thioguanosine monophosphate (TGMP), preventing the incorporation of thiopurine metabolites into DNA (DNA-TG), and thereby negatively regulating thiopurine activation and resulting cytotoxicity. The ratio of DNA-TG (in white blood cells) to mercaptopurine dosage was assessed (that is, the amount of DNA-TG converted from every unit mercaptopurine dose). Two cohorts were used: Singaporean and Japanese. Those with the *1/*1 genotype (normal activity) had the lowest ratio, followed by those with *1/*3 or *1/*5 genotype (intermediate activity) and then the *2/*3, *3/*3 or *3/*5 genotype (low activity). NUDT15 *1/*1 (assigned as high activity phenotype) is associated with increased metabolism of mercaptopurine in children with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to NUDT15 *1/*3 + *1/*5 + *2/*3 + *3/*3 + *3/*5 (assigned as intermediate and low activity phenotype) . 26878724 1447945146
NUDT15 rs116855232 CT mercaptopurine dosage not stated The average dose of mercaptopurine was 22.3 mg/m2 per day in those with the CT genotype and 32.7 mg/m2 per day in those with the CC genotype. This was only significant in children <7 years old, when considering all children in the study (n=51; age range 1.6 - 15.8) or children >7 years old (n= 20) there was no statistically significant difference between patients with the CT and CC genotype (p=0.27 and p=0.42, respectively). No significant difference was seen in hematological toxicity or hepatotoxicity, or in relapse rate. Genotype CT is associated with decreased dose of mercaptopurine in children with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to genotype CC. 27193222 1447989974
NUDT15 rs116855232 CT mercaptopurine dosage yes One patient had the CT genotype and tolerated only 33.33% of the planned mercaptopurine dose, a statistically significant difference from the median-tolerated dose in the rest of the cohort (in those who did not carry this variant: 74%, in those who did not carry this variant OR TPMT*3A: 76%). Genotype CT is associated with decreased dose of mercaptopurine in children with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to genotype CC. 27577869 1448260651
NUDT15 NUDT15*1, NUDT15*2, NUDT15*3, NUDT15*5 *1/*2 + *1/*3 + *1/*5 mercaptopurine toxicity yes The mean mercaptopurine (MP) dosages were 48.0 ± 21.2, 34.1 ± 17.0, and 3.2 ± 1.2 mg/m2 for the normal-activity (*1/*1 n=44), intermediate-activity (*1/*2 + *1/*3 + *1/*5 n=10), and low-activity (*2/*3 n=1) NUDT15 groups, respectively (P = 4.8×10-4). TGN (thioguanine nucleotides, not further specified) levels was correlated negatively with the number of NUDT15 risk alleles (P=5.3×10-6) and this association remained significant after adjusting for MP dosage (P = 1.7 × 10 - 6). NUDT15 *1/*2 + *1/*3 + *1/*5 are associated with decreased dose of mercaptopurine in children with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to NUDT15 *1/*1. 28445187 1448624581
NUDT15 NUDT15*1, NUDT15*2, NUDT15*3 *2/*3 mercaptopurine toxicity yes The mean mercaptopurine (MP) dosages were 48.0 ± 21.2, 34.1 ± 17.0, and 3.2 ± 1.2 mg/m2 for the normal-activity (*1/*1 n=44), intermediate-activity (*1/*2 + *1/*3 + *1/*5 n=10), and low-activity (*2/*3 n=1) NUDT15 groups, respectively (P =4.8×10-4). TGN (thioguanine nucleotides, not further specified) levels was correlated negatively with the number of NUDT15 risk alleles (P=5.3×10-6) and this association remained significant after adjusting for MP dosage (P = 1.7 × 10 - 6). The ratio of DNA-TG to TGN (i.e. the percent of TGN converted to DNA-TG) was significantly higher in NUDT15-deficient patients (P=3.6× 10 - 9). NUDT15 *2/*3 are associated with decreased dose of mercaptopurine in children with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to NUDT15 *1/*1. 28445187 1448624596
NUDT15 NUDT15*1, NUDT15*2 *1/*2 mercaptopurine "dosage","toxicity" no One East Asian patient in Singapore was compound heterozygous for rs554405994insGACTCC and rs116855232C>T (corresponding to NUDT15 *2) as well as p.K35E; c.103A>G, which has no rsID. He was very sensitive to mercaptopurine with tolerated dosage of 8.5 mg/m2/day. NUDT15 *1/*2 is associated with decreased dose of mercaptopurine in children with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to NUDT15 *1/*1. 28659275 1448635204
NUDT15 rs186364861 A mercaptopurine dosage yes Significance measured for dose reduction of greater than 50% of protocol dose. Allele A is associated with decreased dose of mercaptopurine in children with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to allele G. 28418010 1449749318
NUDT15 rs116855232 T mercaptopurine dosage yes Significance measured for dose reduction of greater than 50% of protocol dose. Allele T is associated with decreased dose of mercaptopurine in children with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to allele C. 28418010 1449749328
NUDT15 rs116855232 T mercaptopurine "dosage","toxicity" no as measured by 6-MP dose intensity, which is a measure dose adjustment due to toxicity calculated by the ratio of the prescribed 6-MP dose over the protocol dose of 50 mg/m2/d. TT had lowest intensity, heterozygotes had intermediate intensity and CC highest intensity. Allele T is associated with decreased dose of mercaptopurine in children with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to allele C. 29720126 1449750266
NUDT15 NUDT15*1, NUDT15*2, NUDT15*3, NUDT15*5, NUDT15*6 *1/*3 mercaptopurine "dosage","toxicity" no Doses were adjusted to give maintain a leukocyte count of 1500–3000 /µl. Mean dose for *1/*1, *1/*2, *1/*5 or *1/*6 was approximately 40mg/m2, and for *1/*3 was approx 20mg/m2 and for *3/*3 and *3/*5 was approx 5mg/m2. NUDT15 *1/*3 is associated with decreased dose of mercaptopurine in children with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to NUDT15 *1/*1 + *1/*5 + *1/*6 + *1/*2. 29967377 1449750346
NUDT15 NUDT15*1, NUDT15*3, NUDT15*5 *3/*3 + *3/*5 mercaptopurine "dosage","toxicity" no Doses were adjusted to give maintain a leukocyte count of 1500–3000 /µl. Mean dose for *1/*1, *1/*2, *1/*5 or *1/*6 was approximately 40mg/m2, and for *1/*3 was approx 20mg/m2 and for *3/*3 and *3/*5 was approx 5mg/m2. NUDT15 *3/*3 + *3/*5 is associated with decreased dose of mercaptopurine in children with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to NUDT15 *1/*3 + *1/*1. 29967377 1449750363
NUDT15 rs116855232 CT + TT mercaptopurine dosage yes Children with the CT or TT genotypes received 80.3%, 61.5% and 61.1% of the median cumulative dose of those with the CC genotype at 2, 4 and 6 months of the mercaptopurine maintenance phase, respectively. Additionally, patients with the CT or TT genotype were given a median dose of 28 mg/m2/day, 56% of the standard initial dose. Genotypes CT + TT is associated with decreased dose of mercaptopurine in children with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to genotype CC. 26405151 1447682392
NUDT15 rs746071566 del mercaptopurine "dosage","toxicity" not stated The variant was in 3 patients at St Jude's. One patient tolerated 43.5 mg/m2/day of mercaptopurine during the maintenance phase, The second patient was treated on the TOT XIIIB protocol, for which maintenance therapy consisted of drug pairs administered in weekly rotation and mercaptopurine given for only 1 week every 4-week period but did not experience significant toxicity and tolerated dosage was 82.5 mg/m2/day for that week. In the 3rd patient, the variant was present along with rs116855232 C>T, and another variant with no rsID (K35E c.103A>G). Nucleotide diphosphotase activity could not be detected in in vitro studies. Allele del is associated with decreased dose of mercaptopurine in children with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to allele GGAGTC. 28659275 1448635132
NUDT15 rs116855232 TT azathioprine toxicity yes As the number of copies of the T allele increased, the dose of azathioprine at which leukopenia occured decreased...it was lowest in patients with the TT genotype and showed a gene-dose effect in the order of TT<CT<CC. Genotype TT is associated with decreased dose of azathioprine in people with Leukopenia as compared to genotype CC. 25108385 1184514020
NUDT15 rs116855232 CT + TT azathioprine metabolism/PK no No significant difference in azathioprine dose (includes mercaptopurine dose, converted to equivalent dose using factor of 2.08; p=0.27) or 6-thioguanine nucleotide (6-TGN) levels (p=0.36) were seen at white blood cell (WBC) nadir between the genotypes, suggesting that this genotype did not affect thiopurine metabolism. Genotypes CT + TT is not associated with metabolism of azathioprine or mercaptopurine in people with Inflammatory Bowel Diseases as compared to genotype CC. 26590936 1447682840
NUDT15 rs116855232 CT + TT azathioprine dosage yes The mean azathioprine dose in patients with the CC genotype was 1.01 mg/kg/day and the mean azathioprine dose in patients with the CT or TT genotype was 0.73 mg/kg/day. No patients had the TPMT*2A, *3A, *3B or *3C variants. Genotypes CT + TT are associated with decreased dose of azathioprine in people with Colitis, Ulcerative, Crohn Disease and Hepatitis, Autoimmune as compared to genotype CC. 27416873 1448124080
NUDT15 rs116855232 CT + TT azathioprine dosage yes Meta-analysis with 13 studies. T allele carriers required 28% lower mean daily thiopurine dose as compared to those with the CC genotype. When patients with acute lymphoblastic leukemia (ALL) and inflammatory bowel disease (IBD) were separated, there was a similar statistically significant dose reduction for both groups. Genotypes CT + TT are associated with decreased dose of azathioprine in people with Inflammatory Bowel Diseases and Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to genotype CC. 28088792 1448531631
NUDT15 rs116855232 T thioguanine metabolism/PK no after treatment with azathioprine and 6-TGN was not significantly different between patients with leukopenia or the controls. Allele T is not associated with concentrations of thioguanine in people with Autoimmune Diseases, Lupus Erythematosus, Systemic or Sjogren's Syndrome as compared to allele C. 29867468 1449750688
NUDT15 rs116855232 TT azathioprine dosage yes The doses of thiopurines at the time when severe leukopenia was diagnosed were 39.4 ± 3.1 mg/day in TT which was significantly lower than 69.1 ± 28.1 mg/day in CC (8.50E-06) and 54.6 ± 19.1 mg/day in CT (p = 2.46E-02 ), Genotype TT is associated with decreased dose of azathioprine or mercaptopurine in people with Inflammatory Bowel Diseases as compared to genotypes CC + CT. 29923122 1449575844
NUDT15 rs116855232 CT azathioprine toxicity yes Patients with the CT genotype required treatment discontinuation or dose modification earlier than patients with the CC genotype. The most frequent reason for azathioprine discontinuation was leukopenia. Genotype CT is associated with increased discontinuation of azathioprine or mercaptopurine in people with Inflammatory Bowel Diseases as compared to genotype CC. 26076924 1447682726
NUDT15 rs116855232 CT azathioprine dosage yes The mean azathioprine maintenance dose (mg/kg per day, including mercaptopurine dose which was adjusted to azathioprine equivalents by multiplying with 2) in patients with the CT genotype was 0.574 as compared to 1.03 for the CC genotype. Genotype CT is associated with decreased dose of azathioprine and mercaptopurine in people with Inflammatory Bowel Diseases as compared to genotype CC. 26076924 1447682735
NUDT15 rs116855232 CT + TT azathioprine dosage not stated in patients referred for TPMT testing. Most were adult female patients with inflammatory diseases receiving azathioprine, one was male child receiving 6MP for ALL. Genotypes CT + TT is associated with decreased dose of azathioprine or mercaptopurine. 27095468 1447989193
NUDT15 rs766023281 C mercaptopurine "dosage","toxicity" no The variant was recurrent in two patients: one from Taiwan and one from Singapore. Both patients tolerated very low doses of mercaptopurine (17.9 and16.4 mg/m /day). Nucleotide diphosphotase activity could not be detected in in vitro studies. Allele C is associated with decreased dose of mercaptopurine in children with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to allele G. 28659275 1448635118
NUDT15 NUDT15*1, NUDT15*2, NUDT15*3, NUDT15*4, NUDT15*6 *1/*2 + *1/*3 + *1/*4 + *1/*6 mercaptopurine dosage yes When combined with TPMT *1/*2 and *1/*3A. Patients were assigned based on the number of risk alleles they had: 0 (no NUDT15 or TPMT variants), 1 (presence of NUDT15 OR TPMT variant), or 2 (presence of TPMT AND NUDT15 variants). Patients with 1 or 2 risk variants had significantly lower cumulative mercaptopurine dose at week 8 (p=0.0001), 16 (p=0.0000) and 24 (p=0.0004) of treatment, as well as significantly lower mean weekly mercaptopurine dose (p=0.0000), as compared to patients with 0 risk variants. Note that when cumulative mercaptopurine dose was compared between individuals with 2 risk alleles and 1 risk allele, significant results were only found for weeks 8 and 16, not week 24 - the authors suggest this may be due to low number of individuals with 2 risk alleles or more accurate mercaptopurine dosing during the maintenance phase. NUDT15 *1/*2 + *1/*3 + *1/*4 + *1/*6 are associated with decreased dose of mercaptopurine in children with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to NUDT15 *1/*1. 28146264 1448576430