A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia

Abstract

Thiopurine therapy, commonly used in autoimmune conditions, can be complicated by life-threatening leukopenia. This leukopenia is associated with genetic variation in TPMT (encoding thiopurine S-methyltransferase). Despite a lower frequency of TPMT mutations in Asians, the incidence of thiopurine-induced leukopenia is higher in Asians than in individuals of European descent. Here we performed an Immunochip-based 2-stage association study in 978 Korean subjects with Crohn’s disease treated with thiopurines. We identified a nonsynonymous SNP in NUDT15 (encoding p.Arg139Cys) that was strongly associated with thiopurine-induced early leukopenia (odds ratio (OR) = 35.6; Pcombined = 4.88 × 10−94). In Koreans, this variant demonstrated sensitivity and specificity of 89.4% and 93.2%, respectively, for thiopurine-induced early leukopenia (in comparison to 12.1% and 97.6% for TPMT variants). Although rare, this SNP was also strongly associated with thiopurine-induced leukopenia in subjects with inflammatory bowel disease of European descent (OR = 9.50; P = 4.64 × 10−4). Thus, NUDT15 is a pharmacogenetic determinant for thiopurine-induced leukopenia in diverse populations.

NUDT15 c.415C>T increases risk of 6-mercaptopurine induced myelosuppression during maintenance therapy in children with acute lymphoblastic leukemia

“…Determination of TPMT polymorphisms, therefore, has limited clinical benefits to children with ALL in most Asian countries. More recently, single nucleotide polymorphisms (SNPs) of inosine triphosphate pyrophosphohydrolase (ITPA) and nucleoside diphophate-linked moiety X-type motif 15 (NUDT15) have been shown to be associated with myelosuppression induced by 6-MP or other drugs in the thiopurine group, in both benign and malignant conditions [10][11][12][13][14] . We present data on the association between the ITPA c.94C>A (rs1127354) and NUDT15 c.415C>T (rs116855232) and 6-MP induced myelosuppression in our cohort of pediatric ALL children.…”

Thiopurine metabolite level and toxicity in Indians with inflammatory bowel disease

“…Asians are less likely (approximately 3%) to have TPMT mutation as compared with Caucasians (10%) 10. In Asians, NUDT‐15 mutation is more relevant for thiopurine‐induced toxicity than TPMT (risk allele frequency of 0.2% in Europeans,36 7.2% in Indians,15 8.5% in Thai,37 10.2–16.3% in Japanese,38 11.6% in Taiwanese,39 and 23.2% in Koreans14). Although it is said that Asian patients need a lower dose, almost half of our patients (31/57) on low dose and 5 of 17 on high dose (>2 mg/kg body weight) had subtherapeutic level.…”

“…Hence, the role of TPMT mutation may not be very relevant amongst Asians. Recently, nucleoside diphosphate‐linked moiety X‐type (NUDT‐15) genetic variant has been found to be significantly associated with thiopurine toxicity amongst Asians 14, 15…”

Using Markers in IBD to Predict Disease and Treatment Outcomes: Rationale and a Review of Current Status

“…Two recent studies have extended these associations with variants in the HLA associated with the development of pancreatitis aft er thiopurine exposure ( 79 ). Another study demonstrated that the NUDT15 gene harbors a polymorphism associated with risk of bone marrow toxicity in a Korean population ( 80 ).…”