Should Thiopurine Methyltransferase Genotypes and Phenotypes be Measured Before Thiopurine Therapy in Patients With Inflammatory Bowel Disease?
ABSTRACT BACKGROUND AND AIMS:: Not all of the adverse effects to thiopurine therapy can be explained by thiopurine methyltransferase (TPMT) polymorphisms. This study was intended to evaluate the value of TPMT genotype and phenotype measurement during the first year of thiopurine therapy. METHODS:: Consecutive patients with inflammatory bowel disease (IBD) who were receiving azathioprine or 6-mercaptopurine were followed up for 12 months. TPMT genotypes and phenotypes were examined in patients with IBD before thiopurine therapy and in unrelated healthy volunteers by polymerase chain reaction and high-performance liquid chromatography. RESULTS:: A total of 199 patients and 300 healthy volunteers were included at 2 centers. Forty-seven of the 199 patients (23.62%) exhibited adverse effects during the entire course of thiopurine therapy. Two (1%) patients carrying TPMT*3C developed leucopenia at week 4 of azathioprine treatment. The TPMT*3C had a specificity of 100% (163/163) but a sensitivity of 5.56% (2/36) for predicting leucopenia. The calculated optimal cutoff activity for high TPMT activity and decreased TPMT activity was 4.75 U/mL red blood cells. The risk of leucopenia increased in the decreased TPMT group (odds ratio: 20.25; 95% confidence interval: 2.19-187.17; P = 0.004) and increased more during the initial 3 months of thiopurine therapy (odds ratio: 34.80; 95% confidence interval: 3.71-326.77; P = 0.001). Leucopenia occurred more frequently in the patients cotreated with 5-aminosalicylates than in those not cotreated (32.81% versus 11.11%, respectively, P < 0.001). CONCLUSIONS:: The results of this study suggest that the value of TPMT genotyping before thiopurine therapy is limited in Chinese patients with IBD, considering the low sensitivity of predicting leucopenia, and that phenotyping is a more cost-effective tool that can be successfully used in patients. The coadministration of 5-aminosalicylates results in a high frequency of leucopenia in patients receiving azathioprine or 6-mercaptopurine.
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ABSTRACT: BACKGROUND AND AIMS: Thiopurine S-methyltransferase (TPMT) is responsible for inactivation of thiopurine drugs which are commonly used in leukemia, organ transplantation and autoimmune diseases. The gene encoding TPMT is polymorphic, and both phenotyping and genotyping studies have shown ethnic variations in gene sequence and enzyme activity worldwide. The aim of this study is to identify the most common genetic polymorphisms of TPMT in healthy Jordanian volunteers and patients with rheumatoid arthritis (RA). METHODS: A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was used to identify the frequency of TPMT (*2, *3A, *3B, and *3C) polymorphisms in 250 healthy Jordanian volunteers and 110 RA patients. RESULTS: Only four healthy subjects (1.6%) and one RA patient (0.9%) with variant alleles were identified in this study. Two healthy subjects had the TPMT*3A allele and the other two had the TPMT*3B allele, whereas the one RA patient had the TPMT*3A allele. No homozygous polymorphisms were detected and all genotypes detected were heterozygous (*1/*3A) (*1/*3B). None of the subjects had TPMT*2 or TPMT*3C variant alleles. CONCLUSIONS: Mutant alleles identified in this study have a low frequency. TPMT (*3, *3B) were the only detected heterozygous alleles. No homozygous variant allele was detected. Further studies are necessary to identify other variant alleles that might uniquely occur in Jordanians.Archives of medical research 02/2013; DOI:10.1016/j.arcmed.2013.01.006 · 2.41 Impact Factor
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ABSTRACT: Azathioprine (AZA) is indicated for the treatment of systemic lupus erythematosus (SLE). Thiopurine methyltransferase (TPMT) is the rate-limiting enzyme in the steps of AZA metabolization. Heritable deficiency of TPMT enzyme activity and polymorphisms may lead to leukopenia. This study aims to detect TPMT polymorphisms and TPMT enzyme activity in Chinese SLE patients and to describe the association between TPMT genotypes and adverse effects of AZA. One hundred and twenty-six SLE patients with present or previous thiopurine therapy were identified from a local database. Adverse effects were documented. No TPMT*2, TPMT*3A, or TPMT*3B mutant alleles were detected. TPMT*3C was detected in four patients (3.17 %). The heterozygotes had significantly lower mean TPMT activity as compared to the homozygotes (2.38 ± 1.24 vs. 12.56 ± 7.02 U/mL, P < 0.001). Twenty-seven cases (21.42 %) exhibited adverse effects. All of the heterozygotes (4/4, 100 %) developed severe leukopenia, and three cases (3/4, 75 %) of whom exhibited alopecia simultaneously. The specificity of TPMT*3C for predicting leukopenia and alopecia was 100 and 99.17 %, respectively, and the sensitivity was 28.57 and 60.00 %, respectively. The mean value of TPMT activity with leukopenia (4.67 ± 3.01 vs. 13.2 ± 6.94 U/mL RBC, P < 0.001) or alopecia (2.31 ± 1.16 vs. 12.65 ± 6.98 U/mL RBC, P < 0.001) was significantly lower than those without. TPMT*3C was the most common mutant polymorphism found in the study group. TPMT activity is reduced in TPMT*3C mutant. AZA-induced leukopenia and alopecia were partly correlated to TPMT*3C heterozygotes and low TPMT activity. The results of this study suggest that the value of TPMT genotyping before AZA therapy was limited in Chinese SLE patients, considering the low sensitivity. Routine monitoring of TPMT activity before prescribing and continuous hematological monitoring dose were recommended.Clinical Rheumatology 12/2013; 33(4). DOI:10.1007/s10067-013-2441-x · 1.77 Impact Factor
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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.Nature Genetics 08/2014; 46(9). DOI:10.1038/ng.3060 · 29.65 Impact Factor