Combined Detection of NUDT15 Variants Could Highly Predict Thiopurine-induced Leukopenia in Chinese Patients with Inflammatory Bowel Disease

Chao, Kang; Wang, Xueding; Cao, Qian; Qian, Jiaming; Wu, Kaichun; Zhu, Xia; Yang, Hong; Liang, Jie; Lin, Lang; Huang, Zicheng; Zhang, Yu; Huang, Yue; Sun, Ying; Xue, Xianmin; Huang, Min; Hu, Pinjin; Lan, Ping; Gao, Xiang

doi:10.1097/mib.0000000000001148

Cited by 50 publications

(90 citation statements)

References 27 publications

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“…The association of TPMT genotype polymorphisms and TIL was assessed in 31 studies, the association of TPMT enzymatic activity and TIL in 12 (Table S1). …”

Section: Resultsmentioning

confidence: 99%

“…Thirteen studies were identified that evaluated NUDT15 variants as risk factors for TIL in IBD patients, one also described the association of NUDT15 activity and TIL (Table S3). The majority of studies were performed in East‐Asian cohorts, one study included only patients of European ancestry . Studied NUDT15 variants were NUDT15 R139C (rs116855232) in 13 studies, NUDT15 c.36_37ins/delGGAGTC (rs746071566) in six studies and c.52G > A (rs186364861) in four studies.…”

Section: Resultsmentioning

confidence: 99%

“…Relatively new important genetic predictors for TIL in Asian IBD patients, but probably also in other populations, are NUDT15 gene variants (R193C, 36_37ins/delGGAGTC and G52A) . NUDT15 is thought to act as a convertor of 6‐TGTP into 6‐TGMP, and low NUDT15 enzymatic activity might therefore result in 6‐TGTP accumulation, leading to cell apoptosis .…”

Section: Discussionmentioning

confidence: 99%

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Systematic review with meta‐analysis: risk factors for thiopurine‐induced leukopenia in IBD

Gennep

Konté

Meijer

et al. 2019

Aliment Pharmacol Ther

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Background: Thiopurine-induced leukopenia, a frequently observed and potentially life-threatening adverse event, complicates the clinical management of IBD patients. Aim:To assess risk factors for thiopurine-induced leukopenia in IBD.Methods: MEDLINE, EMBASE, BIOSIS and Cochrane library were searched for studies reporting at least one risk factor for thiopurine-induced leukopenia.Pooled odds ratio (OR) was calculated for each potential risk factor using a random effects model. Studies that were not eligible for meta-analysis were described qualitatively.Results: Seventy articles were included, 34 (11 229 patients) were included in meta-analyses. A significantly higher thiopurine-induced leukopenia risk was found for TPMT (OR 3.9, 95% [CI] 2.5-6.1) and for NUDT15 R139C (OR 6.9, 95% CI 5.2-9.1), G52A (OR 3.2, 95% CI 1.3-7.9) and 36_37ins/delGGAGTC variant carriers (OR 5.6, 95% CI 2.8-11.4). A potential association between high 6-thioguanine nucleotides (6-TGN) or 6-methylmercaptopurine (6-MMP) levels and leukopenia was observed, since most studies reported higher metabolite levels in leukopenic patients (6-TGN: 204-308 (Lennard method) and 397 (Dervieux method), 6-MMP: 4020-10 450 pmol/8 x 10 8 RBC) compared to controls (6-TGN: 170-212 (Lennard method) and 269 (Dervieux method), 6-MMP: 1025-4550 pmol/8 x 10 8 RBC). Conclusions:TPMT and NUDT15 variants predict thiopurine-induced leukopenia.High 6-TGN and 6-MMP levels might induce leukopenia, although exact cut-off values remain unclear. Potential preventive measures to reduce the risk of thiopurineinduced leukopenia include pre-treatment TPMT and NUDT15 genotyping. Routine thiopurine metabolite measurement might be efficient, yet cut-off levels must be validated in advance. | 485VAN GENNEP Et Al.

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“…The association of TPMT genotype polymorphisms and TIL was assessed in 31 studies, the association of TPMT enzymatic activity and TIL in 12 (Table S1). …”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Systematic review with meta‐analysis: risk factors for thiopurine‐induced leukopenia in IBD

Gennep

Konté

Meijer

et al. 2019

Aliment Pharmacol Ther

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“…Approximately 3‐14% of patients possess one variant allele of thiopurine methyltransferase . In a recent report, 24.2% of Chinese Han patients with IBD experienced leukopenia when using thiopurine and adverse events were related to NUDT15 variants . Another report showed that heterozygous and homozygous variant NUDT15 p.Arg139Cys alleles were found in 21.9% and 5.0% of Japanese IBD patients, respectively .…”

Section: Discussionmentioning

confidence: 99%

“…26 In a recent report, 24.2% of Chinese Han patients with IBD experienced leukopenia when using thiopurine and adverse events were related to NUDT15 variants. 27 Another report showed Although some studies on rheumatoid arthritis have excluded age as a predictive factor for the effects of MTX treatment, [30][31][32] no studies, to our knowledge, have evaluated both age and MTX efficacy in patients with IBD. Regardless of the small sample size, we found that those who failed to maintain remission were elder than those who maintained remission after MTX treatment.…”

Section: Discussionmentioning

confidence: 99%

A single‐center experience with methotrexate in the treatment of Chinese Crohn’s disease patients

Wang

Qiao

Zou

et al. 2018

J of Digest Diseases

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Objective Methotrexate (MTX) can be used as an alternative for patients with Crohn’s disease (CD) who are intolerant of thiopurine. This retrospective study aimed to provide some clues about MTX treatment in Chinese patients with CD. Methods Medical records of 27 adult patients with CD who were treated with MTX between 2012 and 2017 at Renji Hospital were reviewed. MTX was administered at 15 mg or 20 mg intramuscularly once per week. The remission and response rates and adverse reactions of MTX were recorded and analyzed. Results Thirteen (48.1%) of the patients achieved remission for more than 12 months, whereas four (14.8%) responded clinically. Eight (29.6%) patients discontinued MTX due to adverse events. The mean age of those who maintained remission was significantly younger than that of those who did not ([35.62 ± 10.99] years vs. [45.43 ± 11.93] years, P < 0.05). The pretreatment C‐reactive protein (CRP) level was higher in the group who maintained remission than that in those who did not ([17.20 ± 17.26] mg/L vs. [6.98 ± 5.66] mg/L, P < 0.05). Conclusions MTX is effective and relatively safe for patients at doses of 15 mg/week or 20 mg/week and may be an alternative therapy for patients who are intolerant of thiopurine. Elderly patients with CD and patients with normal pretreatment CRP level may have a reduced response to MTX.

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DNA‐Thioguanine Nucleotides as a Marker for Thiopurine Induced Late Leukopenia after Dose Optimizing by NUDT15 C415T in Chinese Patients with IBD

Zhu

Chao

Yang

et al. 2022

Clin Pharma and Therapeutics

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Thiopurine dose optimization by thiopurine‐S‐methyltransferase (TPMT) or nudix hydrolase‐15 (NUDT15) significantly reduced early leucopenia in Asia. However, it fails to avoid the late incidence (> 2 months). Although laboratory monitoring of 6‐thioguanine nucleotides (6TGN) to optimize thiopurine dose was suggested in White patients the exact association between leucopenia and 6TGN was controversial in Asian patients. In the present study, we aimed to explore whether DNA‐thioguanine nucleotides (DNA‐TGs) in leukocytes, compared with 6TGN in erythrocytes, can be a better biomarker for late leucopenia. This was a prospective, observational study. Patients with inflammatory bowel disease (IBD) prescribed thiopurine from February 2019 to December 2019 were recruited. Thiopurine dose was optimized by NUDT15 C415T (rs116855232). DNA‐TG and 6TGN levels were determined at the time of late leucopenia or 2 months after the stable dose was obtained. A total of 308 patients were included. Thiopurine induced late leucopenia (white blood cells < 3.5 × 109/L) were observed in 43 patients (14.0%), who had significantly higher DNA‐TG concentration than those without leucopenia (P = 4.1 × 10–9, 423.3 (~ 342.2 to 565.7) vs. 270.5 (~ 188.1 to 394.3) fmol/μg DNA). No difference in 6TGN concentrations between leucopenia and non‐leucopenia was found. With a DNA‐TG threshold of 340.1 fmol/μg DNA, 83.7% of leucopenia cases could be identified. Multivariate analysis showed that DNA‐TG was an independent risk factor for late leucopenia. Quantification of DNA‐TG, rather than 6TGN, can be applied to gauge thiopurine therapy after NUDT15 screening in Chinese patients with IBD.

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Combined Detection of NUDT15 Variants Could Highly Predict Thiopurine-induced Leukopenia in Chinese Patients with Inflammatory Bowel Disease

Cited by 50 publications

References 27 publications

Systematic review with meta‐analysis: risk factors for thiopurine‐induced leukopenia in IBD

Systematic review with meta‐analysis: risk factors for thiopurine‐induced leukopenia in IBD

A single‐center experience with methotrexate in the treatment of Chinese Crohn’s disease patients

DNA‐Thioguanine Nucleotides as a Marker for Thiopurine Induced Late Leukopenia after Dose Optimizing by NUDT15 C415T in Chinese Patients with IBD

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