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A composition for predicting the risk of thiopurine-induced leukopenia comprising a single nucleotide polymorphism marker in the nudt15 gene

A technology for leukopenia and thiopurine, applied in the direction of recombinant DNA technology, biochemical equipment and methods, microbial measurement/inspection, etc., can solve problems such as practicality doubts

Active Publication Date: 2020-02-14
UNIV OF ULSAN FOUND FOR IND COOPERATION +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, previous studies have shown that only 1 / 4 of IBD patients who experience myelosuppression during azathioprine therapy have TPMT mutations, suggesting that in most patients myelosuppression is caused by other factors
Therefore, the usefulness of pre-testing TPMT status prior to initiation of thiopurine therapy has been questioned

Method used

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  • A composition for predicting the risk of thiopurine-induced leukopenia comprising a single nucleotide polymorphism marker in the nudt15 gene
  • A composition for predicting the risk of thiopurine-induced leukopenia comprising a single nucleotide polymorphism marker in the nudt15 gene
  • A composition for predicting the risk of thiopurine-induced leukopenia comprising a single nucleotide polymorphism marker in the nudt15 gene

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Exploratory correlation analysis in premature leukopenia

[0058]The inventors performed an exploratory association analysis of 96,048 genotyped SNPs in 33 patients with early-onset leukopenia and 307 controls, looking at the tail of the quantile-quantile distribution. to a P-value that is too high, while the total distribution does not show any signs of inflation due to population stratification (λ GC = 1.041). Exploratory analysis showed P-5 Four associations were found at rs9843344 (FBLN2) on 3p25.1, rs1986731 (CMAHP-pseudogene) on 6p22.3, rs2945770 (ST3GAL1) on 8q24.22 and rs17109616 (NRXN3) on 14q31.1. In addition, a suggestive association was also found within the TPMT locus, with the most dominant SNP being rs1142345(TPMT*3C) (odds ratio, 7.11; P=1.61×10 -4 ) (see Table 2). To improve the coverage of genetic variation in exploratory analyses, the inventors also performed an association analysis of 453,532 imputed SNPs and found 4 P-5 additional loci. Only th...

Embodiment 2

[0066] Reproducibility analysis

[0067] To validate the SNPs discovered by the exploratory analysis, the inventors first genotyped 10 SNPs in an additional 33 LEU patients and 325 controls. rs142829497, which was excluded from further analysis due to assay failure, was replaced by rs73481212. The genome-wide significance of 2 SNPs within the SUCLA2 / NUDT15 / MED4 region on 13q14 was confirmed (Table 2). The non-synonymous SNP rs116855232 (R139C) showed the most significant and strongest association in the immunochip and validated combined analysis (odds ratio, 35.6; combined P = 4.88 × 10 -94 )(table 3). Another SNP rs73481212 showed a combined P value of 1.92 × 10 -70 (Table 2). rs73481212 is in linkage disequilibrium (LD) with rs116855232 and its association is not independent of rs116855232 (R139C). The well-defined TPMT*3C allele (rs1142345) also showed a consistent association in the validation sample (P-5 ) did not reach genome-wide significance (Table 2).

[0068] ...

Embodiment 3

[0082] NUDT15R139C as a risk predictor of leukopenia

[0083] Based on pooled samples from exploratory analysis and recurrence analysis, the inventors found that the NUDT15 139C allele was present in 42.5% (147 / 346) of all leukopenia cases and in 6.8% (43 / 632) of controls (Table 5), It was shown that the presence of NUDT15 139C had a sensitivity of 42.5% (147 / 346) and a specificity of 93.2% (589 / 632) as a risk predictor of total leukopenia, with an area under the curve (AUC) value of 0.68. In terms of predicting thiopurine-induced leukopenia, the positive and negative predictive values ​​of the NUDT15 139C allele were 77.4% (147 / 190) and 74.7% (589 / 788), respectively.

[0084] table 5

[0085]

[0086] P values ​​were calculated using Fisher's exact test.

[0087] P values ​​were calculated using allelic association tests.

[0088] CI means confidence interval; NA means not applicable.

[0089] When the analysis was narrowed to early-onset leukopenia, the NUDT15 13...

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Abstract

The present invention relates to a composition for predicting the risk of thiopurine-induced leukopenia, containing a single nucleotide polymorphism marker within NUDT15 gene, and specifically, to: a composition for predicting the risk of thiopurine-induced leukopenia in Crohn's disease, ulcerative colitis, leukemia or transplant patients, containing a single nucleotide polymorphism marker within NUDT15 gene; a kit for predicting the risk; and a method for predicting the risk. According to the present invention, a patient having high sensitivity to leukopenia, which occurs during thiopurine therapy, in Crohn's disease, ulcerative colitis, leukemia or transplant patients can be rapidly classified early on, and thus patient-customized therapy can be efficiently carried out.

Description

technical field [0001] The concept of the present invention relates to a composition for predicting the risk of thiopurine-induced leukopenia in patients with Crohn's disease, ulcerative colitis, leukemia or organ transplantation, said composition comprising NUDT15 A single nucleotide polymorphism marker in a gene; a kit for predicting the risk; and a method for predicting the risk. Background technique [0002] The thiopurine drugs Azathioprine (AZA) and 6-mercaptopurine (6-MP) are widely used in the treatment of patients with cancer, organ transplantation and autoimmune or inflammatory diseases such as inflammatory bowel disease (IBD). Recommended doses for the treatment of IBD are 2.0-3.0 mg / kg / day for AZA and 1.0-1.5 mg / kg / day for 6-MP. However, one of the major drawbacks of the use of AZA / 6-MP is myelosuppression, which occurs in 2% to 5% of Caucasian IBD patients treated with these agents. Therefore, to reduce the risk of myelosuppression, the FDA recommends thiopuri...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12Q1/6883C12N15/11
CPCC12Q1/6888C12Q2600/112C12Q2600/156
Inventor 宋圭暎梁硕均
Owner UNIV OF ULSAN FOUND FOR IND COOPERATION
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