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P096 Combined detection variants of NUDT15 could highly predict thiopurine-induced leukopenia in Chinese patients with inflammatory bowel disease: a multi-center analysis

Chao K.*1, Zhu X.1, Cao Q.2, Yang H.3, Liang J.4, Lin L.1, Huang Z.1, Zhang Y.2, Huang Y.2, Sun Y.3, Xue X.4, Huang M.5, Hu P.1, Wu K.4, Lan P.6, Wang X.5, Qian J.3, Gao X.1

1The Sixth Affiliated Hospital, Sun Yat-sen University, Department of Gastroenterology, Guangzhou, China 2Sir Run Run Shaw Hospital, Department of Gastroenterology, Hangzhou, China 3Peking Union Medical College Hospital, Department of Gastroenterology, Beijing, China 4Xijing Hospital, Department of Gastroenterology, Xi'an, China 5School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China 6The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

Background

UDT15c.415C>T was a novel genetic marker discovered in our center for thiopurine-induced leukopenia in Chinese inflammatory bowel disease (IBD). For validation, a large cohort study is needed. Meanwhile, the newly discovered NUDT15 coding variants (c.36_37insGGAGTC, c.52G>A) has not been studied in IBD patients.We aimed to further confirm the influences of NUDT15 three variants (c.415C>T, c.36_37insGGAGTC and c.52G>A) on thiopurine-induced leukopenia in Chinese IBD patients.

Methods

Patients prescribed on thiopurines for at least two weeks were recrutied from four tertiary hospitals. Clinical data were collected. NUDT15 genotypes were determined with PCR-RFLP and sequencing. The interactions between variants and leukopenia were analyzed.

Results

A total of 732 patients were included, 177 (24.3%) of which developed leukopenia. There were strong associstion of NUDT15 c.415C>T, c.36_37insGGAGTC and c.52G>A with thiopurine-induced leukopenia (p=1.81×10–20, p=4.74×10–8, p=0.04 respectively), while there was no relevance for TPMT genotypes (p=0.25). The predictive sensitivity of NUDT15 c.415C>T was 49.2%, while it increased to 55.4% when combined analysis with c.36_37insGGAGTC and c.52G>A. Notably, not only the homozygotes with NUDT15 c.415C>T, but also the heterozygotes both carrying c.415C>T and c.52G>A developed early leukopenia. The average dosage for NUDT15 c.415C>T carriers was significant lower than that for wild type (p<0.001).

Conclusion

We confirmed NUDT15 c.415C>T, c.36_37ins GGAGTC and c.52G>A variants were risk factors for thiopurine-induced leukopenia. Combined detection of the three variants could increase the predictive sensitivity of thiopurine-induced leukopenia and help to distinguish early leukopenia in heterozygotes of c.415C>T. Treatment monitoring by NUDT15 variants may be promising in individualized therapy.