NUDT15 R139C Variants Increase the Risk of Azathioprine-Induced Leukopenia in Chinese Autoimmune Patients

被引：20

作者：

Fei, Xiang ^{[1
,2
]}

Shu, Qing ^{[1
]}

Zhu, Huaijun ^{[1
]}

Hua, Bingzhu ^{[3
]}

Wang, Shiying ^{[3
]}

Guo, Ling ^{[4
]}

Fang, Yun ^{[1
]}

Ge, Weihong ^{[1
]}

机构：

[1] Nanjing Drum Tower Hosp, Dept Pharm, Nanjing, Jiangsu, Peoples R China

[2] China Pharmaceut Univ, Sch Basic Med & Clin Pharm, Nanjing, Jiangsu, Peoples R China

[3] Nanjing Drum Tower Hosp, Dept Rheumatol & Immunol, Nanjing, Jiangsu, Peoples R China

[4] Nanjing Univ Chinese Med, Nanjing Drum Tower Hosp, Clin Coll Tradit Chinese & Western Med, Nanjing, Jiangsu, Peoples R China

来源：

FRONTIERS IN PHARMACOLOGY | 2018年 / 9卷

关键词：

azathioprine; NUDT15; R139C; leukopenia; Chinese; autoimmune patients; INFLAMMATORY-BOWEL-DISEASE; THIOPURINE S-METHYLTRANSFERASE; SYSTEMIC-LUPUS-ERYTHEMATOSUS; METABOLITE MEASUREMENT; CLINICAL-SIGNIFICANCE; MAINTENANCE THERAPY; GENE POLYMORPHISMS; JAPANESE PATIENTS; KOREAN PATIENTS; CROHNS-DISEASE;

D O I：

10.3389/fphar.2018.00460

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

The aim of this study was to investigate the influence of NUDT15 R139C, thiopurine S-methyltransferase (TPMT), and 6-TGN on azathioprine (AZA) induced leukopenia in Chinese autoimmune patients. Among 87 enrolled patients, 23 (26.4%) had leukopenia. The NUDT15 R139C variant was associated with leukopenia (p = 1.86 x 10(-7); OR: 7.59; 95% CI: 3.16-18.21). However, TPMT genotype was not shown to be correlated with the incidence of leukopenia (p = 0.95). There was no significant difference of 6-TGN concentration between patients with or without leukopenia (p = 0.15) and no association was found in patients with NUDT15 R139C variants alleles (p = 0.62). Finally, we found that the range of 6-TGN concentrations in autoimmune diseases was much lower than the established 6-TGN monitoring range for inflammatory bowel diseases. Therefore, the variant of NUDT15 R139C is strongly associated with AZA-induced leukopenia in Chinese patients with various autoimmune diseases such as systemic lupus erythematosus, Sjogren's syndrome, etc.

引用

页数：8

共 51 条

[1] Prospective evaluation of the pharmacogenetics of azathioprine in the treatment of inflammatory bowel disease [J].

Ansari, A. ;

Arenas, M. ;

Greenfield, S. M. ;

Morris, D. ;

Lindsay, J. ;

Gilshenan, K. ;

Smith, M. ;

Lewis, C. ;

Marinaki, A. ;

Duley, J. ;

Sanderson, J. .

ALIMENTARY PHARMACOLOGY & THERAPEUTICS, 2008, 28 (08) :973-983

[2] Evaluating the use of metabolite measurement in children receiving treatment with a thiopurine [J].

Armstrong, L. ;

Sharif, J. -A. ;

Galloway, P. ;

McGrogan, P. ;

Bishop, J. ;

Russell, R. K. .

ALIMENTARY PHARMACOLOGY & THERAPEUTICS, 2011, 34 (09) :1106-1114

[3] NUDT15 R139C-related thiopurine leukocytopenia is mediated by 6-thioguanine nucleotide-independent mechanism in Japanese patients with inflammatory bowel disease [J].

Asada, Ayumi ;

Nishida, Atsushi ;

Shioya, Makoto ;

Imaeda, Hirotsugu ;

Inatomi, Osamu ;

Bamba, Shigeki ;

Kito, Katsuyuki ;

Sugimoto, Mitsushige ;

Andoh, Akira .

JOURNAL OF GASTROENTEROLOGY, 2016, 51 (01) :22-29

[4] Analysis of Thiopurine S-Methyltransferase Genotypes in Japanese Patients with Inflammatory Bowel Disease [J].

Ban, Hiromitsu ;

Andoh, Akira ;

Tanaka, Aiko ;

Tsujikawa, Tomoyuki ;

Sasaki, Masaya ;

Saito, Yasuharu ;

Fujiyama, Yoshihide .

INTERNAL MEDICINE, 2008, 47 (19) :1645-1648

[5] EULAR recommendations for the management of systemic lupus erythematosus. Report of a task force of the EULAR standing committee for international clinical studies including therapeutics [J].

Bertsias, G. ;

Ioannidis, J. P. A. ;

Boletis, J. ;

Bombardieri, S. ;

Cervera, R. ;

Dostal, C. ;

Font, J. ;

Gilboe, I. M. ;

Houssiau, F. ;

Huizinga, T. ;

Isenberg, D. ;

Kallenberg, C. G. M. ;

Khamashta, M. ;

Piette, J. C. ;

Schneider, M. ;

Smolen, J. ;

Sturfelt, G. ;

Tincani, A. ;

van Vollenhoven, R. ;

Gordon, C. ;

Boumpas, D. T. .

ANNALS OF THE RHEUMATIC DISEASES, 2008, 67 (02) :195-205

[6] The MutT proteins or ''nudix'' hydrolases, a family of versatile, widely distributed, ''housecleaning'' enzymes [J].

Bessman, MJ ;

Frick, DN ;

OHandley, SF .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (41) :25059-25062

[7] Azathioprine-induced fatal myelosuppression in systemic lupus erythematosus patient carrying TPMT*3C polymorphism [J].

Boonsrirat, U. ;

Angsuthum, S. ;

Vannaprasaht, S. ;

Konapurivijit, J. ;

Hirankarn, N. ;

Tassaneeyakul, W. ;

Avihingsanon, Y. .

LUPUS, 2008, 17 (02) :132-134

[8] Thiopurine Methyltransferase Gene Polymorphisms in Chinese Patients with Inflammatory Bowel Disease [J].

Cao, Qian ;

Zhu, Qin ;

Shang, Yan ;

Gao, Min ;

Si, Jianmin .

DIGESTION, 2009, 79 (01) :58-63

[9] Crystal structure, biochemical and cellular activities demonstrate separate functions of MTH1 and MTH2 [J].

Carter, Megan ;

Jemth, Ann-Sofie ;

Hagenkort, Anna ;

Page, Brent D. G. ;

Gustafsson, Robert ;

Griese, Julia J. ;

Gad, Helge ;

Valerie, Nicholas C. K. ;

Desroses, Matthieu ;

Bostrom, Johan ;

Berglund, Ulrika Warpman ;

Helleday, Thomas ;

Stenmark, Pal .

NATURE COMMUNICATIONS, 2015, 6

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

Chiengthong, Kanhatai ;

Ittiwut, Chupong ;

Muensri, Sasipa ;

Sophonphan, Jiratchaya ;

Sosothikul, Darintr ;

Seksan, Panya ;

Suppipat, Koramit ;

Suphapeetiporn, Kanya ;

Shotelersuk, Vorasuk .

HAEMATOLOGICA, 2016, 101 (01) :E24-E26

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