P702 Influences of XDH genotype on thiopurine-induced leukopenia in Korean patients with Crohn's disease determined by gene-gene interactions
P. Soo-kyung*1, Y. Suk-Kyun2, H. Myunghee3, B. Jiwon3, C. Hyunchul3, J. Yusun3, Y. Byong Duk2, K. Kyung-Jo2, P. Sang Hyoung2, Y. Dong-Hoon2, C. Jae Myung4, S. Kyuyoung3
1SoonChunHyang University Bucheon Hospital, Digestive Disease Center and Research Institute, Department of Internal Medicine, Bucheon, Korea, Republic of, 2Asan Medical Center, University of Ulsan College of Medicine, Gastroenterology, Seoul, Korea, Republic of, 3University of Ulsan College of Medicine, Biochemistry and Molecular Biology, Seoul, Korea, Republic of, 4Kyung Hee University Hospital at Gang Dong, Kyung Hee University School of Medicine, Internal Medicine, Seoul, Korea, Republic of
Thiopurine therapy, commonly utilized in inflammatory bowel disease, can be complicated by life-threatening leukopenia. Although the impact of genetic variation in the thiopurine S-methyltransferase (TPMT) gene on toxicity has been well emonstrated, only about a quarter of inflammatory bowel disease patients with thiopurine-induced leukopenia carry a TPMT mutation. As xanthine dehydrogenase (XDH) is the second major contributor to azathioprine breakdown besides TPMT, we conducted an association analysis in Crohn's disease (CD) population in order to identify association between XDH variation and thiopurine-induced leukopenia by gene-gene interaction.
A total of 978 of Korean CD patients treated with thiopurines were recruited from CD registry database of a tertiary referral center. The association between two XDH variants (G172R, N1109T) and thiopurine-induced leukopenia was analyzed in case with early leukopenia (n=66), case with late leukopenia (n=280) and control without leukopenia (n=632). Three nonsynonymous SNPs, NUDT15 (R139C), SUCLA2 (S199T) and TPMT (T240C) were selected for epistasis analysis with XDH variants.
There was no significant association for two variants of XDH and thiopurine- induced early and late leukopenia. In the epistasis analysis, only XDH (N1109T) * SUCLA2 (S199T) showed statistically significant association with early leukopenia [odds ratio (OR) = 0.16; P= 0.02]. After genotype stratification, positive association on the background of SUCLA2 wild type (199S) for XDH (1109T) G allele with thiopurine-induced early leukopenia (OR = 4.38; P= 0.01) was detected.
The present study has shown that genes were associated with thiopurine-induced leukopenia can act in a complex interactive manner. Further studies to explore the mechanisms of combination of XDH (N1109T) and SUCLA2 (S199T) in thiopurine-induced leukopenia are warranted.