Influences of XDH genotype by gene–gene interactions with SUCLA2 for thiopurine-induced leukopenia in Korean patients with Crohn's disease. (2nd June 2016)

• Record Type: Journal Article
• Authors: Park, Soo-Kyung; Hong, Myunghee; Ye, Byong Duk; Kim, Kyung-Jo; Park, Sang Hyoung; Yang, Dong-Hoon; Hwang, Sung-Wook; Kwak, Min Seob; Lee, Ho-Su; Song, Kyuyoung; Yang, Suk-Kyun
• Is Part Of: Scandinavian journal of gastroenterology. Volume 51:Number 6(2016)
• Page Start: 684
• Page End: 691
• Publication Date: 2016-06-02
• Subjects: Crohn's disease -- epistasis analysis -- gene -- leukopenia -- thiopurine; Gastroenterology -- Periodicals; Digestive organs -- Diseases -- Periodicals; 616.33
• DOI: 10.3109/00365521.2015.1133698
• Languages: English
• ISSNs: 0036-5521

Abstract

ABSTRACT: Background The impact of genetic variation in the thiopurine S-methyltransferase (TPMT) gene on thiopurine-induced leukopenia has been well demonstrated. Although xanthine dehydrogenase ( XDH) is the second major contributor to azathioprine breakdown, polymorphisms in XDH have rarely been studied in IBD patients. We aim to access association between XDH variants and thiopurine-induced leukopenia by gene–gene interaction in a Crohn's disease (CD) population.Study A total of 964 CD patients treated with thiopurines were recruited from a tertiary referral center. The association between four XDH variants (p.Gly172Arg, p.Asn1109Thr, p.Arg149Cys, and p.Thr910Lys) and thiopurine-induced leukopenia was analyzed in cases with early leukopenia ( n = 66), late leukopenia ( n = 264), and in controls without leukopenia ( n = 632). Three non-synonymous SNPs, which we previously reported association with thiopurine-induced leukopenia, NUDT15 (p.Arg139Cys), SUCLA2 (p.Ser199Thr), and TPMT *3C were selected for epistasis analysis with the XDH variants.Results There was no significant association for two variants of XDH and thiopurine-induced leukopenia. In the epistasis analysis, only XDH (p.Asn1109Thr) * SUCLA2 (p.Ser199Thr) showed a statistically significant association with early leukopenia [odds ratio (OR) = 0.16; p = 0.03]. After genotype stratification, a positive association on the background of SUCLA2 wild-type (199Ser) between the XDH (p.Asn1109Thr) and early leukopenia (OR = 4.39; p = 0.01) was detected.Conclusion Genes associated with thiopurine-induced leukopenia can act in a complex interactive manner. Further studies are warranted to explore the mechanisms underlying the effects of the combination of XDH (p.Asn1109Thr) and SUCLA2 (199Ser) on thiopurine-induced leukopenia.