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BackgroundThe impact of genetic variation in thethiopurine 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 inXDHhave rarely been studied in IBD patients. We aim to access association betweenXDHvariants and thiopurine-induced leukopenia by gene–gene interaction in a Crohn’s disease (CD) population.StudyA total of 964 CD patients treated with thiopurines were recruited from a tertiary referral center. The association between fourXDHvariants (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), andTPMT *3Cwere selected for epistasis analysis with theXDHvariants.ResultsThere was no significant association for two variants ofXDHand thiopurine-induced leukopenia. In the epistasis analysis, onlyXDH(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 ofSUCLA2wild-type (199Ser) between theXDH(p.Asn1109Thr) and early leukopenia (OR = 4.39;p = 0.01) was detected.ConclusionGenes 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 ofXDH(p.Asn1109Thr) andSUCLA2(199Ser) on thiopurine-induced leukopenia. [ABSTRACT FROM PUBLISHER]