title: Influences of XDH genotype by gene-gene interactions with SUCLA2 for thiopurine-induced leukopenia in Korean patients with Crohn's disease.
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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors: a Department of Internal Medicine , Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine , Seoul , Korea ;
authors: Soo-Kyung
authors: SK
authors: Park
authors: b Department of Biochemistry and Molecular Biology , University of Ulsan College of Medicine , Seoul , Korea ;
authors: Myunghee
authors: M
authors: Hong
authors: c Department of Gastroenterology, Asan Medical Center , University of Ulsan College of Medicine , Seoul , Korea ;
authors: Byong Duk
authors: BD
authors: Ye
authors: c Department of Gastroenterology, Asan Medical Center , University of Ulsan College of Medicine , Seoul , Korea ;
authors: Kyung-Jo
authors: KJ
authors: Kim
authors: c Department of Gastroenterology, Asan Medical Center , University of Ulsan College of Medicine , Seoul , Korea ;
authors: Sang Hyoung
authors: SH
authors: Park
authors: c Department of Gastroenterology, Asan Medical Center , University of Ulsan College of Medicine , Seoul , Korea ;
authors: Dong-Hoon
authors: DH
authors: Yang
authors: c Department of Gastroenterology, Asan Medical Center , University of Ulsan College of Medicine , Seoul , Korea ;
authors: Sung-Wook
authors: SW
authors: Hwang
authors: c Department of Gastroenterology, Asan Medical Center , University of Ulsan College of Medicine , Seoul , Korea ;
authors: Min Seob
authors: MS
authors: Kwak
authors: d Health Screening and Promotion Center, University of Ulsan College of Medicine , Seoul , Korea.
authors: Ho-Su
authors: HS
authors: Lee
authors: b Department of Biochemistry and Molecular Biology , University of Ulsan College of Medicine , Seoul , Korea ;
authors: Kyuyoung
authors: K
authors: Song
authors: c Department of Gastroenterology, Asan Medical Center , University of Ulsan College of Medicine , Seoul , Korea ;
authors: Suk-Kyun
authors: SK
authors: Yang
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002648:Child; D003424:Crohn Disease / Q000150:complications / Q000188:drug therapy* / Q000235:genetics*; D004843:Epistasis, Genetic; D005260:Female; D005500:Follow-Up Studies; D005819:Genetic Markers; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D007970:Leukopenia / Q000139:chemically induced* / Q000235:genetics; D016015:Logistic Models; D008297:Male; D015122:Mercaptopurine / Q000009:adverse effects* / Q000627:therapeutic use; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D056910:Republic of Korea; D013389:Succinate-CoA Ligases / Q000235:genetics*; D016896:Treatment Outcome; D014968:Xanthine Dehydrogenase / Q000235:genetics*; D055815:Young Adult
chemical_list: D005819:Genetic Markers; D007166:Immunosuppressive Agents; D015122:Mercaptopurine; D014968:Xanthine Dehydrogenase; D013389:Succinate-CoA Ligases; C518788:SUCLA2 protein, human
keywords: Crohn’s disease; epistasis analysis; gene; leukopenia; thiopurine