TY - JOUR
T1 - Crohn's Disease and Early Exposure to Thiopurines are Independent Risk Factors for Mosaic Chromosomal Alterations in Patients with Inflammatory Bowel Diseases
AU - MENDEL Study Group
AU - Kakuta, Yoichi
AU - Iwaki, Hideya
AU - Umeno, Junji
AU - Kawai, Yosuke
AU - Kawahara, Masahiro
AU - Takagawa, Tetsuya
AU - Shimoyama, Yusuke
AU - Naito, Takeo
AU - Moroi, Rintaro
AU - Kuroha, Masatake
AU - Shiga, Hisashi
AU - Watanabe, Kenji
AU - Nakamura, Shiro
AU - Nakase, Hiroshi
AU - Sasaki, Makoto
AU - Hanai, Hiroyuki
AU - Fuyuno, Yuta
AU - Hirano, Atsushi
AU - Matsumoto, Takayuki
AU - Kudo, Hisaaki
AU - Minegishi, Naoko
AU - Nakamura, Minoru
AU - Hisamatsu, Tadakazu
AU - Andoh, Akira
AU - Nagasaki, Masao
AU - Tokunaga, Katsushi
AU - Kinouchi, Yoshitaka
AU - Masamune, Atsushi
N1 - Publisher Copyright:
© 2021 The Author(s).
PY - 2022/4/1
Y1 - 2022/4/1
N2 - Background and Aims: Mosaic chromosomal alterations [mCAs] increase the risk for haematopoietic malignancies and may be risk factors for several other diseases. Inflammatory bowel diseases [IBDs], including Crohn's disease [CD] and ulcerative colitis [UC], are associated with mCAs, and patients may be at risk for haematopoietic malignancy development and/or modification of IBD phenotypes. In the present study, we screened patients with IBD for the presence of mCAs and explored the possible pathophysiological and genetic risk factors for mCAs. Methods: We analysed mCAs in peripheral blood from 3339 patients with IBD and investigated the clinical and genetic risk factors for mCAs. Results: CD and exposure to thiopurines before the age of 20 years were identified as novel independent risk factors for mCAs [odds ratio = 2.15 and 5.68, p = 1.17e-2 and 1.60e-3, respectively]. In contrast, there were no significant associations of disease duration, anti-tumour necrosis factor alpha antibodies, or other clinical factors with mCAs. Gene ontology enrichment analysis revealed that genes specifically located in the mCAs in patients with CD were significantly associated with factors related to mucosal immune responses. A genome-wide association study revealed that ERBIN, CD96, and AC068672.2 were significantly associated with mCAs in patients with CD [p = 1.56e-8, 1.65e-8, and 4.92e-8, respectively]. Conclusions: The difference in mCAs between patients with CD and UC supports the higher incidence of haematopoietic malignancies in CD. Caution should be exercised when using thiopurines in young patients with IBD, particularly CD, in light of possible chromosomal alterations.
AB - Background and Aims: Mosaic chromosomal alterations [mCAs] increase the risk for haematopoietic malignancies and may be risk factors for several other diseases. Inflammatory bowel diseases [IBDs], including Crohn's disease [CD] and ulcerative colitis [UC], are associated with mCAs, and patients may be at risk for haematopoietic malignancy development and/or modification of IBD phenotypes. In the present study, we screened patients with IBD for the presence of mCAs and explored the possible pathophysiological and genetic risk factors for mCAs. Methods: We analysed mCAs in peripheral blood from 3339 patients with IBD and investigated the clinical and genetic risk factors for mCAs. Results: CD and exposure to thiopurines before the age of 20 years were identified as novel independent risk factors for mCAs [odds ratio = 2.15 and 5.68, p = 1.17e-2 and 1.60e-3, respectively]. In contrast, there were no significant associations of disease duration, anti-tumour necrosis factor alpha antibodies, or other clinical factors with mCAs. Gene ontology enrichment analysis revealed that genes specifically located in the mCAs in patients with CD were significantly associated with factors related to mucosal immune responses. A genome-wide association study revealed that ERBIN, CD96, and AC068672.2 were significantly associated with mCAs in patients with CD [p = 1.56e-8, 1.65e-8, and 4.92e-8, respectively]. Conclusions: The difference in mCAs between patients with CD and UC supports the higher incidence of haematopoietic malignancies in CD. Caution should be exercised when using thiopurines in young patients with IBD, particularly CD, in light of possible chromosomal alterations.
KW - Autosomal mosaicism
KW - Crohn's disease
KW - thiopurines
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UR - http://www.scopus.com/inward/citedby.url?scp=85126112949&partnerID=8YFLogxK
U2 - 10.1093/ecco-jcc/jjab199
DO - 10.1093/ecco-jcc/jjab199
M3 - Article
C2 - 34751398
AN - SCOPUS:85126112949
SN - 1873-9946
VL - 16
SP - 643
EP - 655
JO - Journal of Crohn's and Colitis
JF - Journal of Crohn's and Colitis
IS - 4
ER -