Association Study of 71 European Crohnʼs Disease Susceptibility Loci in a Japanese Population

Hirano, Atsushi; Yamazaki, Keiko; Umeno, Junji; Ashikawa, Kyota; Aoki, Masayuki; Matsumoto, Takayuki; Nakamura, Shotaro; Ninomiya, Toshiharu; Matsui, Toshiyuki; Hirai, Fumihito; Kawaguchi, Takaaki; Takazoe, Masakazu; Tanaka, Hiroki; Motoya, Satoshi; Kiyohara, Yutaka; Kitazono, Takanari; Nakamura, Yusuke; Kamatani, Naoyuki; Kubo, Michiaki

doi:10.1097/mib.0b013e31828075e7

Cited by 61 publications

(42 citation statements)

References 37 publications

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“…In contrast, we found that LRRK2 M2397T, a susceptibility allele for European ancestry but not for Japanese or Korean CD (3,23,25,33,54), was associated with Paneth cell defect in Japanese, but not North American CD. There are several important considerations when interpreting these findings.…”

Section: Discussioncontrasting

confidence: 51%

“…In particular, the NOD2 variants associated with European ancestry CD are not polymorphic in Japanese populations (24). In addition, while ATG16L1 T300A is polymorphic in Japanese cohorts, it has not been associated with CD susceptibility (25). In contrast, SNPs that are more frequently associated with CD in Asian populations include those that tag TNFSF15, IL23R, ATG16L2, STAT3, GPR35, MHC Class II, and ZNF365, among others (5,(21)(22)(23)25).…”

Section: L I N I C a L M E D I C I N Ementioning

confidence: 97%

“…In addition, while ATG16L1 T300A is polymorphic in Japanese cohorts, it has not been associated with CD susceptibility (25). In contrast, SNPs that are more frequently associated with CD in Asian populations include those that tag TNFSF15, IL23R, ATG16L2, STAT3, GPR35, MHC Class II, and ZNF365, among others (5,(21)(22)(23)25). Therefore, a Japanese CD patient cohort represents a unique cohort to identify novel genetic determinants of Paneth cell phenotypes.…”

Section: L I N I C a L M E D I C I N Ementioning

confidence: 99%

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LRRK2 but not ATG16L1 is associated with Paneth cell defect in Japanese Crohn’s disease patients

Liu¹,

Naito²,

Liu³

et al. 2017

JCI Insight

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IntroductionCrohn's disease (CD) and ulcerative colitis are 2 main classical types of inflammatory bowel disease (IBD) (1, 2). The etiology of IBD involves genetic susceptibility and environmental triggers. Over 200 single nucleotide polymorphisms (SNPs) have been associated with susceptibility to IBD (3-7). This complex genetic network indicates that IBD likely encompasses more than the 2 classical subtypes. Therefore, novel, rationally designed biomarkers that can lead to disease stratification and personalized treatments are needed (8). One candidate method to subtype CD is to define the morphological patterns of small intestinal Paneth cells based on the intracellular distribution of granules containing antimicrobial proteins (Paneth cell phenotypes) (7). Paneth cells are specialized secretory cells located at the bases of the crypts of Lieberkühn in the small intestine (9-11). These cells produce a wide repertoire of antimicrobial BACKGROUND. Morphological patterns of Paneth cells are a prognostic biomarker in Western Crohn's disease (CD) patients, and are associated with autophagy-associated ATG16L1 and NOD2 variants. We hypothesized that genetic determinants of Paneth cell phenotype in other ethnic CD cohorts are distinct but also involved in autophagy.

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Section: Discussioncontrasting

confidence: 51%

Section: L I N I C a L M E D I C I N Ementioning

confidence: 97%

Section: L I N I C a L M E D I C I N Ementioning

confidence: 99%

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LRRK2 but not ATG16L1 is associated with Paneth cell defect in Japanese Crohn’s disease patients

Liu¹,

Naito²,

Liu³

et al. 2017

JCI Insight

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“…3 Genome-wide association studies have identified 163 susceptibility loci associated with inflammatory bowel disease (IBD), 140 of which are associated with CD. 2 A non-synonymous single nucleotide polymorphism (SNP) in the gene encoding the autophagy-related 16-like protein (ATG16L1) has been associated with increased risk for developing CD in multiple populations [4][5][6][7] and specifically with the development of ileal CD. 8 The ATG16L1 CD-associated gene variant is common in the population with 33.2% of people from Western European descent being homozygous for the risk variant.…”

Section: Introductionmentioning

confidence: 99%

The Crohn’s disease-associated polymorphism in ATG16L1 (rs2241880) reduces SHIP gene expression and activity in human subjects

et al. 2015

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Crohn's disease (CD) is a polygenic immune-mediated disease characterized by gastrointestinal inflammation. Mice deficient in the hematopoietic-restricted SH2 domain-containing inositolpolyphosphate 5'-phosphatase (SHIP) develop spontaneous CD-like ileal inflammation. Intriguingly, SHIP mRNA is not upregulated in biopsies from patients with ileal CD despite immune cell infiltration, but SHIP's role in human CD remains unknown. We analyzed SHIP mRNA expression and activity in biopsies and peripheral blood mononuclear cells (PBMCs) from control and treatment-naive subjects with ileal CD, and demonstrated that SHIP mRNA and activity were lower in hematopoietic cells in ileal biopsies and PBMCs from subjects with CD. In all tissues from our patient cohort and in PBMCs from a second healthy control cohort, subjects homozygous for the autophagy-related 16-like protein (ATG16L1) CD-associated gene variant (rs2241880), had low SHIP mRNA expression and activity. SHIP protein expression increased during autophagy and SHIP upregulation was dependent on ATG16L1 and/or autophagy, as well as the ATG16L1 CD-associated gene variant. Finally, homozygosity for the ATG16L1 risk variant and low SHIP mRNA expression is inversely related to increased (LPS+ATP)-induced IL-1β production by PBMCs in our cohorts and was regulated by increased transcription of ILIB. These data suggest a novel mechanism by which the ATG16L1 CD-associated gene variant may predispose people to develop intestinal inflammation.

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“…99 Specifically with regards to the TL1A-DR3 pathway in IBD, a TNFSF15 haplotype is associated with higher TL1A expression, increased risk of CD, intestinal fibrostenosis, and greater need for surgery. [100][101][102] In mice, constitutive TL1A overexpression causes spontaneous ileitis with increased collagen deposition. 103,104 Under colitogenic conditions induced by chronic dextran sulfate sodium (DSS) treatment or adoptive T-cell transfer, increased inflammation, fibrosis, and fibrostenotic lesions in the gut are seen.…”

Section: Tl1amentioning

confidence: 99%

Cytokine and anti-cytokine therapies in prevention or treatment of fibrosis in IBD

Jacob

Targan

Shih

2016

United European Gastroenterology Journal

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The frequency of fibrosing Crohn's disease (CD) is significant, with approximately 40% of CD patients with ileal disease developing clinically apparent strictures throughout their lifetime. Although strictures may be subdivided into fibrotic, inflammatory, or mixed forms, despite immunosuppressive therapy in CD patients in the form of steroids or immunomodulators, the frequency of fibrostenosing complications has still remained significant. A vast number of genetic and epigenetic variables are thought to contribute to fibrostenosing disease, including those that affect cytokine biology, and therefore highlight the complexity of disease, but also shed light on targetable pathways. Exclusively targeting fibrosis may be difficult, however, because of the relatively slow evolution of fibrosis in CD, and the potential adverse effects of inhibiting pathways involved in tissue repair and mucosal healing. Acknowledging these caveats, cytokine-targeted therapy has become the mainstay of treatment for many inflammatory conditions and is being evaluated for fibrotic disorders. The question of whether anti-cytokine therapy will prove useful for intestinal fibrosis is, therefore, acutely relevant. This review will highlight some of the current therapeutics targeting cytokines involved in fibrosis.

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Association Study of 71 European Crohnʼs Disease Susceptibility Loci in a Japanese Population

Abstract: Our study suggests that there is a differential genetic background of CD susceptibility between Japanese and European populations.

Cited by 61 publications

References 37 publications

LRRK2 but not ATG16L1 is associated with Paneth cell defect in Japanese Crohn’s disease patients

LRRK2 but not ATG16L1 is associated with Paneth cell defect in Japanese Crohn’s disease patients

The Crohn’s disease-associated polymorphism in ATG16L1 (rs2241880) reduces SHIP gene expression and activity in human subjects

Cytokine and anti-cytokine therapies in prevention or treatment of fibrosis in IBD

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