Deep resequencing of 131 Crohn's disease associated genes in pooled DNA confirmed three reported variants and identified eight novel variants

Hong, Sung Noh; Park, Chang-Ho; Park, Soo Jung; Lee, Chang Kyun; Ye, Byong Duk; Kim, You Sun; Lee, Seungbok; Chae, Jeesoo; Kim, Jong‐Il; Kim, Young Ho

doi:10.1136/gutjnl-2014-308617

Cited by 67 publications

(81 citation statements)

References 58 publications

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“…We next examined the potential associations of type I Paneth cell phenotype with 56 SNPs, selected based on known CD susceptibility associations (3,5,(21)(22)(23)(27)(28)(29) or known association with Paneth cell function (17) (Supplemental Table 3). These SNPs include coding variants for ATG16L1 (T300A) associated with Paneth cell defects in North American CD cohorts and in genetic mouse models (18,19,30).…”

Section: Resultsmentioning

confidence: 99%

“…Thus, studying CD patients from other ethnicities, especially those who possess a spectrum of susceptibility genes distinct from those found in European ancestry CD, would be helpful in identifying novel genetic determinants of Paneth cell phenotype. The genetic landscape of CD patients from Korea and Japan is partially overlapping but largely different than that of European ancestry CD (5,(21)(22)(23). In particular, the NOD2 variants associated with European ancestry CD are not polymorphic in Japanese populations (24).…”

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

confidence: 99%

“…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: Resultsmentioning

confidence: 99%

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

confidence: 99%

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

confidence: 99%

See 1 more Smart Citation

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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“…Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn disease (CD), are chronic, relapsing, immunemediated intestinal inflammatory diseases of complex etiology (1)(2)(3)(4), found predominantly in white people (1,3) and incurring substantial socioeconomic costs; in excess of $1.7 billion/y in Canada (5). The exact contributions of environmental factors (6), immune dysregulations (7), and genetics (8) are unknown, which impairs therapeutic success.…”

Section: Introductionmentioning

confidence: 99%

The SLC2A14 gene, encoding the novel glucose/dehydroascorbate transporter GLUT14, is associated with inflammatory bowel disease

Shaghaghi

Zhouyao

et al. 2017

The American Journal of Clinical Nutrition

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Background: Variations in intestinal antioxidant membrane transporters are implicated in the initiation and progression of inflammatory bowel disease (IBD). Facilitated glucose transporter member 14 (GLUT14), encoded by the solute carrier family 2 member 14 (SLC2A14) gene, is a putative transporter for dehydroascorbic acid and glucose. Although information on the gene is limited, shorter and longer GLUT14 isoforms have been identified. We hypothesized that GLUT14 mediates glucose and dehydroascorbic acid uptake. If this function could be validated, then genetic variations may associate with IBD. Objective: This study aimed to determine the substrate(s) for the GLUT14 protein and interrogated genetic associations of SLC2A14 with IBD. Design: The uptake of radiolabeled substrates into Xenopus laevis oocytes expressing the 2 GLUT14 isoforms was assessed. Examination of gene-targeted genetic association in the Manitoba Inflammatory Bowel Disease Cohort Study was conducted through the genotyping of single nucleotide polymorphisms (SNPs) representing linkage blocks of the SLC2A14 gene. Results: Both GLUT14 isoforms mediated the uptake of dehydroascorbic acid and glucose into X. laevis oocytes. Three alleles in the SLC2A14 gene associated independently with IBD. The odds of having ulcerative colitis (UC) or Crohn disease (CD) were elevated in carriers of the SLC2A14 SNP rs2889504-T allele (OR: 3.60; 95% CI: 1. 95, 6.64 and OR: 4.68; 95% CI: 2.78, 8.50, respectively). Similarly, the SNP rs10846086-G allele was associated with an increased risk of both UC and CD (OR: 2.91; 95% CI: 1.49, 5.68 and OR: 3.00; 95% CI: 1.55, 5.78, respectively). Moreover, the SNP rs12815313-T allele associated with increased susceptibility to CD and UC (OR: 2.12; 95% CI: 1.33, 3.36 and OR: 1.61; 95% CI: 1.01, 2.57, respectively). Conclusion: These findings strengthen the hypothesis that genetically determined local dysregulation of dietary vitamin C or antioxidants transport contributes to IBD development. These transporter proteins are targetable by dietary interventions, opening the avenue to a precision intervention for patients of specific genotypes with IBD. This trial was registered at clinicaltrials.gov as NCT03262649.Am J Clin Nutr 2017;106:1508-13.

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“…Genome wide association studies (GWAS) and subsequent meta-analysis for CD have identified more than 140 susceptible genes contributing to CD, such as NOD2, IL23R, ATG16L1, TNFSF15, IL17 etc. [13,14]. These researches focused on the functional relevance of genetic variations, the mechanisms of how these susceptible genes lead to the pathogenesis of CD has not been fully explained [15].…”

Section: Discussionmentioning

confidence: 99%

A Novel Strategy to Identify mRNA 3′ UTR and mRNA Level Difference in Crohn’s Disease

Hu¹,

Liu²,

Zhou³

et al. 2017

Chemotherapy (Los Angel)

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Background and Aims: Crohn's disease (CD) is a chronic and refractory intestinal inflammatory disease. The 3′ untranslated region (3′ UTR) of mRNA transcript can regulate its own translational process post-transciptionally, and its role in CD remains unclear. The aim of this study was to identify the critical genes influencing CD phenotype via the regulation of mRNA 3′ UTR. Methods:Isoform Structural Change Model (IsoSCM) was used to evaluate the length of 3′ UTR of the whole transciptome from a RNA-seq based online CD database. Correlations between 3′ UTR length status and mRNA level were analyzed by Spearman coefficients. Correlated genes list was overlapped with published critical CD related gene list. Univariate and multivariate analysis were performed to identify the genes associated with CD phenotype. Results:Compared with normal control, 3′ UTR of 34192 genes were shortened and 57389 were lengthened among 432784 genes in CD patients. The 3′ UTR changes of 255 genes were found significantly correlated with their mRNA level. Furthermore, 8 overlapped genes were shared by above 255 correlated genes and known CD related gene list (ABCB1, FAF1, TUT2, IL27, JAK2, LTB, NAGLU and PTPN2). The mRNA level of ABCB1 and JAK2, and shortened 3′ UTR length of JAK2 transcript were found to be correlated with deep ulcer in CD patients by univariate and multivariate analysis. Conclusions:The 3′ UTR changes of CD related genes were confirmed to be related to the phenotype of CD. Our findings may provide further insight into the epigenetic mechanisms and therapeutic strategies for CD.

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Deep resequencing of 131 Crohn's disease associated genes in pooled DNA confirmed three reported variants and identified eight novel variants

Abstract: Our deep resequencing of 131 CD associated genes confirmed 3 reported risk loci and identified 8 novel risk loci for CD in Koreans, providing new insights into the genetic architecture of CD.

Cited by 67 publications

References 58 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 SLC2A14 gene, encoding the novel glucose/dehydroascorbate transporter GLUT14, is associated with inflammatory bowel disease

A Novel Strategy to Identify mRNA 3′ UTR and mRNA Level Difference in Crohn’s Disease

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