Autophagy and inflammatory bowel disease: Association between variants of the autophagy-related IRGM gene and susceptibility to Crohn's disease

Rufini, Sara; Ciccacci, Cinzia; Fusco, Davide Di; Ruffa, A.; Pallone, Francesco; Novelli, Giuseppe; Biancone, Livia; Borgiani, Paola

doi:10.1016/j.dld.2015.05.012

Cited by 37 publications

(21 citation statements)

References 52 publications

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“…Besides, a recent study suggested IRGM polymorphisms were related to gastric cancer in Chinese [ 23 ]. In accordance with previous findings, IRGM rs13361189 and rs4958847 polymorphisms were confirmed to be crucial for CD susceptibility and phenotype modulation [ 24 ]. Interestingly, it was reported that the polymorphisms of IRGM gene were involved in susceptibility to SLE [ 25 ].…”

Section: Discussionsupporting

confidence: 91%

Polymorphisms in Autophagy-Related Gene IRGM Are Associated with Susceptibility to Autoimmune Thyroid Diseases

Yao

Zhu

Wang

et al. 2018

BioMed Research International

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Background To date, studies have shown that polymorphisms in an autophagy-related gene, IRGM, are linked with different diseases, especially autoimmune diseases. The present study aimed to examine the roles of IRGM polymorphisms in autoimmune thyroid diseases (AITD). Methods Three polymorphisms in IRGM gene (rs10065172, rs4958847, and rs13361189) were genotyped in 1569 participants (488 with Graves' disease, 292 with Hashimoto's thyroiditis, and 789 healthy controls) using PCR-based ligase detection reaction method. Gene-disease associations were evaluated for the three SNPs. Results T allele of rs10065172, A allele of rs4958847, and C allele of rs13361189 were all higher in Graves' disease patients than controls, and the ORs were OR = 1.207 (P = 0.022), OR = 1.207 (P = 0.027), and OR = 1.200 (P = 0.027), respectively. After adjusting for sex and age, rs10065172 and rs13361189 were still associated with GD under both the allele model and dominant model, and the adjusted ORs for rs10065172 were 1.20 (P = 0.033) and 1.33 (P = 0.024), while the adjusted ORs for rs13361189 were 1.19 (P = 0.042) and 1.33 (P = 0.026), respectively. No significant difference was found between Hashimoto's thyroiditis patients and controls. Haplotype analysis found that CTA frequency was distinguishingly higher in Graves' disease patients (OR = 1.195, P = 0.030). The frequency of TCG haplotype was distinguishingly lower in AITD and Graves' disease patients (OR = 0.861, P = 0.044; OR = 0.816, P = 0.017). Conclusions Our study reveals IRGM as a susceptibility gene of AITD and Graves' disease for the first time.

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Section: Discussionsupporting

confidence: 91%

Polymorphisms in Autophagy-Related Gene IRGM Are Associated with Susceptibility to Autoimmune Thyroid Diseases

Yao

Zhu

Wang

et al. 2018

BioMed Research International

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“…Taken together, these findings identify a large number of CpG sites that are differentially methylated across the microbiota-defined clusters, whereof many in proximity to genes known to play a role in IBD. Based on the mucosal DNA of all subjects, we investigated whether the 264 reported gene loci associated with IBD [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] in the present study. While the sample size was insufficient for a Genome-Wide Association Study, a principal component analysis on nominal categorical data of the known IBD loci indicated a significant overlap of the three cohorts, albeit with a slight shift along the second component for UC ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Colonic microbiota is associated with inflammation and host epigenomic alterations in inflammatory bowel disease

et al. 2020

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Studies of inflammatory bowel disease (IBD) have been inconclusive in relating microbiota with distribution of inflammation. We report microbiota, host transcriptomics, epigenomics and genetics from matched inflamed and non-inflamed colonic mucosa [50 Crohn's disease (CD); 80 ulcerative colitis (UC); 31 controls]. Changes in community-wide and within-patient microbiota are linked with inflammation, but we find no evidence for a distinct microbial diagnostic signature, probably due to heterogeneous host-microbe interactions, and show only marginal microbiota associations with habitual diet. Epithelial DNA methylation improves disease classification and is associated with both inflammation and microbiota composition. Microbiota sub-groups are driven by dominant Enterbacteriaceae and Bacteroides species, representative strains of which are pro-inflammatory in vitro, are also associated with immune-related epigenetic markers. In conclusion, inflamed and non-inflamed colonic segments in both CD and UC differ in microbiota composition and epigenetic profiles.

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“…Genetic variation in autophagy genes has been linked to susceptibility to Crohn's disease, [40, 41] which makes clarification of the involvement of autophagy in the thiopurine mechanism of action even more interesting and important. For instance, a recent study in two IBD cohorts have shown that a risk variant of the autophagy-related protein 16L1 (ATG16L1) gene associates with response to thiopurine treatment in patients with CD [42].…”

Section: Discussionmentioning

confidence: 99%

Interconnections between apoptotic and autophagic pathways during thiopurine-induced toxicity in cancer cells: the role of reactive oxygen species

Chaabane

Appell

2016

Oncotarget

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Thiopurines (azathioprine, 6-mercaptopurine and 6-thioguanine) are a class of genotoxic drugs extensively used in the treatment of various illnesses including leukemia. Their underlying molecular mechanism of action involves the activation of apoptosis and autophagy but remains widely unclear. Here we present evidence that autophagy induction by thiopurines is a survival mechanism that antagonizes apoptosis and is involved in degrading damaged mitochondria through mitophagy. On the other hand, apoptosis is the main cell death mechanism by thiopurines as its inhibition prohibited cell death. Thus a tight interplay between apoptosis and autophagy controls cell fate in response to thiopurine treatment. Moreover, thiopurines disrupt mitochondrial function and induce a loss of the mitochondrial transmembrane potential. The involvement of the mitochondrial pathway in thiopurine-induced apoptosis was further confirmed by increased formation of reactive oxygen species (ROS). Inhibiting oxidative stress protected the cells from thiopurine-induced cell death and ROS scavenging prohibited autophagy induction by thiopurines. Our data indicate that the anticarcinogenic effects of thiopurines are mediated by complex interplay between cellular mechanisms governing redox homeostasis, apoptosis and autophagy.

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Autophagy and inflammatory bowel disease: Association between variants of the autophagy-related IRGM gene and susceptibility to Crohn's disease

Cited by 37 publications

References 52 publications

Polymorphisms in Autophagy-Related Gene IRGM Are Associated with Susceptibility to Autoimmune Thyroid Diseases

Polymorphisms in Autophagy-Related Gene IRGM Are Associated with Susceptibility to Autoimmune Thyroid Diseases

Colonic microbiota is associated with inflammation and host epigenomic alterations in inflammatory bowel disease

Interconnections between apoptotic and autophagic pathways during thiopurine-induced toxicity in cancer cells: the role of reactive oxygen species

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