Non-coding DNA in IBD: from sequence variation in DNA regulatory elements to novel therapeutic potential

Meddens, Claartje A.; List, Amy C. J. van der; Nieuwenhuis, Edward E. S.; Mokrý, Michal

doi:10.1136/gutjnl-2018-317516

Cited by 25 publications

(27 citation statements)

References 169 publications

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“…Pathological GVs, affecting the binding activity of TFBSs, can be located not only in promoter regions, but also in regulatory regions located at considerable distance from transcription start sites (TSSs) of genes: enhancers (Lewinsky et al, 2005;Zhang et al, 2018;Meddens et al, 2019) Fig. 1.…”

Section: Disturbances Of Lipid Metabolism Rs174537 G→tmentioning

confidence: 99%

“…It is known that non-coding regions of the genome contain regions that perform a wide range of regulatory functions: promoter regions, enhancers, negative regulatory elements, nuclear matrix attachment regions, regions that determine the structure of topologically associating domains (TADs), and other features of 3D organization of genome (Mathelier et al, 2015;Meddens et al, 2019;Ibrahim, Mundlos, 2020). The proportion of regions in the human genome potentially involved in the transcriptional regulation is extremely high.…”

Section: Introductionmentioning

confidence: 99%

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Disease-associated genetic variants in the regulatory regions of human genes: mechanisms of action on transcription and genomic resources for dissecting these mechanisms

Ignatieva

Matrosova

2021

Vestn. VOGiS

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Whole genome and whole exome sequencing technologies play a very important role in the studies of the genetic aspects of the pathogenesis of various diseases. The ample use of genome-wide and exome-wide association study methodology (GWAS and EWAS) made it possible to identify a large number of genetic variants associated with diseases. This information is accumulated in the databases like GWAS central, GWAS catalog, OMIM, ClinVar, etc. Most of the variants identified by the GWAS technique are located in the noncoding regions of the human genome. According to the ENCODE project, the fraction of regions in the human genome potentially involved in transcriptional control is many times greater than the fraction of coding regions. Thus, genetic variation in noncoding regions of the genome can increase the susceptibility to diseases by disrupting various regulatory elements (promoters, enhancers, silencers, insulator regions, etc.). However, identification of the mechanisms of influence of pathogenic genetic variants on the diseases risk is difficult due to a wide variety of regulatory elements. The present review focuses on the molecular genetic mechanisms by which pathogenic genetic variants affect gene expression. At the same time, attention is concentrated on the transcriptional level of regulation as an initial step in the expression of any gene. A triggering event mediating the effect of a pathogenic genetic variant on the level of gene expression can be, for example, a change in the functional activity of transcription factor binding sites (TFBSs) or DNA methylation change, which, in turn, affects the functional activity of promoters or enhancers. Dissecting the regulatory roles of polymorphic loci have been impossible without close integration of modern experimental approaches with computer analysis of a growing wealth of genetic and biological data obtained using omics technologies. The review provides a brief description of a number of the most well-known public genomic information resources containing data obtained using omics technologies, including (1) resources that accumulate data on the chromatin states and the regions of transcription factor binding derived from ChIP-seq experiments; (2) resources containing data on genomic loci, for which allele-specific transcription factor binding was revealed based on ChIP-seq technology; (3) resources containing in silico predicted data on the potential impact of genetic variants on the transcription factor binding sites.

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Section: Disturbances Of Lipid Metabolism Rs174537 G→tmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Disease-associated genetic variants in the regulatory regions of human genes: mechanisms of action on transcription and genomic resources for dissecting these mechanisms

Ignatieva

Matrosova

2021

Vestn. VOGiS

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“…Considering accumulating evidence for a role of non-coding common genetic variation in human health in general [26,27], as well as in inflammatory responses in specific [28,29]. All common variants (cohort AF>0.05) within a set were pruned for Linkage Disequilibrium (LD), using within cohort R 2 metrics.…”

Section: Immunological Response To C Albicans Reflects a Common Varimentioning

confidence: 99%

Impact of rare and common genetic variation in the Interleukin-1 pathway on human cytokine responses

Deuren

Arts

Cavalli

et al. 2020

Preprint

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Interleukin(IL)-1 signaling is of major importance in human innate cytokine responses. Common variants in underlying genes have been linked to various inflammation-mediated diseases and stimulation induced cytokine responses, but the role of rare variants remains to be elucidated.In this study, we characterize the role of rare and common genetic variation, as identified by molecular inversion probe-based sequencing, in 48 genes related to the IL-1 pathway. We examined the inter-individual variability in in vitro stimulation-specific human cytokine responses from 463 healthy individuals of the Human Functional Genomics Project and assessed the role of rare and common genetic variants, separately and combined, by means of the Sequence Kernel Association Test with various variant grouping strategies.We identified strong NCF4 and CASP1 rare genetic variant associations with IL-6 cytokine production in response to PHA (P=7.2E -05 ) and LPS (P=3.0E -05 ) stimulation. In addition, common variants in IL36A and IL38 were associated to both C. albicans induced IL-1β and IL-6 (IL36A P=0.0442 and 0.0037; IL38 P=0.0092 and 0.0082), an effect that was magnified on the respective IL-30 subpathway level (IL-1β P=0.0017; IL-6 P=1.8E -04 ). The inflammatory-phenotype level analysis confirmed the common variant signature for the immunological response to C. albicans by an association with the anti-inflammatory group (IL-1β P=1.87E -03 ; IL-6 P=5.75E -04 ), and we validated this finding for non-coding common variants. Lastly, we identified a rare variant signature for LPS-induced IL-6 production with the pro-inflammatory group (P=2.42E -04 ), and we detected a new role for anti-inflammatory rare variants on S. aureus stimulated IL-6 cytokine (P=6.71E -03 ).In conclusion, we show that both common and rare genetic variation in genes of the IL-1 pathway, separately and combined, differentially influence in vitro cytokine responses to various stimuli in healthy individuals. This study therefore provides insight into potential mechanisms that are translatable into new hypothesis-driven characterization of common and rare genetic variant involvement in a wide variety of inflammatory and immunological mechanisms and diseases.

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“…It is also important that over the last years, some functions of noncoding DNA have been discovered, and the role of regulatory sequences in transcriptional regulation, development of the disease process, and determination of cell type specificity is nowadays widely appreciated [11].…”

Section: Ahr and Its Role In Regulating Intestinal Inflammationmentioning

confidence: 99%

“…GWAS research was aimed at searching the SNPs that are over-represented in IBD patients when compared with healthy controls. SNPs that occurred more frequently in IBD patients are thus called disease-associated variants [11].…”

Section: Introductionmentioning

confidence: 99%

Single-Nucleotide Polymorphisms in Inflammatory Bowel Disease

Dudzińska¹

2020

The Recent Topics in Genetic Polymorphisms

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Inflammatory bowel disease (IBD) mainly includes ulcerative colitis (UC) and Crohn's disease (CD). Both conditions are characterized by chronic inflammation of the gastrointestinal tract, with alternating periods of relapse and remission. Both forms of IBD involve an uncontrolled inflammatory process in the intestines, leading to worsening quality of life and requiring long-term medical and/or surgical intervention. Epidemiological and clinical studies suggest that the pathogenesis of inflammatory bowel disease is strongly linked to genetic predisposition. CD and UC are considered polygenic diseases in which familial clustering is observed in 5-10% of patients. Among genetic factors associated with IBD development, it has been found that many single nucleotide polymorphisms are associated with susceptibility to IBD progression. SNP can affect the production or function of a protein and thus affect the development of the disease. However, although the overall role of genes involved in the development of IBD is already in most cases known, as of today it is unclear how the SNPs in these genes affect cellular function, or how such changed cellular functions would contribute to the development of IBD. In the present work several selected polymorphisms in genes involved in IBD development are discussed.

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Non-coding DNA in IBD: from sequence variation in DNA regulatory elements to novel therapeutic potential

Cited by 25 publications

References 169 publications

Disease-associated genetic variants in the regulatory regions of human genes: mechanisms of action on transcription and genomic resources for dissecting these mechanisms

Disease-associated genetic variants in the regulatory regions of human genes: mechanisms of action on transcription and genomic resources for dissecting these mechanisms

Impact of rare and common genetic variation in the Interleukin-1 pathway on human cytokine responses

Single-Nucleotide Polymorphisms in Inflammatory Bowel Disease

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