DGIdb 3.0: a redesign and expansion of the drug-gene interaction database

Cotto, Kelsy C.; Wagner, Alex H.; Feng, Yangyang; Kiwala, Susanna; Coffman, Adam; Spies, Gregory C.; Wollam, Alex; Spies, Nicholas C.; Griffith, Obi L.; Griffith, Malachi

doi:10.1101/200527

Cited by 117 publications

(137 citation statements)

References 25 publications

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“…Genes whose expression levels were significantly correlated with insertion counts (FDR <0.05; adjusted combined P-values across all cancer types using the Fisher's method) were defined as key genes for each pathway. We annotated key genes for each significant immune pathway with their druggability using the Drug Gene Interaction Database (DGIdb) (Cotto et al 2018). We obtained additional gene sets reflecting diverse aspects of the immune system (Rooney et al 2015) and known L1 inhibitors from previous publications (Goodier 2016).…”

Section: Pathway Activity Analysismentioning

confidence: 99%

Immune signatures correlate with L1 retrotransposition in gastrointestinal cancers

2018

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Long interspersed nuclear element-1 (LINE-1 or L1) retrotransposons are normally suppressed in somatic tissues mainly due to DNA methylation and antiviral defense. However, the mechanism to suppress L1s may be disrupted in cancers, thus allowing L1s to act as insertional mutagens and cause genomic rearrangement and instability. Whereas the frequency of somatic L1 insertions varies greatly among individual tumors, much remains to be learned about underlying genetic, cellular, or environmental factors. Here, we report multiple correlates of L1 activity in stomach, colorectal, and esophageal tumors through an integrative analysis of cancer whole genome and matched RNA sequencing profiles. Clinical indicators of tumor progression, such as tumor grade and patient age, showed positive association. A potential L1 expression suppressor, TP53, was mutated in tumors with frequent L1 insertions. We characterized the effects of somatic L1 insertions on mRNA splicing and expression, and demonstrated an increased risk of gene disruption in retrotransposition-prone cancers. In particular, we found that a cancer-specific L1 insertion in an exon of MOV10, a key L1 suppressor, caused exon skipping and decreased expression of the affected allele due to nonsense-mediated decay in a tumor with a high L1 insertion load. Importantly, tumors with high immune activity, for example, those associated with Epstein-Barr virus infection or microsatellite instability, tended to carry a low number of L1 insertions in genomes with high expression levels of L1 suppressors such as APOBEC3s and SAMHD1. Our results indicate that cancer immunity may contribute to genome stability by suppressing L1 retrotransposition in gastrointestinal cancers.

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Section: Pathway Activity Analysismentioning

confidence: 99%

Immune signatures correlate with L1 retrotransposition in gastrointestinal cancers

2018

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“…A p ‐value <.05 was considered to be statistically significant. Finally, the inclusion of identified genes in the druggable genome was checked using DGIdb (Cotto et al, ), while the functional effect of top scoring SNPs on gene expression in brain regions was checked using GTEx V.8 (GTEx Consortium, ).…”

Section: Methodsmentioning

confidence: 99%

A pharmacogenetic risk score for the evaluation of major depression severity under treatment with antidepressants

Kanders

Pisanu

Bandstein

et al. 2019

Drug Development Research

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The severity of symptoms as well as efficacy of antidepressants in major depressive disorder (MDD) is modified by single nucleotide polymorphisms (SNPs) in different genes, which may contribute in an additive or synergistic fashion. We aimed to investigate depression severity in participants with MDD under treatment with antidepressants in relation to the combinatory effect of selected genetic variants combined using a genetic risk score (GRS). The sample included 150 MDD patients on regular AD therapy from the population‐based Swiss PsyCoLaus cohort. We investigated 44 SNPs previously associated with antidepressant response by ranking them with regard to their association to the Center for Epidemiologic Studies Short Depression Scale (CES‐D) score using random forest. The three top scoring SNPs (rs12248560, rs878567, rs17710780) were subsequently combined into an unweighted GRS, which was included in linear and logistic regression models using the CES‐D score, occurrence of a major depressive episode (MDE) during follow‐up and regular antidepressant treatment during the 6 months preceding follow‐up assessment as outcomes. The GRS was associated with MDE occurrence (p = .02) and ln CES‐D score (p = .001). The HTR1A rs878567 variant was associated with ln CES‐D after adjustment for demographic and clinical variables [p = .02, lower scores for minor allele (G) carriers]. Additionally, rs12248560 (CYP2C19) CC homozygotes showed a six‐fold higher likelihood of regular AD therapy at follow‐up compared to minor allele homozygotes [TT; ultrarapid metabolizers (p = .03)]. Our study suggests that the cumulative consideration of pharmacogenetic risk variants more reliably reflects the impact of the genetic background on depression severity than individual SNPs.

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“…The Drug Gene Interaction database, DGIdb (www.dgidb.org) has been used to integrate, organize and display drugs, gene interactions and gene-drug information from published articles and web resources (10). It can be standardized content from 30 different sources and allows to search and lter information.…”

Section: Drug Prediction Of Degsmentioning

confidence: 99%

Bioinformatics Analysis of the Regulatory lncRNA-miRNA-mRNA Network in Patients with Neuropathic Pain

Zhang

Liu

Song

et al. 2020

Preprint

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Background: Neuropathic pain (NP) is the main form of chronic pain, caused by damage to the nervous system and dysfunction. Methods: Here, we explore the key molecules involved in the development of NP condition via identification of lncRNA-miRNA-mRNA expression pattern of patients with NP. We identified differentially expressed miRNAs, lncRNA and mRNA through a comprehensive analysis strategy. Subsequently, we used bioinformatics approach to perform pathway enrichment analysis on DEGs and protein-protein interaction analysis. Combined with the three datasets, the lncRNA-miRNA-mRNA network was constructed. It will then be used as targets for drug prediction. Results: The results showed that a total of 8,251 DEGs (4,193 upregulated and 4,058 downregulated) were identified from the three microarray datasets, 959 DEmiRs (455 upregulated and 504 downregulated), 2,848 DElncs (1,324 upregulated and 1,524 downregulated). GO analysis showed that DEGs are mainly enriched in blood circulation, regulation of membrane potential and regulation of ion transmembrane transport. KEGG results showed that DEGs are enriched in neuroactive ligand-receptor interaction, PI3K-Akt signaling pathway and MAPK signaling pathway. When the correlation is set to above 0.8, a total of 31 lncRNAs, 36 miRNAs and 24 mRNAs were screened in the lncRNA-miRNA-mRNAs network. The results of drug prediction indicated the targeted drugs mainly include INDOMETHACIN, GLUTAMIC ACID and PIRACETAM. Conclusion: The lncRNA-miRNA-mRNA network has been carried out a comprehensive biological information analysis and predicted the potential therapeutic application of drugs in patients with NP. The corresponding data has a certain reference for studying the pathological mechanism of NP.

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DGIdb 3.0: a redesign and expansion of the drug-gene interaction database

Cited by 117 publications

References 25 publications

Immune signatures correlate with L1 retrotransposition in gastrointestinal cancers

Immune signatures correlate with L1 retrotransposition in gastrointestinal cancers

A pharmacogenetic risk score for the evaluation of major depression severity under treatment with antidepressants

Bioinformatics Analysis of the Regulatory lncRNA-miRNA-mRNA Network in Patients with Neuropathic Pain

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