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- Shameer, S., et al.
(författare)
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TrypanoCyc: a community-led biochemical pathways database for Trypanosoma brucei
- 2015
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 43:D1, s. D637-D644
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Tidskriftsartikel (refereegranskat)abstract
- The metabolic network of a cell represents thecatabolic and anabolic reactions that interconvertsmall molecules (metabolites) through the activity ofenzymes, transporters and non-catalyzed chemicalreactions. Our understanding of individual metabolicnetworks is increasing as we learn more aboutthe enzymes that are active in particular cells underparticular conditions and as technologies advanceto allow detailed measurements of the cellularmetabolome. Metabolic network databases areof increasing importance in allowing us to contextualisedata sets emerging from transcriptomic,proteomic and metabolomic experiments. Here wepresent a dynamic database, TrypanoCyc (http://www.metexplore.fr/trypanocyc/), which describesthe generic and condition-specific metabolic networkof Trypanosoma brucei, a parasitic protozoan responsiblefor human and animal African trypanosomiasis.In addition to enabling navigation through the BioCyc-based TrypanoCyc interface, we have alsoimplemented a network-based representation of theinformation through MetExplore, yielding a novel environmentin which to visualise the metabolism ofthis important parasite.
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| 2. |
- Glicksberg, Benjamin S., et al.
(författare)
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Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits
- 2019
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Ingår i: BMC Medical Genomics. - : BMC. - 1755-8794. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundGenetic loss-of-function variants (LoFs) associated with disease traits are increasingly recognized as critical evidence for the selection of therapeutic targets. We integrated the analysis of genetic and clinical data from 10,511 individuals in the Mount Sinai BioMe Biobank to identify genes with loss-of-function variants (LoFs) significantly associated with cardiovascular disease (CVD) traits, and used RNA-sequence data of seven metabolic and vascular tissues isolated from 600 CVD patients in the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) study for validation. We also carried out in vitro functional studies of several candidate genes, and in vivo studies of one gene.ResultsWe identified LoFs in 433 genes significantly associated with at least one of 10 major CVD traits. Next, we used RNA-sequence data from the STARNET study to validate 115 of the 433 LoF harboring-genes in that their expression levels were concordantly associated with corresponding CVD traits. Together with the documented hepatic lipid-lowering gene, APOC3, the expression levels of six additional liver LoF-genes were positively associated with levels of plasma lipids in STARNET. Candidate LoF-genes were subjected to gene silencing in HepG2 cells with marked overall effects on cellular LDLR, levels of triglycerides and on secreted APOB100 and PCSK9. In addition, we identified novel LoFs in DGAT2 associated with lower plasma cholesterol and glucose levels in BioMe that were also confirmed in STARNET, and showed a selective DGAT2-inhibitor in C57BL/6 mice not only significantly lowered fasting glucose levels but also affected body weight.ConclusionIn sum, by integrating genetic and electronic medical record data, and leveraging one of the world's largest human RNA-sequence datasets (STARNET), we identified known and novel CVD-trait related genes that may serve as targets for CVD therapeutics and as such merit further investigation.
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