Monthly Archives: February 2016

  • Strobing the tissues

    Opus 23 provides many unique opportunities for data integration and visualization. One app that I’ve just been added to the Opus toolbox is STROBE, a new Opus analytic app that allows you drill-down client genomic data by organ, tissue or cell distribution. To do this Opus mashes up its own internal SNP data with gene tissue expression data derived from a variety of public databases. I then sub-organized the tissue expression data by system (immune, cardiovascular, etc) so that the user could filter by clinical relevance.

    Once STROBE is fired up you’re presented with the screen depicted above. It is a typical squarified heat-map rendered in Highcharts. Values are assigned by virtue of the aggregate power factors of client SNP mutations number of genes associated with that tissue. Clicking on any tissue brings up a modal popup with a Manhattan-type gene distribution display.

    strobe1

    Y axis shows cumulative power factors of SNPs testing positive for that gene. The X axis is rough approximation of gene locus position. Yellow points indicate genes with exclusively heterozygous mutations. Orange points denote genes that contain homozygous mutations. Drag a rectangle around any area to zoom into that part of the map. Use the ‘Reset Zoom’ to return to full zoom.

    Clicking on any data point to bring up the information screen on that gene. Here you can notate, or even move on to examining SNPS, agents and algorithms associated with the gene.

    strobe2

    From them main screen you can use the select pull-down menu to limit tissues to specific systems. Here we limit the display to tissues, organs and cells of the immune system:

    strobe0a

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  • Don’t Fall into the Methyl Trap!

    Methyl trapping is a situation in which folate becomes trapped and unusable by the body. It is defined as a functional folate deficiency that alters homocysteine metabolism such that folatedependent resynthesis of methionine is compromised.

    Methyl trapping was originally described in Downs Syndrome (trisomy 21) where plasma levels of homocysteine, methionine, S-adenosylhomocysteine and S-adenosylmethionine were all significantly decreased, suggesting a depression in cellular methylation capacity.  Elevated transsulfation activity with depletion of glutathione was also observed in Downs Syndrome due to the presence of an additional CBS allele, and up-regulated chromosome 21 SOD SNPs causing oxidative stress.(1)

    DS HcyThe term methyl trapping is now applied to the cascade of symptoms of neuroexcitation following supplementation with folate,  or B12 or SAMe as a first line treatment for MTHFR SNPs. The unassuming consumer who takes supplements with methylating B vitamins may experience varying degrees of neurotoxic symptoms manifested as apparently unprovoked insomnia, rage, anxiety, brain fog and alcohol intolerance (induced sulfite and aldehyde toxicity), often after experiencing a brief period of improvement from low energy and cognitive impairment.

    Methylation ModulationLow energy and irritability occur because of a dysregulation within the methionine cycle due to one-carbon metabolism SNPcausing an accumulation of Homocysteine Pathwaymethyl compounds often complicating histamine degradation. A build up of homocysteine is the consequence, often worsened by a bottleneck at CBS (cystathionine beta synthase) due to down-regulating SNPs in the homocysteine clearing transsulfation pathway.

    Neuroexcitatory and depression symptoms ensue from the complication of BH2-BH4 pathway reversal, resulting in incomplete ammonia-clearing by the urea cycle and reduced neurotransmitter formation.BH4-Chart3

    SNPs in MAO and COMT reduce degradation and transporter protein SNPs contribute to dopamine-serotonin imbalance.(2) Patients can also experience poor wound healing, aggravated digestive symptoms of bloating, alternating constipation and diarrhoea, or worsened IBS as a result of reduced methylation capacity.

    Clinicians should screen for conditions that may overwhelm transsulfation and detoxification pathways including infection, autoimmunity, toxic body burden, problems with blood sugar and fat metabolism and other inflammatory indications. Non-methylating nutritional support should be provided for mutations in MTR/MTRR, BHMT, SHMT2, MAT1A, CBS, QDPR, OTC, CPS, ARG2, PCBD1, MAOA or B, COMT, HNMT, DHPR, NOS1, 2, 3, SOD1, SOD2, PEMT, PON1, ABCB1, cytochrome P 450 genes and Soluble Carrier Family transporter protein SNPs, ACAT1-02, in deciding when to support Methylation cycle SNPs.

    Methyl trapping at a glance:

    Practitioners can use cutting-edge cloud-based software curated by naturopathic physicians. Mobocaster is a cutting edge application in Opus23 Pro offering the practitioner scenario-specific genetic analysis including power factors and relevant descriptions.

    References:

    1. Pogribna M, Melnyk S, Pogribny I, Chango A, Yi P, James SJ. Homocysteine
      metabolism in children with Down syndrome: in vitro modulation. Am J Hum Genet.
      2001 Jul;69(1):88-95. PMID: 11391481.
    2. Finkelstein JD. Pathways and regulation of homocysteine metabolism in mammals.
      Semin Thromb Hemost. 2000;26(3):219-25. Review. PMID: 11011839.
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  • Psychic

    The Opus 23 PSYCHIC app allows you to search for natural products known to control gene expression. However, unlike a simple search engine, PSYCHIC is able to crawl up and down the molecular ‘Interactome’ (protein-protein interactions and gene expression data) to determine the upstream and downstream genes that interact with the gene you’ve searched for. In addition PSYCHIC allows you to chose which type of natural products (agonists/ antagonists) to include in the upstream and downstream results.

    As seen above, when the PSYCHIC screen loads you will be presented with the results of the default search term for the current client, the MTOR gene. The main infographic is comprised of a bar graph divided into two halves. The left half displays the upstream results, while the right half displays the downstream results, based on MTOR’s position in the interactome. The labels along the x-axis display the various natural products and their gene targets PSYCHIC has found that meet the search criteria. The y-axis value of each bar in the graph is determined by the evidence basis and strength of the position in the network for the gene depicted.

    At the bottom is a small half-pie chart depicts the SNPs for that gene contained in the Opus 23 Pro database.

    psychic2

    You can set filters on each half of the graph to limit results to a specific type (agonism or antagonism) by selecting an option from the pull down menu below. There are four options:

    • Inhibit/ Drain: This will tell PSYCHIC to return all upstream antagonists and downstream agonists
    • Inhibit/ Bottleneck: This will tell PSYCHIC to return all upstream antagonists and downstream antagonists
    • Stimulate/Drain: This will tell PSYCHIC to return all upstream agonists and downstream agonists
    • Stimulate/ Bottleneck: This will tell PSYCHIC to return all upstream agonists and downstream antagonists

    To select a gene to run in PSYCHIC, simply begin typing in its gene symbol in the text input field; PSYCHIC will auto-complete the entry with any genes for which it has data. If multiple options are displayed, simply select the gene you wish to analyze.

    When you’re ready, press the ‘Run Psychic’ button to have PSYCHIC run results.

    PSYCHIC uses highcharts.js for its data depiction, the CPAN Perl module graph.pm for creating the abstract data structures, the PPI (protein-protein interactions) database, and Opus 23’s own internal agent/gene expression database of PubMed citations.

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