Jonathan Edwards
Senior Member (Voting Rights)
it may also be worth remembering that 'MHC' originally refers to gene products that determine histocompatibility of allograft cells - which is not to do with their antigen presenting function.
The relevance here is that in the first exposure of the DecodeME data to the advisory board Chris showed a nice peak in MHC. I was puzzled when I saw the published data with a peak for BTN2A2 on chromosome 6 but nothing else. As far as I can see the reason is that BTN2A2 is within MHC.
Do they mention why they had reason to distrust it anywhere?It wasn’t mentioned much at all in the manuscript because the DecodeME team had reason to distrust the association.
DCC is a netrin-1 receptor, and it seems to be relevant to the functioning of epithelial cells of various sorts.To put this into a biological systems context, some physiology is required. In the gastrointestinal tract, epithelial cells proliferate and die rapidly. The division of these cells occurs at the base of villi, and cells are pushed upwards by subsequent divisions to the tip where they enter apoptosis and shed off into the lumen. Netrin-1 is produced in the base of the villi, so a gradient of netrin is present that is weakest at the tip. In normal physiology, the presence of netrin-1 inhibits DCC-mediated cell death until the epithelial cell reaches the tip of the villus, where the now unbound DCC causes the cell to enter apoptosis. In a cancer state, the absence of DCC prevents the gradient from having an effect on the cell, making it more likely to continue to survive.
LRRC7
What is Epithelial Cell Polarity?Predicted to be involved in several processes, including establishment or maintenance of epithelial cell apical/basal polarity
Co-culture with acutely and chronically activated T cells decreased the magnitude of ion flux through the pore pathway, which was maintained in the presence of acutely activated T cells. Chronically activated T cells after 30 hours induced a precipitous increase in the magnitude of both ion and molecular flux, resulting in an increase in the unrestricted pathway, destruction of microvilli, expansion in cell surface area, and cell death. These fluctuations in permeability were the result of changes in the assembly and expression of tight junction proteins, cell morphology, and viability.
Yes it was in the results section on HLA, had to do with lack of linkage disequilibrium where it was expected leading them to suspect an imputation issue, if my memory serves. I am on my phone so cannot quote the textDo they mention why they had reason to distrust it anywhere?
Yes it was in the results section on HLA, had to do with lack of linkage disequilibrium where it was expected leading them to suspect an imputation issue, if my memory serves. I am on my phone so cannot quote the text
Indeed. And the alleles that matter for compatibility are the ones in the actual HLA protein complexes.it may also be worth remembering that 'MHC' originally refers to gene products that determine histocompatibility of allograft cells - which is not to do with their antigen presenting function.
The DCC gene is an netrin-1 receptor. LRRC4B is a netrin-G3 ligand (that is, it binds to a receptor).LRRC4B
We also identified a missense variant in TAOK3 (the gene for tau kinase 3) as the top association signal in this locus. The risk allele (rs428073-T) substitutes the 47th amino acid of TAOK3 fromserine to asparagine (S47N), whose functional role remains unknown. S47 is located at the loop region between strands β2and β3, and the substitution should not change the overall strucure of the protein, despite being well conserved among orthologous proteins during evolutionary courses (SupplementaryFigure 10, on the Arthritis & Rheumatology website at https://onlinelibrary.wiley.com/doi/10.1002/art.42021). Taok3 plays animportant role in DNA damage–induced activation of the p38/MAPK14 stress-activated MAPK cascade. It enhances T cell receptor signaling by regulating its negative feedback by SH2domain–containing phosphatase 1 (44), and Taok3 deficiency in mice was found to cause defects in the development of marginalzone B cells but not follicular B cells (45).
Is this for the same hit that was annotated to SUDS3 in DecodeME?A gene that hasn't been disucssed much is TAOK3 on chromosome 12 (it wasn't a Tier 1 gene). It has been previously been associated with Lupus at around the same region as in DecodeME. The vertical dotted line in the graph below shows the location for the Lupus hit (12:118244946) with the SNP summary data from DecodeME.
View attachment 28547
The Lupus GWAS said this about it:
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Identification of Shared and Asian-Specific Loci for Systemic Lupus Erythematosus and Evidence for Roles of Type III Interferon Signaling and Lysosomal Function in the Disease: A Multi-Ancestral Genome-Wide Association Study - PubMed
In this study both shared and Asian-specific loci for SLE were identified, and functional annotation provided evidence of the involvement of increased type III IFN signaling and reduced lysosomal function in SLE.pubmed.ncbi.nlm.nih.gov