evotec_Nov23_PanOmicsDriven - 28

The PanHunter Platform
human signaling network containing protein-protein,
miRNA-mRNA. and transcription factor
binding interactions. Unsupervised clustering
algorithms grouped these patient-specific networks
into four distinct clusters driven by PRKCB, HLA,
SNAI1/CEBPB/PTPN1 and VEGFA/XPO5/POLH
hubs. Pathway analysis identified calcium homeostasis,
wound healing, and cell motility as key
processes in UC pathogenesis.
" Using transcriptomic data from an independent
patient cohort, we validated the regulatory impact
of non-coding SNPs. iSNP identified regulatory
effects for disease-associated non-coding SNPs,
and by predicting the patient-specific pathogenic
processes, proposes a systems-level way to stratify
patients. "
" The workflow's ability to identify cohorts of
disease associated mutations and pathways isn't
limited to IBD; it has the potential for use in other
complex disease including mental health, heart
disease and autoimmune conditions, " said co-lead
study author Tamas Korcsmaros, PhD, from the
Earlham Institute and the Quadram Institute.
" To develop precision therapies based on patient
specific genetics opens up the possibility of much
needed personalized medicine approaches to tackle
these complex and poorly understood conditions. "
Inflammatory Bowel Disease affects around
500,000 people in the U.K., causing a range of
painful and debilitating symptoms linked to
inflammation of the gut. The causes of IBD are not
understood but are linked to dysfunction of the
immune system and how it reacts to food and the
gut microbiome. There is also a strong genetic link
to IBD susceptibility.
To unpick how these complex factors interact in
the development of IBD, the research team came
together to link the genetic component of IBD
susceptibility to its effects on patients. Previous
studies have linked the disease to specific alterations
in the genetic code, finding minor changes
of just one letter in the genetic code that associate
with IBD. These single nucleotide polymorphisms
(SNPs) can be mapped to the human genome.
If a SNP linked to IBD maps to a gene, it identifies
that gene and its genetic code as being important
in the disease. For some conditions this has led
to improved therapies.
However, for IBD, less than 10% of the identified
SNPs were in genes. Instead, over 90% of SNPs were
in non-coding regions of the genome. This is not
surprising, as most of the human genome is made
up of this non-coding DNA, with genes comprising
just 1%. The other 99% was once thought to just be
junk DNA, but we now know it has important roles
in controlling and regulating gene activity.
Additionally, some SNPs may only have subtle
effects, but in combination lead to disease progression.
Given the complex nature of IBD, it was likely
this was the case for this condition. The immune
system functions by taking a wide range of different
inputs that trigger different signaling networks
within the cell, integrating these to produce a
balanced, appropriate response.
Understanding how all of the IBD associated
SNPs in non-coding regions of the genome combine
to influence these intricately interlinked signals in
the development of IBD would fill in major gaps in
our knowledge.
28
GENengnews.com
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evotec_Nov23_PanOmicsDriven

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