Lecture 4 - Dr Francesca Capon Flashcards
What is a biomarker according to the US National Institutes of health?
“A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention”
What do genetic biomarkers include?
- DNA mutations
- HLA alleles
- Gene re-arrangements
- Gene deletions/duplications
A GWAS investing psoriasis identified how many disease susceptibility loci?
> 60
Can the psoriasis susceptibility loci identified by the GWAS be classed as diagnostic biomarkers?
Give an explanation for your answer
No
Individual susceptibility alleles identified from GWAS are also found in the general population who are psoriasis free
Susceptibility alleles in TYK2, TNFAIP3, IL23R also confer susceptibility to other conditions
Why can the psoriasis susceptibility loci identified by GWAS not be classed as prognostic biomarkers?
A marker that was identified by comparing cases and controls is unlikely to have prognostic value
How can psoriasis prognostic markers be identified using GWAS?
Comparison of patients with a more favourable outcome (Cutaneous psoriasis), with those with a more severe outcome (psoriatic arthritis).
How can GWAS be used for the Identification of prognostic markers in Crohn’s disease?
Severe (frequently flaring) vs mild disease (indolent) course compared
What did the GWAS for the Identification of prognostic markers in Crohn’s disease find?
4 loci associated with poor prognosis
None of the 4 prognostic markers had been associated with crohn’s disease susceptibility in previous GWAS
None of the 170 known Crohn’s disease susceptibility loci was associated with poor prognosis
Prognostic biomarkers are distinct from disease susceptibility loci
True or false
True
What key pathogenic pathways have been identified using the Psoriasis GWAS?
Psoriasis susceptibility alleles typically cluster to immune system pathway IL-23/IL-17, this is important for disease pathogenesis and thus for disease treatment
Cytokine composed of two subunits- IL12B and IL23A which bind to a dynamic receptor signal through several mediators , trigger production of IL-17 which binds receptors and activates downstream signal transduction and this culminates with the activation and then event of NFKBIA and the transcription and translation of inflammatory molecules
How has Psoriasis GWAS studies changed treatment options?
Prior to GWAS, molecule ustekinumab that functions to block IL12B was used for psoriasis treatment
Now:
Class of IL-17 molecule blockers – bimekizumab is currently under investigation, ixekizumab, secukinumab
and broadalumab are being incorporated in clinics,
IL23A molecule blockers- risanzikumab
guselkumab and tildrakizumabAll are all utilized in clinics
Thus GWAS has identified immune axis crucial for disease development and can be targeted by monoclonal antibodies for efficient disease treatment
What are the issues with the treatments identified through Psoriasis GWAS studies?
All treatments have equal first-line weighting. No particular recommendation as to which biological for severe psoriasis should be administered first.
1/3 of patients fail to respond to first biological. This results to a trial and error approach whereby clinician administers range of IL-23/IL-17 blockers and TNFα blockers.
This leads to patient, economy and NHS cost, physical and psychological morbidity and adverse drug effects.
What is the examined phenotype for theranostic biomarker identification?
Drug response- Drug responders vs non drug responders should be compared.
What are potential confounders when identifying a theranostic biomarker?
Missing data, co-therapy, arbitrary threshold for response
Disease allele identified in GWAS are predictive biomarkers
True or false
False
Disease allele identified in GWAS are NOT predictive biomarkers
