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Non-T2 Asthma Disease Study

Better diagnostics and therapy selection

>20

novel genes identified in the non-T2 population with strong, testable hypotheses for their mechanism of action

targets

multiple promising novel drug targets for the development of personalized therapies for non-allergic asthma patients

stratification

clear stratification of pathways, between the two asthma subtypes, with different underlying mechanisms of action

Overview

The Global Initiative for Asthma estimates that 334 million people are affected by asthma.  Patients that experience persistent symptoms, frequent asthma attacks, or low lung function despite taking asthma medication form a relatively large group of patients known as treatment-refractory asthmatics.

We analyzed SNP genotype data from 42,000 asthma patients using combinatorial analytics followed by k-means clustering and pathway enrichment to identify statistically significant combinations of up to five SNP genotypes.

Our analysis found that many of the most critical SNP clusters are related to immune system pathways, and antigen presentation and processing.

Our comparative study between the T2 and non-T2 asthma patient populations clearly demonstrated the opportunity and means to address the unmet medical need of non-T2 patients. These findings hold significant potential for better patient stratification, diagnosis biomarkers, and new treatment options.

Background

Asthma is a broad diagnostic label given to a range of conditions that exhibit similar clinical features, including: chronic airway inflammation, reversible airflow obstruction, wheezing, shortness of breath, chest tightness.

Several pathophysiological processes can lead to asthma and patients can be broadly categorized into two molecular phenotypes: those with high type 2 T-helper cell expression (T2), and those with low type 2 T-helper cell expression (non-T2).

Asthma patients with a T2 phenotype currently have a range of targeted biologic treatment options available to them. However, non-T2 patients lack targeted therapy, and must often rely on conventional symptomatic control therapies (such as bronchodilators and inhaled corticosteroids) that do little to combat the underlying disease pathology.

Non-T2 Asthma Disease Architecture

570 disease risk loci (SNPs)

>200 risk-associated genes mapped to disease associated mechanisms.

>20 druggable targets

281 drug repurposing compounds

 

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Asthma

Outcomes

Better patient stratification, diagnosis biomarkers and treatment options

The study confirmed the key genetic differences between T2 and non-T2 asthma, and further differentiated these two major asthma subtypes as radically different diseases based on genetic architecture.

Our findings are well-aligned with the common understanding that cytokine regulation (especially IL-5 and IL-13) plays a key role in T2 asthma, and provide some promising novel indications of the mechanisms underpinning the pathogenesis of non-T2 asthma.

The clear segregation of pathways demonstrates that they are two distinct diseases with different underlying mechanisms of action.

We have identified over 20 novel genes that are significant only in the non-T2 population with strong, testable hypotheses for their mechanism of action.

These represent promising opportunities for the development of personalized therapies for patients presenting with non-allergic asthma.

fig 11. PrecisionLife improving health, for everyone-min

Collaborators

HDRUK Breathe

BREATHE Health Data Research Hub

Uni of Nottingham

University of Nottingham

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