Late Breaking Abstract - Patient stratification of two asthma populations reveal distinct genetic and mechanistic differences between T2-high and T2-low asthma

Asthma can be viewed as two major endotypes (T2-high and T2-low), characterised by distinct molecular drivers. The PrecisionLife (PL) platform uses a hypothesis-free method for identifying combinations of genetic variants (SNPs) that are strongly associated with variations in disease risk, progression and clinical phenotypes in patient subgroups, generating high-resolution, mechanistic patient stratification of complex diseases. Using patients with blood eosinophil data from UK Biobank, PL identified genetic differences between T2-high and T2-low asthma cohorts, with 2,483 SNPs highly associated with T2-high asthma and 1,182 SNPs with T2-low and only 36 SNPs common between both. Comparative pathway enrichment indicates the unique SNPs relate to clear differences in biological processes; genes associated with T2-high asthma regulate T2-driven allergic immune pathways, whereas patients with T2-low asthma have combinations of variants associated with neutrophilic inflammation, apoptosis, metal ion binding and lipid metabolism. In 2024, PL accessed a secondary population derived from the GASP (Genetics of Asthma Severity and Phenotypes) study. Analysis of genotype data recapitulated PL’s findings from UK Biobank, confirming the genetic differences between T2-high and T2-low asthma and validating 12 shortlisted drug targets in T2-low asthma. Greater understanding of mechanisms driving T2-low asthma can be used to develop more targeted and efficient treatments to improve asthma control. The additional confirmation derived from analysis of the GASP population has provided further validation in the prioritisation of potential new drug targets in T2-low asthma.