Genome-wide association study identifies kallikrein 5 in type 2 inflammation-low asthma

Area of Science:

• Genetics
• Immunology
• Respiratory Medicine

Background:

• A significant portion of asthma patients with low type 2 (T2) inflammation do not respond to T2 cytokine-targeting therapies.
• Non-T2 inflammatory pathways in asthma are not well understood, representing a critical unmet medical need.

Purpose of the Study:

• To investigate the genetic factors contributing to T2-low asthma.
• To identify novel genes and pathways involved in non-T2 asthma mechanisms.

Main Methods:

• Genome-wide association study (GWAS) in moderate to severe asthma patients, stratified by periostin levels (a T2 biomarker).
• Expression and biological analyses were performed on top genetic associations.

Main Results:

• A protective single nucleotide polymorphism (SNP) at chr19q13.41 was identified, specifically linked to T2-low asthma.
• Kallikrein-related peptidase 5 (KLK5) was established as the causal gene; reduced KLK5 expression was observed in carriers of the protective SNP.
• KLK5, secreted by bronchial epithelial cells and elevated in asthma, is downregulated by T2 cytokines (IL-4, IL-13) and induces airway inflammation.

Conclusions:

• KLK5 is identified as the causal gene at the chr19q13.41 locus associated with T2-low asthma.
• This discovery provides a new understanding of the genetic underpinnings of non-T2 asthma.
• KLK5 emerges as a potential therapeutic target for a subset of asthma patients unresponsive to current T2-targeted treatments.