IL-33 Gene Splice Variant Could Play Role in Early Onset Asthma

Investigators have proposed a rare splice variant in the interleukin-33 (IL-33) gene may be protective against the development of early onset asthma.

The findings, planned for presentation at the American Thoracic Society (ATS) 2020 International Conference, may help dictate future assessment of potential IL-targeting therapies in allergic and asthmatic care.

A team of AstraZeneca-led investigators looked into expanding the clinical understanding of IL-33, particularly in asthmatic patients. Its role as an emerging therapeutic target, along with other biologic candidates, had led to increased available clinical data.

“While numerous Genome Wide Association studies have independently identified the IL-33 gene as associated with asthma susceptibility, little is known of asthma subtype(s) that may have IL-33 driven disease,” they wrote.

The team used whole exome sequence data from subjects in the UK Biobank (UKBB) to interrogate the relationship between a rare, loss-of-function splice variant within IL-33 and asthma clinical characteristics. Their patient population included 20,479 patients with asthma, and 109,902 controls.

Investigators used gene-level collapsing and variant-level Exome Wide Association Study (ExWAS) analysis to understand the role of IL-33 splice variant and early asthma onset.

The variant (rs146597587), previously proposed as leading to a loss of function, was identified as conferring protection against asthma in the UKBB cohort. IL-33 splice carrier rates for rs146597857 were significantly lower in earlier onset asthmatics (0.26%) than later onset (≥18 years old) (0.52%; OR, 0.49; P = .015), when compared to controls without asthma.

Carriers of the splice variant were also less likely to show an elevated blood eosinophil count as per >150 cells/mcL than those without (OR, 0.62; P-value = 2.6x10^-12).

Investigators cited a previous Icelandic cohort which showed the same rare variant was protective of asthma in observed patients, and was functionally characterized as leading to a loss of IL-33 function.

Combined with these newest findings, they believe the data support an established IL-33 drive in asthma.

“We propose a rare splice variant in IL-33 is protective against development of early onset asthma,” they concluded.

The study, “A Rare IL-33 Loss-of-Function Splice Variant Protects Against Early Onset Asthma,” was published online by ATS.