LAUSR

Interleukin‐1 alpha (IL‐1α) is a powerful cytokine that drives inflammation and modulates adaptive immunity. Due to these powerful effects, IL‐1α is controlled at multiple levels from transcription to cleavage and release from the cell. Genome‐wide association studies can identify loci that drive important diseases, although often the functional effect of the variant on phenotype remains unknown or small, with most risk variants in non‐coding regions. We find that the common variant rs17561 changes a conserved amino acid in the central region of IL‐1α linking the pro piece to the cytokine domain. Using a recall‐by‐genotype study and whole blood stimulation, we find that minor allele homozygotes release ~50% less IL‐1α than the major allele, with IL‐1β release equivalent. IL‐1α transcript level was identical between groups, implying a post‐transcriptional effect, whilst cleavage of recombinant pro‐IL‐1α by multiple proteases was also equivalent for both forms. Importantly, transfected macrophages also release less minor allele IL‐1α upon inflammasome activation, revealing that reduced secretion is directly caused by the missense amino acid substitution and more minor allele IL‐1α was retained within the cell. Thus, rs17561 represents a very common hypomorphic mutation in IL‐1α. We believe this novel data will be important for determining the potential contribution of IL‐1α to disease and/or physiological processes, for example, by Mendelian randomisation, and may aid patient stratification when considering anti‐IL‐1 therapies.