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The common IL1A single nucleotide polymorphism rs17561 is a hypomorphic mutation that significantly reduces interleukin-1α release from human blood cells.

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Wiggins, Kimberley A 
Pyrillou, Katerina 
Humphry, Melanie 
Butterworth, Adam S 


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.


Funder: Cambridge NIHR Biomedical Research Centre


cytokines, genomics, inflammasome, inflammation, Humans, Interleukin-1alpha, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Interleukin-1beta, Inflammation, Blood Cells

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British Heart Foundation (FS/18/19/33371)
British Heart Foundation (FS/18/19/33371)
British Heart Foundation (None)
British Heart Foundation (RG/16/8/32388)
British Heart Foundation (None)
British Heart Foundation (None)
British Heart Foundation (None)
British Heart Foundation (CH/12/2/29428)
British Heart Foundation (RG/18/13/33946)
British Heart Foundation (FS/20/19/34976)
This work was funded by BHF Grants FS/13/3/30038, FS/18/19/33371 and RG/16/8/32388 to MCHC, the BHF Cambridge Centre for Research Excellence RE/13/6/30180, and the Cambridge NIHR Biomedical Research Centre