The common IL1A single nucleotide polymorphism rs17561 is a hypomorphic mutation that significantly reduces interleukin-1α release from human blood cells.
Immunology
; 168(3): 459-472, 2023 03.
Article
em En
| MEDLINE
| ID: mdl-36175368
ABSTRACT
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-1ß 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.
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Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Polimorfismo de Nucleotídeo Único
/
Interleucina-1alfa
Tipo de estudo:
Clinical_trials
Limite:
Humans
Idioma:
En
Revista:
Immunology
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Reino Unido