Impact of rare and common genetic variation in the interleukin-1 pathway on human cytokine responses

• DOI: 10.1186/s13073-021-00907-w
• Publication Date: 2021-05-25T07:02:27Z
• Authors: Rosanne C. van De...; Peer Arts; Giulio Cavalli; Martin Jaeger; Marloes Steehouwer; Maartje van de Vorst; Christian Gilissen; Leo A. B. Joosten; Charles A. Dinarello; Musa M. Mhlanga; Vinod Kumar; Mihai G. Netea; Frank L. van de V...; Alexander Hoischen
• Keywords: 0301 basic medicine; BLOCKADE; Interleukin-1beta; SUSCEPTIBILITY; QH426-470; DISEASE; common variants; Radboudumc 4: lnfectious Diseases and Global Health RIMLS: Radboud Institute for Molecular Life Sciences; 0303 health sciences; IMMUNE-RESPONSES; Systems Biology; R; High-Throughput Nucleotide Sequencing; Healthy Volunteers; FAMILY; 3. Good health; MOLECULAR INVERSION PROBES; Interleukin-1 pathway; Medicine; Cytokines; AUTOPHAGY; Disease Susceptibility; Radboudumc 6: Metabolic Disorders RIMLS: Radboud Institute for Molecular Life Sciences; Systems biology; Signal Transduction; immunological mechanisms; Radboud University Medical Center; Immunophenotyping; region-based analysis; 03 medical and health sciences; INFLAMMATION; Region-based analysis; Genetics; Humans; Inflammation; RECEPTOR; Common variants; Research; Gene Expression Profiling; rare variants; Genetic Variation; Rare variants; Cell Biology; SKAT; Immunity, Innate; Gene Expression Regulation; Immunological mechanisms; Human Genetics - Radboud University Medical Center; interleukin-1 pathway; VARIANT ASSOCIATION; Biomarkers; Interleukin-1

AbstractBackgroundThe interleukin (IL)-1 pathway is primarily associated with innate immunological defense and plays a major role in the induction and regulation of inflammation. Both common and rare genetic variation in this pathway underlies various inflammation-mediated diseases, but the role of rare variants relative to common variants in immune response variability in healthy individuals remains unclear.MethodsWe performed molecular inversion probe sequencing on 48 IL-1 pathway-related genes in 463 healthy individuals from the Human Functional Genomics Project. We functionally grouped common and rare variants, over gene, subpathway, and inflammatory levels and performed the Sequence Kernel Association Test to test for association with in vitro stimulation-induced cytokine responses; specifically, IL-1β and IL-6 cytokine measurements upon stimulations that represent an array of microbial infections: lipopolysaccharide (LPS), phytohaemagglutinin (PHA),Candida albicans(C. albicans), andStaphylococcus aureus(S. aureus).ResultsWe identified a burden ofNCF4rare variants with PHA-induced IL-6 cytokine and showed that the respective carriers are in the 1% lowest IL-6 producers. Collapsing rare variants in IL-1 subpathway genes produces a bidirectional association with LPS-induced IL-1β cytokine levels, which is reflected by a significant Spearman correlation. On the inflammatory level, we identified a burden of rare variants in genes encoding for proteins with an anti-inflammatory function withS. aureus-induced IL-6 cytokine. In contrast to these rare variant findings which were based on different types of stimuli, common variant associations were exclusively identified withC. albicans-induced cytokine over various levels of grouping, from the gene, to subpathway, to inflammatory level.ConclusionsIn conclusion, this study shows that functionally grouping common and rare genetic variants enables the elucidation IL-1-mediated biological mechanisms, specifically, for IL-1β and IL-6 cytokine responses induced by various stimuli. The framework used in this study may allow for the analysis of rare and common genetic variants in a wider variety of (non-immune) complex phenotypes and therefore has the potential to contribute to better understanding of unresolved, complex traits and diseases.