2 June 2021

Rosanne van Deuren, a PhD student under the supervision of Alexander Hoischen, theme Infectious diseases and global health, published a study that shows that rare and common genetic variants together shape our immune response and highlight the inter-individual differences of it. Moreover, the presented framework and example can help others in similar studies – and offers novel ways to analyse and visualize complex data sets. This is yet another example of the great value of cohorts established in the human functional genomics project, which is co-coordinated by Mihai Netea. The current study is published in Genome Medicine.

Background

The 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.

Methods

We 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), and Staphylococcus aureus (S. aureus).

Results

We identified a burden of NCF4 rare 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 with S. 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 with C. albicans-induced cytokine over various levels of grouping, from the gene, to subpathway, to inflammatory level.

Conclusions

In 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.

read more

Related news items


New ultra-high field MRI system available for Radboudumc and Radboud University

10 June 2021

Recently, the Hahn institute in Essen has received a new heart: a 20-ton ultra-high-field MRI scanner from Siemens Healthcare with a magnetic field strength of 7 Tesla. The new CE-approved scanner is ready for business, and projects on body and brain imaging are starting up.

read more

On the prevalence of cerebral amyloid angiopathy a systematic review and meta-analysis

10 June 2021

Published in ‘Alzheimers and Dementia’, researchers at Radboudumc performed a systematic review and meta-analysis on the prevalence of Cerebral Amyloid Angiopathy. They scrutinized and analyzed 170 publications, comprising publications using either a neuroimaging or a neuropathological approach.

read more

Retina-on-chip modeling and treating eye diseases in a dish

10 June 2021

Alex Garanto, together with Anneke den Hollander and Andries van der Meer (UTwente) have received 1,17M€ to develop a retina-on-chip model to improve our understanding in eye diseases and to develop treatments against them.

read more

A tipping point in cancer-immune dynamics leads to divergent immunotherapy responses

8 June 2021

Jeroen Creemers and Johannes Textor published in the Journal for ImmunoTherapy of Cancer that a tipping point in cancer-immune dynamics leads to divergent immunotherapy responses and hampers biomarker discovery.

read more

New method to prevent ovarian cancer increases quality of life

8 June 2021

Researchers at Radboudumc have shown that quality of life is better in women with a BRCA1 or BRCA2 mutation after fallopian tube removal with delayed ovarian removal to prevent ovarian cancer.

read more

Radboud Pluim for Dagmar Eleveld-Trancikova Policy advisor of the three research institutes

8 June 2021

Radboudpluim for research policy adviser Dagmar Eleveld-Trancikova.

read more