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The relationship between extreme inter-individual variation in macrophage gene expression and genetic susceptibility
Claire L O'Brien1,2, Kim M Summers3, Natalia M Martin2
1Centre for Research in Therapeutics Solutions, Faculty of Science and Technology, University of Canberra, Canberra, ACT, Australia.
Abstract:
The differentiation of resident intestinal macrophages from blood monocytes depends upon signals from the macrophage colony-stimulating factor receptor (CSF1R). Analysis of genome-wide association studies (GWAS) indicates that dysregulation of macrophage differentiation and response to microorganisms contributes to susceptibility to chronic inflammatory bowel disease (IBD). Here, we analyzed transcriptomic variation in monocyte-derived macrophages (MDM) from affected and unaffected sib pairs/trios from 22 IBD families and 6 healthy controls. Transcriptional network analysis of the data revealed no overall or inter-sib distinction between affected and unaffected individuals in basal gene expression or the temporal response to lipopolysaccharide (LPS). However, the basal or LPS-inducible expression of individual genes varied independently by as much as 100-fold between subjects. Extreme independent variation in the expression of pairs of HLA-associated transcripts (HLA-B/C, HLA-A/F and HLA-DRB1/DRB5) in macrophages was associated with HLA genotype. Correlation analysis indicated the downstream impacts of variation in the immediate early response to LPS. For example, variation in early expression of IL1B was significantly associated with local SNV genotype and with subsequent peak expression of target genes including IL23A, CXCL1, CXCL3, CXCL8 and NLRP3. Similarly, variation in early IFNB1 expression was correlated with subsequent expression of IFN target genes. Our results support the view that gene-specific dysregulation in macrophage adaptation to the intestinal milieu is associated with genetic susceptibility to IBD.
Insights
Gene expression variation in macrophages, particularly in response to lipopolysaccharide (LPS), is linked to inflammatory bowel disease (IBD) susceptibility. Individual gene dysregulation, not overall network changes, appears crucial for IBD genetic risk.
Area of Science:
- Immunology
- Genetics
- Gastroenterology
Background:
- Resident intestinal macrophages differentiate from blood monocytes, a process regulated by macrophage colony-stimulating factor receptor (CSF1R).
- Genome-wide association studies (GWAS) suggest that altered macrophage differentiation and microbial response contribute to inflammatory bowel disease (IBD) susceptibility.
Purpose of the Study:
- To investigate transcriptomic variation in monocyte-derived macrophages (MDM) from IBD patients and healthy individuals.
- To identify gene expression patterns associated with IBD susceptibility.
Main Methods:
- Analysis of transcriptomic variation in MDM from IBD families and healthy controls.
- Transcriptional network analysis and correlation analysis of gene expression in response to lipopolysaccharide (LPS).
- Investigation of single nucleotide variant (SNV) genotype associations with gene expression.
Main Results:
- No significant overall or inter-sib differences in basal or LPS-induced gene expression were found between affected and unaffected individuals.
- Significant inter-individual variation (up to 100-fold) in basal and LPS-inducible gene expression was observed.
- Extreme variation in HLA-associated transcripts correlated with HLA genotype.
- Variation in early IL1B and IFNB1 expression was associated with local SNV genotype and predicted the expression of downstream target genes.
Conclusions:
- Gene-specific dysregulation in macrophage adaptation to the intestinal environment is linked to genetic susceptibility to IBD.
- Individual genetic variations influencing macrophage response pathways may contribute to IBD pathogenesis.
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