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Targeted genomic analysis reveals widespread autoimmune disease association with regulatory variants in the TNF superfamily cytokine signalling network.
Genome Med 2016; 8(1):76GM

Abstract

BACKGROUND

Tumour necrosis factor (TNF) superfamily cytokines and their receptors regulate diverse immune system functions through a common set of signalling pathways. Genetic variants in and expression of individual TNF superfamily cytokines, receptors and signalling proteins have been associated with autoimmune and inflammatory diseases, but their interconnected biology has been largely unexplored.

METHODS

We took a hypothesis-driven approach using available genome-wide datasets to identify genetic variants regulating gene expression in the TNF superfamily cytokine signalling network and the association of these variants with autoimmune and autoinflammatory disease. Using paired gene expression and genetic data, we identified genetic variants associated with gene expression, expression quantitative trait loci (eQTLs), in four peripheral blood cell subsets. We then examined whether eQTLs were dependent on gene expression level or the presence of active enhancer chromatin marks. Using these eQTLs as genetic markers of the TNF superfamily signalling network, we performed targeted gene set association analysis in eight autoimmune and autoinflammatory disease genome-wide association studies.

RESULTS

Comparison of TNF superfamily network gene expression and regulatory variants across four leucocyte subsets revealed patterns that differed between cell types. eQTLs for genes in this network were not dependent on absolute gene expression levels and were not enriched for chromatin marks of active enhancers. By examining autoimmune disease risk variants among our eQTLs, we found that risk alleles can be associated with either increased or decreased expression of co-stimulatory TNF superfamily cytokines, receptors or downstream signalling molecules. Gene set disease association analysis revealed that eQTLs for genes in the TNF superfamily pathway were associated with six of the eight autoimmune and autoinflammatory diseases examined, demonstrating associations beyond single genome-wide significant hits.

CONCLUSIONS

This systematic analysis of the influence of regulatory genetic variants in the TNF superfamily network reveals widespread and diverse roles for these cytokines in susceptibility to a number of immune-mediated diseases.

Authors+Show Affiliations

Department of Medicine and Cambridge Institute for Medical Research, The University of Cambridge, Box 139, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, UK. Autoimmunity Branch, National Institute for Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.Department of Medicine and Cambridge Institute for Medical Research, The University of Cambridge, Box 139, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, UK.Department of Medicine and Cambridge Institute for Medical Research, The University of Cambridge, Box 139, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, UK.Department of Genetics, Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.Computational Biology Branch, National Center for Biotechnology Information, National Institutes of Health, Bethesda, MD, 20894, USA.Autoimmunity Branch, National Institute for Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.Department of Medicine and Cambridge Institute for Medical Research, The University of Cambridge, Box 139, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, UK.Department of Medicine and Cambridge Institute for Medical Research, The University of Cambridge, Box 139, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, UK. kgcs2@cam.ac.uk.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27435189

Citation

Richard, Arianne C., et al. "Targeted Genomic Analysis Reveals Widespread Autoimmune Disease Association With Regulatory Variants in the TNF Superfamily Cytokine Signalling Network." Genome Medicine, vol. 8, no. 1, 2016, p. 76.
Richard AC, Peters JE, Lee JC, et al. Targeted genomic analysis reveals widespread autoimmune disease association with regulatory variants in the TNF superfamily cytokine signalling network. Genome Med. 2016;8(1):76.
Richard, A. C., Peters, J. E., Lee, J. C., Vahedi, G., Schäffer, A. A., Siegel, R. M., ... Smith, K. G. (2016). Targeted genomic analysis reveals widespread autoimmune disease association with regulatory variants in the TNF superfamily cytokine signalling network. Genome Medicine, 8(1), p. 76. doi:10.1186/s13073-016-0329-5.
Richard AC, et al. Targeted Genomic Analysis Reveals Widespread Autoimmune Disease Association With Regulatory Variants in the TNF Superfamily Cytokine Signalling Network. Genome Med. 2016 07 19;8(1):76. PubMed PMID: 27435189.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Targeted genomic analysis reveals widespread autoimmune disease association with regulatory variants in the TNF superfamily cytokine signalling network. AU - Richard,Arianne C, AU - Peters,James E, AU - Lee,James C, AU - Vahedi,Golnaz, AU - Schäffer,Alejandro A, AU - Siegel,Richard M, AU - Lyons,Paul A, AU - Smith,Kenneth G C, Y1 - 2016/07/19/ PY - 2016/05/09/received PY - 2016/06/21/accepted PY - 2016/7/21/entrez PY - 2016/7/21/pubmed PY - 2017/3/7/medline KW - Autoimmunity KW - Autoinflammation KW - GWAS KW - Gene set analysis KW - Genetics KW - Genomics KW - TNF superfamily KW - eQTL SP - 76 EP - 76 JF - Genome medicine JO - Genome Med VL - 8 IS - 1 N2 - BACKGROUND: Tumour necrosis factor (TNF) superfamily cytokines and their receptors regulate diverse immune system functions through a common set of signalling pathways. Genetic variants in and expression of individual TNF superfamily cytokines, receptors and signalling proteins have been associated with autoimmune and inflammatory diseases, but their interconnected biology has been largely unexplored. METHODS: We took a hypothesis-driven approach using available genome-wide datasets to identify genetic variants regulating gene expression in the TNF superfamily cytokine signalling network and the association of these variants with autoimmune and autoinflammatory disease. Using paired gene expression and genetic data, we identified genetic variants associated with gene expression, expression quantitative trait loci (eQTLs), in four peripheral blood cell subsets. We then examined whether eQTLs were dependent on gene expression level or the presence of active enhancer chromatin marks. Using these eQTLs as genetic markers of the TNF superfamily signalling network, we performed targeted gene set association analysis in eight autoimmune and autoinflammatory disease genome-wide association studies. RESULTS: Comparison of TNF superfamily network gene expression and regulatory variants across four leucocyte subsets revealed patterns that differed between cell types. eQTLs for genes in this network were not dependent on absolute gene expression levels and were not enriched for chromatin marks of active enhancers. By examining autoimmune disease risk variants among our eQTLs, we found that risk alleles can be associated with either increased or decreased expression of co-stimulatory TNF superfamily cytokines, receptors or downstream signalling molecules. Gene set disease association analysis revealed that eQTLs for genes in the TNF superfamily pathway were associated with six of the eight autoimmune and autoinflammatory diseases examined, demonstrating associations beyond single genome-wide significant hits. CONCLUSIONS: This systematic analysis of the influence of regulatory genetic variants in the TNF superfamily network reveals widespread and diverse roles for these cytokines in susceptibility to a number of immune-mediated diseases. SN - 1756-994X UR - https://www.unboundmedicine.com/medline/citation/27435189/Targeted_genomic_analysis_reveals_widespread_autoimmune_disease_association_with_regulatory_variants_in_the_TNF_superfamily_cytokine_signalling_network_ L2 - https://genomemedicine.biomedcentral.com/articles/10.1186/s13073-016-0329-5 DB - PRIME DP - Unbound Medicine ER -