PLoS Genetics: An Immune Response Network Associated with Blood Lipid Levels

An Immune Response Network Associated with Blood Lipid Levels

Circulating lipid concentrations are important predictors of coronary artery disease. The main pathology of coronary artery disease is atherosclerosis, a cycle of lipid adherence to the walls of arteries and an inflammatory response resulting in more adhesion. To investigate the link between lipids and immune cells in circulation, we have generated both genomic and whole blood gene expression profiles for a population-based collection of individuals from the capital region of Finland. Key mediators of inflammation and allergy were shown to be correlated with lipid levels. Further, the expressions of these genes operated in such a highly coordinated fashion that they appeared to function as part of a single pathway, which itself was both highly correlated with and reactive to lipid levels. Our findings offer insight into how lipids activate circulating immune cells, potentially contributing to the pathogenesis of coronary artery disease.


Michael Inouye1,2¤*, Kaisa Silander3, Eija Hamalainen1, Veikko Salomaa4, Kennet Harald4, Pekka Jousilahti4, Satu Männistö4, Johan G. Eriksson4,5,6,7,8, Janna Saarela3,9, Samuli Ripatti3, Markus Perola3, Gert-Jan B. van Ommen2, Marja-Riitta Taskinen10, Aarno Palotie1,3,11,12, Emmanouil T. Dermitzakis1,13, Leena Peltonen1,3,11†

1 Department of Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom, 2 Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands, 3 Institute of Molecular Medicine FIMM, University of Helsinki and Unit of Public Health Genomics, National Institute for Health and Welfare, Helsinki, Finland, 4 Unit of Chronic Disease Epidemiology and Prevention, National Institute for Health and Welfare, Helsinki, Finland, 5 Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland, 6 Helsinki University Central Hospital, Unit of General Practice, Helsinki, Finland, 7 Vasa Central Hospital, Vasa, Finland, 8 Folkhälsan Research Centre, Helsinki, Finland, 9 Institute of Molecular Medicine FIMM Technology Center, University of Helsinki, Helsinki, Finland, 10 Department of Medicine, Helsinki University Hospital, University of Helsinki, Helsinki, Finland, 11 The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America, 12 Department of Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland, 13 Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland


Abstract
While recent scans for genetic variation associated with human disease have been immensely successful in uncovering large numbers of loci, far fewer studies have focused on the underlying pathways of disease pathogenesis. Many loci which are associated with disease and complex phenotypes map to non-coding, regulatory regions of the genome, indicating that modulation of gene transcription plays a key role. Thus, this study generated genome-wide profiles of both genetic and transcriptional variation from the total blood extracts of over 500 randomly-selected, unrelated individuals. Using measurements of blood lipids, key players in the progression of atherosclerosis, three levels of biological information are integrated in order to investigate the interactions between circulating leukocytes and proximal lipid compounds. Pair-wise correlations between gene expression and lipid concentration indicate a prominent role for basophil granulocytes and mast cells, cell types central to powerful allergic and inflammatory responses. Network analysis of gene co-expression showed that the top associations function as part of a single, previously unknown gene module, the Lipid Leukocyte (LL) module. This module replicated in T cells from an independent cohort while also displaying potential tissue specificity. Further, genetic variation driving LL module expression included the single nucleotide polymorphism (SNP) most strongly associated with serum immunoglobulin E (IgE) levels, a key antibody in allergy. Structural Equation Modeling (SEM) indicated that LL module is at least partially reactive to blood lipid levels. Taken together, this study uncovers a gene network linking blood lipids and circulating cell types and offers insight into the hypothesis that the inflammatory response plays a prominent role in metabolism and the potential control of atherogenesis.


Author Summary
Circulating lipid concentrations are important predictors of coronary artery disease. The main pathology of coronary artery disease is atherosclerosis, a cycle of lipid adherence to the walls of arteries and an inflammatory response resulting in more adhesion. To investigate the link between lipids and immune cells in circulation, we have generated both genomic and whole blood gene expression profiles for a population-based collection of individuals from the capital region of Finland. Key mediators of inflammation and allergy were shown to be correlated with lipid levels. Further, the expressions of these genes operated in such a highly coordinated fashion that they appeared to function as part of a single pathway, which itself was both highly correlated with and reactive to lipid levels. Our findings offer insight into how lipids activate circulating immune cells, potentially contributing to the pathogenesis of coronary artery disease.

Citation: Inouye M, Silander K, Hamalainen E, Salomaa V, Harald K, et al. (2010) An Immune Response Network Associated with Blood Lipid Levels. PLoS Genet 6(9): e1001113. doi:10.1371/journal.pgen.1001113

Editor: Gregory S. Barsh, Stanford University, United States of America

Received: April 8, 2010; Accepted: August 5, 2010; Published: September 9, 2010


Copyright: © 2010 Inouye et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This study was funded by the Wellcome Trust, Wellcome Trust grant numbers WT089061 and WT089062, and the Finnish Academy (grant number SA118065 to PJ and grant number 129494 to VS). MP and VS were supported by the Finnish Foundation for Cardiovascular Disease. MP also has support from the Sigrid Jusélius Foundation, and the Finnish Academy SALVE program “Pubgensense” (grant number 10404). GVO was supported by the Centre for Medical Systems Biology, a national genome centre funded by the Netherlands Genome Initiative. ETD was supported by the Wellcome Trust, the Louis Jeantet Foundation and the Swiss National Science Foundation. LP and KS have been supported by the Academy of Finland Centre of Excellence in Complex Disease Genetics, the Biocentrum Helsinki Foundation, Helsinki, Finland and the Finnish Foundation for Cardiovascular Research. This work was supported by the Academy of Finland, Center for Excellence in Complex Disease Genetics (grant numbers: 129680 and 213506). MI was supported by the Wellcome Trust and an NHMRC Biomedical Australian Training Fellowship (no. 637400). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

* E-mail: inouye@wehi.edu.au

¤ Current address: Immunology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia

† Deceased.
full-text:
PLoS Genetics: An Immune Response Network Associated with Blood Lipid Levels