title: An immune response network associated with blood lipid levels.
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.
authors.affiliation: Department of Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom. inouye@wehi.edu.au
authors.forename: Michael
authors.initials: M
authors.lastname: Inouye
authors.forename: Kaisa
authors.initials: K
authors.lastname: Silander
authors.forename: Eija
authors.initials: E
authors.lastname: Hamalainen
authors.forename: Veikko
authors.initials: V
authors.lastname: Salomaa
authors.forename: Kennet
authors.initials: K
authors.lastname: Harald
authors.forename: Pekka
authors.initials: P
authors.lastname: Jousilahti
authors.forename: Satu
authors.initials: S
authors.lastname: Männistö
authors.forename: Johan G
authors.initials: JG
authors.lastname: Eriksson
authors.forename: Janna
authors.initials: J
authors.lastname: Saarela
authors.forename: Samuli
authors.initials: S
authors.lastname: Ripatti
authors.forename: Markus
authors.initials: M
authors.lastname: Perola
authors.forename: Gert-Jan B
authors.initials: GJ
authors.lastname: van Ommen
authors.forename: Marja-Riitta
authors.initials: MR
authors.lastname: Taskinen
authors.forename: Aarno
authors.initials: A
authors.lastname: Palotie
authors.forename: Emmanouil T
authors.initials: ET
authors.lastname: Dermitzakis
authors.forename: Leena
authors.initials: L
authors.lastname: Peltonen
mesh_terms: D000328:Adult; D000368:Aged; D001055:Apolipoproteins B / Q000097:blood; D015331:Cohort Studies; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D006967:Hypersensitivity / Q000097:blood / Q000235:genetics / Q000276:immunology; D007109:Immunity / Q000235:genetics*; D018836:Inflammation Mediators / Q000097:blood; D007962:Leukocytes / Q000378:metabolism; D008055:Lipids / Q000097:blood*; D008075:Lipoproteins, HDL / Q000097:blood; D024821:Metabolic Syndrome / Q000097:blood / Q000235:genetics; D008875:Middle Aged; D008957:Models, Genetic; D009765:Obesity / Q000097:blood / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics; D012044:Regression Analysis; D014280:Triglycerides / Q000097:blood
chemical_list: D001055:Apolipoproteins B; D018836:Inflammation Mediators; D008055:Lipids; D008075:Lipoproteins, HDL; D014280:Triglycerides