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Genetics and beyond - the transcriptome of human monocytes and disease susceptibility

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Item Type:Article
Title:Genetics and beyond - the transcriptome of human monocytes and disease susceptibility
Creators Name:Zeller, T., Wild, P., Szymczak, S., Rotival, M., Schillert, A., Castagne, R., Maouche, S., Germain, M., Lackner, K., Rossmann, H., Eleftheriadis, M., Sinning, C.R., Schnabel, R.B., Lubos, E., Mennerich, D., Rust, W., Perret, C., Proust, C., Nicaud, V., Loscalzo, J., Huebner, N., Tregouet, D., Muenzel, T., Ziegler, A., Tiret, L., Blankenberg, S. and Cambien, F.
Abstract:BACKGROUND: Variability of gene expression in human may link gene sequence variability and phenotypes; however, non-genetic variations, alone or in combination with genetics, may also influence expression traits and have a critical role in physiological and disease processes. METHODOLOGY/PRINCIPAL FINDINGS: To get better insight into the overall variability of gene expression, we assessed the transcriptome of circulating monocytes, a key cell involved in immunity-related diseases and atherosclerosis, in 1,490 unrelated individuals and investigated its association with >675,000 SNPs and 10 common cardiovascular risk factors. Out of 12,808 expressed genes, 2,745 expression quantitative trait loci were detected (P<5.78x10(-12)), most of them (90%) being cis-modulated. Extensive analyses showed that associations identified by genome-wide association studies of lipids, body mass index or blood pressure were rarely compatible with a mediation by monocyte expression level at the locus. At a study-wide level (P<3.9x10(-7)), 1,662 expression traits (13.0%) were significantly associated with at least one risk factor. Genome-wide interaction analyses suggested that genetic variability and risk factors mostly acted additively on gene expression. Because of the structure of correlation among expression traits, the variability of risk factors could be characterized by a limited set of independent gene expressions which may have biological and clinical relevance. For example expression traits associated with cigarette smoking were more strongly associated with carotid atherosclerosis than smoking itself. CONCLUSIONS/SIGNIFICANCE: This study demonstrates that the monocyte transcriptome is a potent integrator of genetic and non-genetic influences of relevance for disease pathophysiology and risk assessment.
Keywords:Atherosclerosis, Base Sequence, Cell Movement, Human, Pair 21 Chromosomes, DNA Probes, Gene Expression Profiling, Gene Expression Regulation, Genetic Predisposition to Disease, Genetic Variation, Human Genome, Genome-Wide Association Study, Immunity, Monocytes, Phenotype, Single Nucleotide Polymorphism, Quantitative Trait Loci, Heritable Quantitative Trait, Risk Factors, Smoking
Source:PLoS ONE
Publisher:Public Library of Science
Page Range:e10693
Date:18 May 2010
Official Publication:https://doi.org/10.1371/journal.pone.0010693
PubMed:View item in PubMed

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