TY - JOUR
T1 - Genetics and beyond - the transcriptome of human monocytes and disease susceptibility
AU - Zeller, Tanja
AU - Wild, Philipp
AU - Szymczak, Silke
AU - Rotival, Maxime
AU - Schillert, Arne
AU - Castagne, Raphaele
AU - Maouche, Seraya
AU - Germain, Marine
AU - Lackner, Karl
AU - Rossmann, Heidi
AU - Eleftheriadis, Medea
AU - Sinning, Christoph R.
AU - Schnabe, Renate B.
AU - Lubos, Edith
AU - Mennerich, Detlev
AU - Rust, Werner
AU - Perret, Claire
AU - Proust, Carole
AU - Nicaud, Viviane
AU - Loscalzo, Joseph
AU - Hübner, Norbert
AU - Tregouet, David
AU - Münze, Thomas
AU - Ziegler, Andreas
AU - Tiret, Laurence
AU - Blankenberg, Stefan
AU - Cambien, François
PY - 2010
Y1 - 2010
N2 - Background: Variability of gene expression in human may link gene sequence variability and phenotypes; however, nongenetic 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<5.78 610-12), 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:lt;3.9 10-7), 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.
AB - Background: Variability of gene expression in human may link gene sequence variability and phenotypes; however, nongenetic 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<5.78 610-12), 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:lt;3.9 10-7), 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.
UR - http://www.scopus.com/inward/record.url?scp=77956637896&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0010693
DO - 10.1371/journal.pone.0010693
M3 - Journal articles
C2 - 20502693
AN - SCOPUS:77956637896
VL - 5
JO - PLoS ONE
JF - PLoS ONE
IS - 5
M1 - e10693
ER -