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


RESULTS
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
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.
Zeller
Tanja
T
Medizinische Klinik und Poliklinik, Johannes-Gutenberg Universität Mainz, Mainz, Germany.
Wild
Philipp
P
Szymczak
Silke
S
Rotival
Maxime
M
Schillert
Arne
A
Castagne
Raphaele
R
Maouche
Seraya
S
Germain
Marine
M
Lackner
Karl
K
Rossmann
Heidi
H
Eleftheriadis
Medea
M
Sinning
Christoph R
CR
Schnabel
Renate B
RB
Lubos
Edith
E
Mennerich
Detlev
D
Rust
Werner
W
Perret
Claire
C
Proust
Carole
C
Nicaud
Viviane
V
Loscalzo
Joseph
J
Hübner
Norbert
N
Tregouet
David
D
Münzel
Thomas
T
Ziegler
Andreas
A
Tiret
Laurence
L
Blankenberg
Stefan
S
Cambien
François
F
D000328:Adult; D000368:Aged; D050197:Atherosclerosis / Q000235:genetics; D001483:Base Sequence; D002465:Cell Movement / Q000235:genetics; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D015342:DNA Probes / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015894:Genome, Human / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D007109:Immunity / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics; D019655:Quantitative Trait, Heritable; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects / Q000235:genetics
D015342:DNA Probes