Identification and validation of genes affecting aortic lesions in mice.
Atherosclerosis represents the most significant risk factor for coronary artery disease (CAD), the leading cause of death in developed countries. To better understand the pathogenesis of atherosclerosis, we applied a likeli-hood-based model selection method to infer gene-disease causality relationships for the aortic lesion trait in a segregating mouse population demonstrating a spectrum of susceptibility to developing atherosclerotic lesions. We identified 292 genes that tested causal for aortic lesions from liver and adipose tissues of these mice, and we experimentally validated one of these candidate causal genes, complement component 3a receptor 1 (C3ar1), using a knockout mouse model. We also found that genes identified by this method overlapped with genes progressively regulated in the aortic arches of 2 mouse models of atherosclerosis during atherosclerotic lesion development. By comparing our gene set with findings from public human genome-wide association studies (GWAS) of CAD and related traits, we found that 5 genes identified by our study overlapped with published studies in humans in which they were identified as risk factors for multiple atherosclerosis-related pathologies, including myocardial infarction, serum uric acid levels, mean platelet volume, aortic root size, and heart failure. Candidate causal genes were also found to be enriched with CAD risk polymorphisms identified by the Wellcome Trust Case Control Consortium (WTCCC). Our findings therefore validate the ability of causality testing procedures to provide insights into the mechanisms underlying atherosclerosis development.
Yang
Xia
X
Department of Molecular Profiling, Rosetta Inpharmactics LLC, a wholly owned subsidiary of Merck & Co. Inc., Seattle, Washington, USA.
Peterson
Larry
L
Thieringer
Rolf
R
Deignan
Joshua L
JL
Wang
Xuping
X
Zhu
Jun
J
Wang
Susanna
S
Zhong
Hua
H
Stepaniants
Serguei
S
Beaulaurier
John
J
Wang
I-Ming
IM
Rosa
Ray
R
Cumiskey
Anne-Marie
AM
Luo
Jane Ming-Juan
JM
Luo
Qi
Q
Shah
Kashmira
K
Xiao
Jianying
J
Nickle
David
D
Plump
Andrew
A
Schadt
Eric E
EE
Lusis
Aldons J
AJ
Lum
Pek Yee
PY
D000273:Adipose Tissue; D000818:Animals; D001011:Aorta; D050197:Atherosclerosis / Q000235:genetics*; D003324:Coronary Artery Disease / Q000235:genetics*; D003327:Coronary Disease / Q000235:genetics*; D005796:Genes; D055106:Genome-Wide Association Study; D006801:Humans; D008099:Liver; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic; D012307:Risk Factors