TY - JOUR
T1 - Human validation of genes associated with a murine atherosclerotic phenotype
AU - Pasterkamp, Gerard
AU - Van Der Laan, Sander W.
AU - Haitjema, Saskia
AU - Asl, Hassan Foroughi
AU - Siemelink, Marten A.
AU - Bezemer, Tim
AU - Van Setten, Jessica
AU - Dichgans, Martin
AU - Malik, Rainer
AU - Worrall, Bradford B.
AU - Schunkert, Heribert
AU - Samani, Nilesh J.
AU - De Kleijn, Dominique P.V.
AU - Markus, Hugh S.
AU - Hoefer, Imo E.
AU - Michoel, Tom
AU - De Jager, Saskia C.A.
AU - Björkegren, Johan L M
AU - Den Ruijter, Hester M.
AU - Asselbergs, Folkert W.
N1 - © 2016 American Heart Association, Inc.
PY - 2016/6/1
Y1 - 2016/6/1
N2 - ObjectiveThe genetically modified mouse is the most commonly used animal model for studying the pathogenesis of atherosclerotic disease. We aimed to assess if mice atherosclerosis-related genes could be validated in human disease through examination of results from genome-wide association studies. Approach and ResultsWe performed a systematic review to identify atherosclerosis-causing genes in mice and carried out gene-based association tests of their human orthologs for an association with human coronary artery disease and human large artery ischemic stroke. Moreover, we investigated the association of these genes with human atherosclerotic plaque characteristics. In addition, we assessed the presence of tissue-specific cis-acting expression quantitative trait loci for these genes in humans. Finally, using pathway analyses we show that the putative atherosclerosis-causing genes revealed few associations with human coronary artery disease, large artery ischemic stroke, or atherosclerotic plaque characteristics, despite the fact that the majority of these genes have cis-acting expression quantitative trait loci. ConclusionsA role for genes that has been observed in mice for atherosclerotic lesion development could scarcely be confirmed by studying associations of disease development with common human genetic variants. The value of murine atherosclerotic models for selection of therapeutic targets in human disease remains unclear.
AB - ObjectiveThe genetically modified mouse is the most commonly used animal model for studying the pathogenesis of atherosclerotic disease. We aimed to assess if mice atherosclerosis-related genes could be validated in human disease through examination of results from genome-wide association studies. Approach and ResultsWe performed a systematic review to identify atherosclerosis-causing genes in mice and carried out gene-based association tests of their human orthologs for an association with human coronary artery disease and human large artery ischemic stroke. Moreover, we investigated the association of these genes with human atherosclerotic plaque characteristics. In addition, we assessed the presence of tissue-specific cis-acting expression quantitative trait loci for these genes in humans. Finally, using pathway analyses we show that the putative atherosclerosis-causing genes revealed few associations with human coronary artery disease, large artery ischemic stroke, or atherosclerotic plaque characteristics, despite the fact that the majority of these genes have cis-acting expression quantitative trait loci. ConclusionsA role for genes that has been observed in mice for atherosclerotic lesion development could scarcely be confirmed by studying associations of disease development with common human genetic variants. The value of murine atherosclerotic models for selection of therapeutic targets in human disease remains unclear.
KW - atherosclerosis
KW - coronary artery disease
KW - genome-wide association study
KW - mice
KW - stroke
UR - http://www.scopus.com/inward/record.url?scp=84971264956&partnerID=8YFLogxK
U2 - 10.1161/ATVBAHA.115.306958
DO - 10.1161/ATVBAHA.115.306958
M3 - Article
C2 - 27079880
SN - 1079-5642
VL - 36
SP - 1240
EP - 1246
JO - Arteriosclerosis, Thrombosis and Vascular Biology
JF - Arteriosclerosis, Thrombosis and Vascular Biology
IS - 6
ER -