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Human Validation of Genes Associated With a Murine Atherosclerotic Phenotype

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  • Gerard Pasterkamp
  • Sander W van der Laan
  • Saskia Haitjema
  • Hassan Foroughi Asl
  • Marten A Siemelink
  • Tim Bezemer
  • Jessica van Setten
  • Martin Dichgans
  • Rainer Malik
  • Bradford B Worrall
  • Heribert Schunkert
  • Nilesh J Samani
  • Dominique P V de Kleijn
  • Hugh S Markus
  • Imo E Hoefer
  • Tom Michoel
  • Saskia C A de Jager
  • Johan L M Björkegren
  • Hester M den Ruijter
  • Folkert W Asselbergs

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Original languageEnglish
Pages (from-to)1240-1246
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume36
Issue number6
Early online date14 Apr 2016
DOIs
Publication statusPublished - Jun 2016

Abstract

OBJECTIVE: The 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 RESULTS: We 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.

CONCLUSIONS: A 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.

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