与小鼠动脉粥样硬化表型相关基因的人体验证
Human Validation of Genes Associated With a Murine Atherosclerotic Phenotype.
作者信息
Pasterkamp Gerard, van der Laan Sander W, Haitjema Saskia, Foroughi Asl Hassan, Siemelink Marten A, Bezemer Tim, van Setten Jessica, Dichgans Martin, Malik Rainer, Worrall Bradford B, Schunkert Heribert, Samani Nilesh J, de Kleijn Dominique P V, Markus Hugh S, Hoefer Imo E, Michoel Tom, de Jager Saskia C A, Björkegren Johan L M, den Ruijter Hester M, Asselbergs Folkert W
机构信息
From the Laboratory of Experimental Cardiology, Division Heart and Lungs (G.P., S.W.v.d.L., S.H., M.A.S., T.B., J.v.S., I.E.H., S.C.A.d.J., H.M.d.R.), Laboratory of Clinical Chemistry and Hematology, Division Laboratories and Pharmacy (G.P.), and Division Heart and Lungs, Department of Cardiology (F.W.A.), University Medical Center Utrecht, Utrecht, The Netherlands; Vascular Biology Unit, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden (H.F.A., J.L.M.B.); Institut für Schlaganfall- und Demenzforschung (ISD) Klinikum der Universität München, Munich, Germany (M.D., R.M.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (M.D.); Department of Neurology, University of Virginia, Charlottesville (B.B.W.); Klinik für Herz- und Kreislauferkrankungen, Deutsches Herzzentrum München, Technische Universität München, Munich, Germany (H.S.); Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK) e.V., Partner Site Munich Heart Alliance, Munich, Germany (H.S.); Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom (N.J.S.); Leicester National Institute of Health Research Biomedical Research Unit in Cardiovascular Disease, Leicester, United Kingdom (N.J.S.); Department of Surgery, National University of Singapore, Singapore (D.P.V.d.K.); Cardiovascular Research Institute (CVRI), National University Health System, Singapore, Singapore (D.P.V.d.K.); Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands (D.P.V.d.K.); Department of Neurosciences, University of Cambridge, Cambridge, United Kingdom (H.S.M.); The Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom (T.M.); Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY (J.L.M.B.); Department of Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estoni
出版信息
Arterioscler Thromb Vasc Biol. 2016 Jun;36(6):1240-6. doi: 10.1161/ATVBAHA.115.306958. Epub 2016 Apr 14.
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.
目的
转基因小鼠是研究动脉粥样硬化性疾病发病机制最常用的动物模型。我们旨在通过检查全基因组关联研究的结果，评估小鼠动脉粥样硬化相关基因是否能在人类疾病中得到验证。
方法与结果
我们进行了一项系统综述，以确定小鼠中导致动脉粥样硬化的基因，并对其人类直系同源基因进行基于基因的关联测试，以确定其与人类冠状动脉疾病和人类大动脉缺血性中风的关联。此外，我们研究了这些基因与人类动脉粥样硬化斑块特征的关联。另外，我们评估了这些基因在人类中组织特异性顺式作用表达数量性状位点的存在情况。最后，通过通路分析，我们发现，尽管这些基因中的大多数具有顺式作用表达数量性状位点，但推测的导致动脉粥样硬化的基因与人类冠状动脉疾病、大动脉缺血性中风或动脉粥样硬化斑块特征之间几乎没有关联。
结论
通过研究疾病发展与常见人类基因变异之间的关联，几乎无法证实小鼠中观察到的基因在动脉粥样硬化病变发展中的作用。小鼠动脉粥样硬化模型在人类疾病治疗靶点选择中的价值仍不明确。
Zotero 插件