Integrative Mouse and Human Studies Implicate ANGPT1 and ZBTB7C as Susceptibility Genes to Ischemic Injury.
Integrative Mouse and Human Studies Implicate ANGPT1 and ZBTB7C as Susceptibility Genes to Ischemic Injury.
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DOI：
10.1161/strokeaha.115.010767
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发表时间：
2015-12
期刊：
影响因子：
8.3
通讯作者：
Weiss ST
中科院分区：
文献类型：
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作者：
Du R;Zhou J;Lorenzano S;Liu W;Charoenvimolphan N;Qian B;Xu J;Wang J;Zhang X;Wang X;Berndt A;Devan WJ;Valant VJ;Wang J;Furie KL;Rosand J;Rost N;Friedlander RM;Paigen B;Weiss ST
The extent of ischemic injury in response to cerebral ischemia is known to be affected by native vasculature. However, the non-vascular and dynamic vascular responses and their genetic basis are not well-understood. We performed a genome-wide association study in 235 mice from 33 inbred strains using the middle cerebral artery occlusion model. Population structure and genetic relatedness were accounted for by using the efficient mixed-model association method. Human orthologs to the genes associated with the significant and suggestive SNPs from the mouse strain survey were examined in patients with M1 occlusions admitted with signs and symptoms of acute ischemic stroke. We identified four genome-wide significant and suggestive SNPs to be associated with infarct volume in mice (rs3694965, p=2.17×10−7; rs31924033, p=5.61×10−6; rs32249495, p=2.08×10−7; rs3677406, p=9.56×10−6). Rs32249495, which corresponds to angiopoietin-1 (ANGPT1), was also significant in the recessive model in humans, while rs1944577, which corresponds to ZBTB7C was nominally significant in both the additive and dominant genetic models in humans. ZBTB7C was shown to be upregulated in endothelial cells using both in vitro and in vivo models of ischemia. Genetic variations of ANGPT1 and ZBTB7C are associated with increased infarct size in both mice and humans. ZBTB7C may modulate the ischemic response via neuronal apoptosis as well as dynamic collateralization and, in addition to ANGPT1, may serve as potential novel targets for treatments of cerebral ischemia.
