Integrative Mouse and Human Studies Implicate ANGPT1 and ZBTB7C as Susceptibility Genes to Ischemic Injury

Abstract

Background and Purpose 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. Methods 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. Results 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. Conclusions 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.

Identification of Novel Alzheimer’s Disease Loci Using Sex-Specific Family-Based Association Analysis of Whole-Genome Sequence Data

“…Interestingly, the FOXO families of transcription factors have previously been implicated in AD pathogenesis by influencing neuronal survival 43 and Aβ-induced neuroinflammation 44 . ZBTB7C has also been suggested as a susceptibility gene for ischemic stroke through modulation of neuronal apoptosis 45 . Finally, a paternally inherited translocation of ZBTB7C has been associated with non-syndromal mental retardation in male twins 46 .…”

Strain-Related Differences in Mouse Neonatal Hypoxia-Ischemia

“…They also corrected for weight and age, strengthening the argument for genetic causality. The same authors previously explored the genetic basis for these vascular differences and identified 4 SNPs associated with infarct volume in mice after middle cerebral artery occlusion, 2 of which were relevant to human stroke susceptibility [16].…”

“…Understanding susceptibility or resistance to injury based on genetic background in mice should not only improve research methods but also our understanding of human variation in injury outcome, and it may ultimately lead to novel targets for intervention [15,16].…”

Cerebral Artery Diameter in Inbred Mice Varies as a Function of Strain

“…At the microvascular level, the number and diameters of collateral vessels between the anterior cerebral artery (ACA) and middle cerebral artery (MCA) have been shown to differ across strains (Maeda et al, 1998 ; Zhang et al, 2010 ). In addition, the susceptibility to ischemia and the percentage of total cortical surface area supplied by the MCA, ACA, and posterior cerebral artery (PCA) can differ significantly across mouse strains (Sheldon et al, 1998 ; Majid et al, 2000 ; Zhang et al, 2010 ; Du et al, 2015 ). Several strains have been utilized for murine stroke models (Hata et al, 1998 ; Orset et al, 2007 ; Zhang et al, 2010 ; Du et al, 2015 ).…”