Genetic Risk Factors for Ischemic and Hemorrhagic Stroke

Abstract

Understanding the genetic risk factors for stroke is an essential step to decipher the underlying mechanisms, facilitate the identification of novel therapeutic targets, and optimize the design of prevention strategies. A very small proportion of strokes are attributable to monogenic conditions, the vast majority being multifactorial, with multiple genetic and environmental risk factors of small effect size. Genome-wide association studies and large international consortia have been instrumental in finding genetic risk factors for stroke. While initial studies identified risk loci for specific stroke subtypes, more recent studies also revealed loci associated with all stroke and all ischemic stroke. Risk loci for ischemic stroke and its subtypes have been implicated in atrial fibrillation (PITX2 and ZFHX3), coronary artery disease (ABO, chr9p21, HDAC9, and ALDH2), blood pressure (ALDH2 and HDAC9), pericyte and smooth muscle cell development (FOXF2), coagulation (HABP2), carotid plaque formation (MMP12), and neuro-inflammation (TSPAN2). For hemorrhagic stroke, two loci (APOE and PMF1) have been identified.

The Characteristics of Mirna Binding Sites in Mrna of Zfhx3 Gene and Its Orthologs

“…We assume that the polysite binds to miR-1322, so the encoded polyGln of ZFHX3 transcription factor can interact with negatively charged regions of DNA-binding proteins. Another our assumption is that the polyGln variability of ZFHX3 protein is associated with the development of several diseases, but the way it happens remains unknown (Liu et al, 2014;Martin et al, 2014;Chauhan et al, 2016;Hauer et al, 2017 The binding site of miR-11-29856-3p encoded the absolutely conservative heptapeptide TETLLQL, presented in the protein of 55 species of animals (Supplementary table 10). Absolutely conservative heptapeptide LLPHFPMT adjoined the N-terminus of the heptapeptide, and the variable region of the ZFHX3 protein -the C-terminus.…”

“…These include the ZFHX3 gene encoding the transcription factor involved in the regulation of expression of many genes. Disruption in ZFHX3 gene expression was identified in stroke, atherosclerosis and other cardiovascular diseases (Liu et al, 2014;Martin et al, 2014;Chauhan et al, 2016;Hauer et al, 2017). Gene ZFHX3, being a transcription factor, can manifest its function in a variety of ways, and be a cause of different stroke subtypes.…”

Advancing stroke genomic research in the age of Trans-Omics big data science: Emerging priorities and opportunities

“…5, 18–23 Although some of these loci have been associated with specific subtypes, genetic overlaps have also been reported among them. 20, 22 For example, large artery atherosclerosis and small vessel disease, which were previously treated as genetically distinct, may share a substantial genetic component. Thus, combined analyses of both subtypes may increase power to identify small-effect alleles influencing shared pathophysiological processes.…”

Established and potential echocardiographic markers of embolism and their therapeutic implications in patients with ischemic stroke

“…Formal stroke risk stratification among patients with left atrial enlargement may further help to identify patients who stand to gain from preventive antithrombotic therapy [43]. The normal left atrial volume index (LAVI) using echocardiography is 22 ± 6 mL/m 2 ; thus, on the basis of the sensitivity and specificity for predicting cardiac events (3,(6)(7)(8), the American Society of Echocardiography (ASE) considers LA enlargement as > 28 mL/m 2 (i.e., 1 SD from the mean). However, for the purpose of identifying LV diastolic dysfunction, an LAVI cut point > 34 mL/m 2 (i.e., 2 SD) was endorsed in both ASE and the European Association of Echocardiography guideline document [26].…”

“…An accurate identification of the cause is essential in order to prepare an adequate preventive strategy. A substantial proportion of stroke risk remains unexplained [3].…”