Monogenic, Polygenic, and MicroRNA Markers for Ischemic Stroke

Abstract

Ischemic stroke (IS) is a leading disease with high mortality and disability, as well as with limited therapeutic window. Biomarkers for earlier diagnosis of IS have long been pursued. Family and twin studies confirm that genetic variations play an important role in IS pathogenesis. Besides DNA mutations found previously by genetic linkage analysis for monogenic IS (Mendelian inheritance), recent studies using genome-wide associated study (GWAS) and microRNA expression profiling have resulted in a large number of DNA and microRNA biomarkers in polygenic IS (sporadic IS), especially in different IS subtypes and imaging phenotypes. The present review summarizes genetic markers discovered by clinical studies and discusses their pathogenic molecular mechanisms involved in developmental or regenerative anomalies of blood vessel walls, neuronal apoptosis, excitotoxic death, inflammation, neurogenesis, and angiogenesis. The possible impact of environment on genetics is addressed as well. We also include a perspective on further studies and clinical application of these IS biomarkers.

Keywords: Biomarkers; Genetics; Ischemic stroke; MicroRNA; Monogenic; Polygenic.

Fig. 1

Etiology, subtype and heredity of ischemic stroke (IS). a, Incidence and genetics of different IS subtypes. The percentages in the boxes indicate incidences and those outside the boxes denote genetics; OD: other determined etiology. b, Etiological factors of IS. The percentages in the boxes indicate incidences and the content in the text boxes indicates risk factors. These investigative data are extracted from references studying on European residents [11, 13, 14, 16].

Fig. 2

Targeted components of blood vessels by genetic defects in monogenic ischemic stroke. The genetic mutations affecting integrity of basement membrane in capillaries and intima elastica in arterioles can lead to cerebral small vessel diseases (SVD); activation of endothelial cells and smooth muscle cells in arterioles and large arteries by dysfunctional expression of growth factors or metabolic enzymes can cause cerebral SVD and large artery atherosclerotic (LAA) stroke; mutations in FBN1 leading to deficient tunica elastica are the main causes of cardioembolic stroke (CES) in Marfan syndrome. The italic scripts in the figure denote genetic markers for monogenic ischemic stroke, the lines indicate the targeted components of blood vessel walls by genetic markers.