Abstract
The etiology of ischemic stroke is multifactorial. Although receiving less emphasis, genetic causes make a significant contribution to ischemic stroke genesis, especially in early-onset stroke. Several stroke classification systems based on genetic information corresponding to various stroke phenotypes were proposed. Twin and family history studies, as well as candidate gene approach, are common methods to discover genetic causes of stroke, however, both have their own limitations. Genome-wide association studies and next generation sequencing are more efficient, promising and increasingly used for daily diagnostics. Some monogenic disorders, despite covering only about 7% of stroke etiology, may cause well-known clinical manifestations that include stroke. Polygenic disorders are more frequent, causing about 38% of all ischemic strokes, and their identification is a rapidly developing field of modern stroke genetics. Current advances in human genetics provide opportunity for personalized prevention of stroke and novel treatment possibilities. Genetic risk scores (GRS) and extended polygenic risk scores (PRS) estimate cumulative contribution of known genetic factors to a specific outcome of stroke. Combining those scores with clinical information and risk factor profiles might result in better primary stroke prevention. Some authors encourage the use of stroke gene panels for stroke risk evaluation and further stroke research. Moreover, new biomarkers for stroke genetic causes and novel targets for gene therapy are on the horizon. In this article, we summarize the latest evidence and perspectives of ischemic stroke genetics that could be of interest to the practitioner and useful for day-to-day clinical work.
Highlights
Stroke is a frequent medical emergency, the burden of which is rising annually [1]
These findings might seem hardly applicable in clinical practice at the first glance, major breakthrough is evident as genetic risk scores and gene therapies are developing
Genetic risk scores (GRS) that estimate a cumulative contribution of genetic factors to a specific outcome can be extended to polygenic risk scores (PRS) by taking into account all known genetic markers possibly correlated to the outcome, covering even the loci of the small effects that do not reach genome-wide significance
Summary
Stroke is a frequent medical emergency, the burden of which is rising annually [1]. In2019, there were 12.2 million incident cases of stroke, making it the second-leading death cause in the world and third-leading cause of death and disability combined. Ischemic stroke was the most frequent among incident cases and constituted 62.4% of all strokes [2]. Traditional modifiable risk factors, such as hypertension, smoking, diabetes and hyperlipidemia, are highlighted frequently [3,4], whereas the role of genetics is usually less accented, though no less substantial. Younger onset cases have a stronger genetic burden from common disease-associated single-nucleotide polymorphisms (SNP) [7], being the extreme phenotypic expression of the genetic disorder. Less severe or older-onset stroke cases might remain genetically untested due to this bias. In such cases, stroke etiology might be attributed only to traditional modifiable risk factors without further risk stratification according to individual genetic profiles
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