Genetic Risk Factors of Intracranial Atherosclerosis

Abstract

Purpose of review: Intracranial atherosclerosis (ICAS) is the most common cause of stroke throughout the world. It also increases the risk of recurrent stroke and dementia. As a complex and multifactorial disease, ICAS is influenced by multiple genetic, biological, and environmental factors. This review summarizes the candidate gene and genome-wide studies aimed at discovering genetic risk factors of ICAS.

Recent findings: Numerous studies have focused on the association between single-nucleotide polymorphisms (SNPs) of atherosclerosis-related genes and the risk of ICAS. Variants in adiponectin Q (ADIPOQ), ring finger protein 213 (RNF213), apolipoprotein E (APOE), phosphodiesterase 4D (PDE4D), methylenetetrahydrofolate reductase (MTHFR), lipoprotein lipase (LPL), α-adducin (ADD1) genes, angiotensin-converting enzyme (ACE), and other genes related to renin-angiotensin-aldosterone system have been associated with ICAS. We review the available evidences on the candidate genes and SNPs associated with genetic susceptibility to ICAS, and point out future developments of this field. Genetic discoveries could have clinical implications for intracranial atherosclerotic disease.

Keywords: Adiponectin Q; Genetic factor; Genome-wide association study; Intracranial atherosclerosis; Ring finger protein 213.

Figure 1. Pathological example of intracranial large artery atherosclerosis, a cholesterol-mediated disease.

Panel A demonstrates a typical example of atherosclerosis, defined by eccentric intima thickening with a necrotic core consisting of cholesterol crystals and necrotic tissue (panel 1). One may observe neoangiogenesis in the border zone between the media and the intima (panel b-c). One of the proposed mechanisms by which atherosclerosis may cause stroke is plaque rupture, with endothelial surface denudation, thrombosis and eventual artery-to-artery embolization or luminal occlusion due to an expanding in-situ thrombus (panel d-c). Images were obtained from the Brain Arterial Remodeling Study (BARS).