Seby John, MD

Yadav S, Cotlarciuc I, Munroe PB, Khan MS, Nalls MA, Bevan S, et al. Genome wide analysis of blood pressure variability and ischemic stroke. Stroke. 2013

Ischemic stroke is a heterogenous disease with multiple etiologies contributing to overall risk. Modifiable risk factors account for only about 60% of the population-attributable risk. Genetics and genomic factors appear to influence the development of vascular disease at all stages, and there is compelling data that genetics plays a major role in the risk of ischemic stroke.

In 2010, Peter Rothwell published a series of papers regarding visit-to-visit variability of systolic blood pressure (BP) being a strong predictor of ischemic stroke. In this article, Yadav et al tudied genetic loci that could influence BP variability by conducting genomewide association studies (GWAS). 3802 subjects were recruited from the UK-Ireland subset of the Anglo-Scandinavian Cardiac Outcome Trial (ASCOT). The GWAS identified a cluster of 17 correlated SNPs within the NLGN1 gene (3q26.31) that were associated with BP variability, with rs976683 having the strongest association. The NLGN1 gene encodes a neuronal cell surface protein implicated in the growth and remodeling of the vascular system. However, analysis of rs976683 in an independent ischemic stroke population from 7 international cohorts (8,624 cases and 12,722 controls) found no association for overall stroke or its subtypes.

Human genome sequencing has allowed for GWAS that may permit the discovery of variant alleles associated with common conditions like stroke. Such studies have identified gene loci associated with stroke risk that also overlap with heart and vascular disease (eg. 4q25 locus near the PITX2 gene is associated with atrial fibrillation and cardioembolic stroke). A limitation of GWAS studies, however, is that the small effect-size of genes may prevent the detection of association with a disease. This limitation may have been a factor in this study as well. 

At this time, the role of genetic factors in stroke is small. Apart from obtaining a family history and in monogenic disorders like CADASIL, the clinical utility of the genetic role remains low. However, such studies are important since they may provide novel clinical applications for stroke in the future, including biomarker development and improvements in risk profiling and classification.