by Rebecca Hiscott
Researchers have identified a new genetic risk factor associated with ischemic stroke, independent of stroke subtype, in a genome-wide association study and meta-analysis published in the August 19 issue of Neurology.
“Our results show, for the first time, a genetic risk locus associated with ischemic stroke as a whole, rather than in a subtype-specific manner,” the authors wrote. They added that the locus was not found to be associated with intracerebral hemorrhage (ICH).
CT scans from children with hemorrhagic and ischemic (arterial and venous) stroke and its mimics.
The researchers used the Immunochip – a targeted genome-wide array containing approximately 200,000 genetic variants associated with immune-related genes, as well as around 3,000 single nucleotide polymorphisms (SNPs) associated with ischemic stroke – to look at genetic risk factors involved in 3,420 cases of ischemic stroke and 6,821 controls. They then conducted a meta-analysis using data from the Wellcome Trust Case Control Consortium 2 (WTCCC2) genome-wide association study (GWAS) of 3,582 cases of ischemic stroke and 5,972 controls, as well as summary statistics from 8,480 ischemic stroke cases and 56,032 controls analyzed in the METASTROKE consortium. Lastly, they conducted a computer-simulated replication study with additional stroke and control cases from the INTERSTROKE and VISP studies.
Analysis of the initial 3,420 cases of ischemic stroke and 6,821 controls identified three SNPs on two independent loci on chromosomes 10q26 and 19q13 for all ischemic stroke, as well as five SNPs across 5 loci for large artery ischemic stroke, the authors reported.
The subsequent meta-analysis confirmed previous findings from the WTCCC2 study associating the histone deacetylase 9 (HDAC9) locus on chromosome 7p21 with large artery ischemic stroke, as well as an association between pituitary homeobox 2 (PITX2) and zinc finger homeobox 3 (ZFHX3) loci at chromosomes 4q25 and 16q22 and cardioembolic stroke.
Importantly, the meta-analysis also identified a new risk locus at 12q24.12, which was included in the Immunochip because of its association with type 1 diabetes mellitus. It has also been associated with several cardiovascular risk factors, including blood pressure and cholesterol, the authors noted. The association was strengthened by targeted replication with data from the INTERSTROKE and VISP studies. In addition, the replication study showed that the risk locus was not associated with intracerebral hemorrhage.
“Unlike all previous GWAS-identified ischemic stroke loci, this locus does not appear to be associated with a single subtype but rather is associated with ischemic stroke as a whole,” the authors wrote.
They also found that 12q24’s association with stroke was independent of cardiovascular risk factors such as hypertension, hypercholesterolemia, smoking history, history of symptomatic coronary artery disease and ischemic heart disease, or diabetes mellitus. However, “the lack of risk factor data in all controls prevented a more conventional stratified analysis,” they wrote.
The authors noted that they could not identify the exact mechanism by which the 12q24 variant might increase the risk of ischemic stroke without increasing risk of intracerebral hemorrhage. However, the study is valuable because it furthers understanding of the biological factors that may contribute to stroke risk, Geoffrey L. Heyer, MD, attending pediatric neurologist at the Nationwide Children’s Hospital and assistant professor of clinical pediatrics at the Ohio State University College of Medicine, and Paul Nyquist, MD, MPH, associate professor in the departments of anesthesiology/critical care medicine and neurological surgery at the Johns Hopkins University School of Medicine, wrote in an editorial published in the same issue of Neurology.
“The greatest value of such discoveries lies not in the calculation of attributable risk but in the identification of underlying biological pathways that confer risk and provide targets for intervention in this dreaded disease,” they wrote.
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