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Gene identified for stroke related to cerebral small vessel disease
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Based on studies in humans and animals, researchers have discovered a new gene linked to stroke related to cerebral small vessel disease.
The researchers undertook a study using genome-wide association and meta-analysis to find previously unknown genes associated with stroke.
In the genome-wide analysis that served as the discovery sample, the researchers analyzed 18 cohorts of 84,961 participants studied between 1948 and 2013. Stroke occurred in 4,348 of those individuals, with mean age at stroke ranging from 46 to 76 years.
For the validation sample, the researchers analyzed 70,804 participants, 19,816 of whom had stroke, from large cross-sectional studies, with the goal of identifying variants significantly associated with any stroke, ischemic stroke, cardioembolic ischemic stroke or non-cardioembolic ischemic stroke.
Any variants identified were analyzed for associations with cerebrovascular phenotypes and further explored in studies of mice and zebrafish.
Novel locus found
The researchers identified a novel locus associated with any stroke (OR = 1.08; 95% CI, 1.05-1.12; P = 1.48 x 10-8). It is located at chromosome 6p25, allele rs12204590, near the FOXF2 gene.
In addition, the allele was associated with elevated white matter hyperintensity, which is a marker for cerebral small vessel disease, in participants without stroke (n = 21,079; P = .0025).
The researchers also found that individuals aged 2 to 32 years with segmental deletions of FOXF2 had high levels of white matter hyperintensity.
When the researchers deleted Foxf2 in adult mice, the result was cerebral infarction and microhemorrhage, and when they examined orthologs of FOXF2 in zebrafish, they found decreased smooth muscle cell and pericyte coverage in cerebral vessels.
“Our research has identified a gene affecting another type of ischemic stroke, due to small vessel disease, and also suggests some genes may be associated with both ischemic and hemorrhagic stroke and may act through a novel pathway affecting pericytes,” Sudha Seshadri, MD, professor of neurology at Boston University School of Medicine, said in a press release. “Unraveling the mechanisms of small vessel disease is essential for the development of therapeutic and preventive strategies for this major cause of stroke.”
New drug targets
In a related editorial, Peter M. Visscher, PhD, from Queensland Brain Institute, University of Queensland, St. Lucia, Brisbane, Australia, and Jan H. Veldink, MD, PhD, from Brain Center Rudolph Magnus, department of neurology, University Medical Center Utrecht, Netherlands, wrote that, “It is still too soon to judge if new genetic loci for stroke can provide new paradigms for drug targets, but the hope is that they will so that avenues beyond cholesterol and clotting mechanisms can be explored for pharmaceutical intervention.” – by Erik Swain
Disclosure: The researchers, Visscher and Veldink report no relevant financial disclosures.
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