Common NOTCH3 Variants and Cerebral Small-Vessel Disease. Issue 6 (June 2015)

• Record Type: Journal Article
• Authors: Rutten-Jacobs, Loes C.A.; Traylor, Matthew; Adib-Samii, Poneh; Thijs, Vincent; Sudlow, Cathie; Rothwell, Peter M.; Boncoraglio, Giorgio; Dichgans, Martin; Bevan, Steve; Meschia, James; Levi, Christopher; Rost, Natalia S.; Rosand, Jonathan; Hassan, Ahamad; Markus, Hugh S.
• Is Part Of: Stroke. Volume 46:Issue 6(2015)
• Publication Date: 2015-06
• Subjects: Cerebrovascular disease -- Periodicals; Cerebral circulation -- Periodicals; 616.81
• DOI: 10.1161/STROKEAHA.114.008540
• Languages: English
• ISSNs: 0039-2499

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Background and Purpose—</title> <p>The most common monogenic cause of cerebral small-vessel disease is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, caused by <italic>NOTCH3</italic> gene mutations. It has been hypothesized that more common variants in <italic>NOTCH3</italic> may also contribute to the risk of sporadic small-vessel disease. Previously, 4 common variants (rs10404382, rs1043994, rs10423702, and rs1043997) were found to be associated with the presence of white matter hyperintensity in hypertensive community-dwelling elderly.</p> </sec> <sec> <title>Methods—</title> <p>We investigated the association of common single nucleotide polymorphisms (SNPs) in <italic>NOTCH3</italic> in 1350 patients with MRI-confirmed lacunar stroke and 7397 controls, by meta-analysis of genome-wide association study data sets. In addition, we investigated the association of common SNPs in <italic>NOTCH3</italic> with MRI white matter hyperintensity volumes in 3670 white patients with ischemic stroke. In each analysis, we considered all SNPs within the <italic>NOTCH3</italic> gene, and within 50-kb upstream and downstream of the coding region. A total of 381 SNPs from the 1000 genome population with a mean allele frequency >0.01 were included in the analysis. A significance level of <italic>P</italic><0.0015 was used, adjusted for the effective number of independent SNPs in the region using the Galwey method.</p> </sec> <sec> <title>Results—</title> <p>We found no association of any common variants in <italic>NOTCH3</italic> (including rs10404382, rs1043994, rs10423702, and rs1043997) with lacunar stroke or white matter hyperintensity volume. We repeated our analysis stratified for hypertension but again found no association.</p> </sec> <sec> <title>Conclusions—</title> <p>Our study does not support a role for common <italic>NOTCH3</italic> variation in the risk of sporadic small-vessel disease.</p> </sec> </abstract>