Phosphodiesterase 4D Gene, Ischemic Stroke, and Asymptomatic Carotid Atherosclerosis

Abstract

Background and Purpose-Phosphodiesterase 4D (PDE4D) was identified recently as the first novel stroke gene to predispose to ischemic stroke independently of conventional risk factors. An association was only found with large vessel and cardioembolic stroke, suggesting a mechanism of accelerated atherosclerosis. We sought to replicate this association in ischemic stroke as a whole, and individual stroke subtypes, in a non-Icelandic European population. To assess a role in early atherosclerosis, we also sought associations with underlying asymptomatic atherosclerosis itself, assessed by carotid ultrasound in a community population. Methods-A total of 737 consecutive white patients with stroke and 933 white community controls free of symptomatic cerebrovascular disease were examined using a case control methodology. For association with atherosclerosis, intima-media thickness (IMT) in a community population (nϭ1000) was assessed using carotid ultrasound. Nineteen single nucleotide polymorphisms (SNPs) and 1 minisatellite in the PDE4D gene were determined, with haplotyping undertaken using Phase 2.0. Results-No association with ischemic stroke overall was identified. Six of the 19 SNPs were associated with cardioembolic stroke and 2 different SNPs with large vessel disease. There was no association with carotid artery IMT or carotid plaque in the asymptomatic community subjects. Conclusions-The PDE4D gene is not a major risk factor for ischemic stroke, or early atherosclerosis, within the 2 European population samples studied. On analysis of individual stroke subtypes, there is a possible association with cardioembolic stroke, but the lack of association with carotid IMT and plaque would suggest that this is via a mechanism other than accelerated atherosclerosis.

Ischaemic stroke in hypertensive patients is associated with variations in the PDE4D genome region

“…There was a significant risk-reducing effect of SNP45 only in our and the Icelandic study, 1 a similar nonsignificant tendency in four other studies, 11,13,14,25 and a nonsignificant tendency to increased risk in the remaining seven studies. 3,5 -7,9,12,15 The overall OR: 0.95 (95% CI: 0.86 -1.05) indicates no significant overall effect in the 13 studies.…”

A large-sample assessment of possible association between ischaemic stroke and rs12188950 in the PDE4D gene

“…[1][2][3][4][5][6][7][8][9][10][11][12][13][24][25][26] The meta-analysis thus involved a total of 20 populations from 17 publications when our current study was included.…”

“…2 However, a meta-analysis in our previous publication in 2008 showed ambiguous results concerning the possible association between IS risk and variants in rs12188950. [3][4][5][6][7][8][9][10][11][12] We were aware of three replicating studies, that showed significant allelic association with IS by detecting and examining haplotype blocks located at the 5¢ end region of the PDE4D gene. 4,13,14 Moreover, a meta-analysis including four studies indicated significantly increased IS risk when considering an at-risk haplotype, including rs12188950.…”

Genetics of stroke

“…In association analyses of an Icelandic population [82] , several SNPs in PDE4D were associated with the combined phenotype of cardioembolism (CE) and largeartery atherosclerosis, suggesting a mechanism of accelerated atherosclerosis. Subsequently, Bevan et al [83] performed a study in a non-Icelandic European population and found a possible association with CE stroke, but the lack of an association found with carotid IMT and plaque would suggest a mechanism other than accelerated atherosclerosis. However, the role of PDE4D is inconclusive, with some investigators [84,85] replicating the association and some not [86] .…”