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 so ught 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 e arly atherosclerosis,we also sought associations with underlying asymptomatic at herosclerosis itself, assessed by carotid ultrasound in a community population. Methods -A total of 737 consecutive white patients with stroke and 933 white co mmunity 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 (n=1000) 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. 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 found only with large vessel and cardioembolic stroke, suggesting a mechanism of accelerated atherosclerosis. Were so ught to replicate this association in ischemic stroke as a whole, and individual stroke subtypes, in a arly atherosclerosis, we also sought associations with underlying asymptomatic at herosclerosis itself, assessed by carotid ultrasound in a community population. Methods-A total of 737 consecutive white patients with stroke and 933 white co mmunity 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 (n = 1000) was assessed using carotid ultrasound. Nineteen single nucleotide polym Results of -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.