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Familial aggregation, the PDE4D gene, and ischemic stroke in a genetically isolated population

From the Departments of Epidemiology and Biostatistics (Ms. van Rijn and Drs. Slooter, Schut, Isaacs, Aulchenko, Snijders, and van Duijn), Neurology (Dr. van Swieten), and Clinical Genetics (Dr. Oostra), Erasmus Medical Center, Rotterdam; Departments of Intensive Care and Neurology, Academic Medical Center, Amsterdam (Dr. Slooter); and Rudolf Magnus Institute for Neuroscience, Department of Neurology, University Medical Center, Utrecht, The Netherlands (Dr. Kappelle).

Address correspondence and reprint requests to Dr. Cornelia M. van Duijn, Department of Epidemiology and Biostatistics, Erasmus Medical Center, PO Box 1738, 3000 DR Rotterdam, The Netherlands; e-mail c.vanduijn{at}erasmusmc.nl

Objective: The purpose of this investigation was to study the familial aggregation of ischemic stroke and the association between the PDE4D gene and ischemic stroke.

Methods: The study was performed in an isolated population in The Netherlands, where the authors identified 91 patients with ischemic stroke. Ischemic stroke was subclassified in large- and small-vessel infarction. The authors calculated kinship and inbreeding coefficients and genotyped all patients for three single-nucleotide polymorphisms (SNPs) in the PDE4D gene.

Results: The proportion of related pairs was higher in patients with ischemic stroke (68.8%) compared with controls (30.7%; p < 0.001). For large-vessel infarction, the proportion of related pairs was higher (71%) compared with small-vessel infarction (62.8%; p < 0.001). Familial aggregation was strongest for patients with early onset (age at onset <45 years). All stroke groups were significantly more inbred compared with controls. In inbred individuals, the C allele of SNP45 increased the risk of small-vessel infarction 4.8 times (95% CI 1.1 to 22.3) compared with controls (p = 0.04). The T allele of SNP39 increased the risk of small-vessel infarction 6.3 times (95% CI 1.4 to 28.7) compared with controls (p = 0.02). No associations were found for large-vessel stroke.

Conclusions: There was familial aggregation of ischemic stroke and a difference in degree of familial clustering between stroke subtypes. The authors also found that the PDE4D gene is significantly associated with small-vessel infarction in inbred individuals.

Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll the Table of Contents for the October 25 issue to find the title link for this article.

This article was previously published in electronic format as an Expedited E-Pub on September 14, 2005, at www.neurology.org.

Disclosure: The authors report no conflicts of interest.

Received March 24, 2005. Accepted in final form July 12, 2005.

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