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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.

Original publication




Journal article



Publication Date





1203 - 1209


Department of Epidemiology and Biostatistics, Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands.


Cerebral Arteries, Microcirculation, Humans, Brain Ischemia, Genetic Predisposition to Disease, Genetic Screening, Risk Factors, DNA Mutational Analysis, Family, Consanguinity, Genotype, Polymorphism, Single Nucleotide, Adult, Aged, Middle Aged, Family Health, Netherlands, Female, Male, 3',5'-Cyclic-AMP Phosphodiesterases, Stroke, Cyclic Nucleotide Phosphodiesterases, Type 3, Cyclic Nucleotide Phosphodiesterases, Type 4