Familial aggregation, the PDE4D gene, and ischemic stroke in a genetically isolated population.
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.
van Rijn
M J E
MJ
Department of Epidemiology and Biostatistics, Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands.
Slooter
A J C
AJ
Schut
A F C
AF
Isaacs
A
A
Aulchenko
Y S
YS
Snijders
P J L M
PJ
Kappelle
L J
LJ
van Swieten
J C
JC
Oostra
B A
BA
van Duijn
C M
CM
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000235:genetics*; D000328:Adult; D000368:Aged; D002545:Brain Ischemia / Q000453:epidemiology* / Q000235:genetics*; D002536:Cerebral Arteries / Q000473:pathology / Q000503:physiopathology; D003241:Consanguinity; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004252:DNA Mutational Analysis; D005190:Family; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D008297:Male; D008833:Microcirculation / Q000473:pathology / Q000503:physiopathology; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D020521:Stroke / Q000453:epidemiology* / Q000235:genetics*
D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517376:PDE4D protein, human