Human Molecular Genetics Advance Access originally published online on July 11, 2006
Human Molecular Genetics 2006 15(16):2468-2478; doi:10.1093/hmg/ddl169
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Phosphodiesterase 4D polymorphisms and the risk of cerebral infarction in a biracial population: the Stroke Prevention in Young Women Study
1 Morehouse School of Medicine, Atlanta, GA 30314, USA, 2 University of Maryland School of Medicine, Baltimore, MD 21201, USA, 3 Veterans Administration Medical Center, Baltimore, MD 21201, USA, 4 Centers for Disease Control, Atlanta, GA 30333, USA and 5 Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
* To whom correspondence should be addressed at: Maryland Stroke Center, University of Maryland School of Medicine, 655 West Baltimore Street, Room 12-006, Baltimore, MD 21201, USA. Tel: +1 4107060414; Fax: +1 4107060816; Email: jcole{at}som.umaryland.edu
Received March 14, 2006; Revised June 29, 2006; Accepted July 2, 2006
An association between polymorphisms within the phosphodiesterase 4D gene (PDE4D) and ischemic stroke was initially reported in older adults from Iceland and has been supported by studies in several other primarily elderly populations. In the present study, we examined the association between PDE4D polymorphisms and early-onset ischemic stroke in a biracial female population. A systematic search for polymorphisms in the highly evolutionary conserved regions of PDE4D was performed on 48 African-American and 48 Caucasian participants. Novel and known polymorphisms were then prioritized and genotyped in the entire study population of 224 cases of first ischemic stroke among women aged 15–49 and 211 age- and ethnicity-balanced control subjects. Forty novel and previously reported polymorphisms with a minor allele frequency greater than 0.05 were determined, with 23 polymorphisms selected for analysis in the full case–control sample. Single nucleotide polymorphism (SNP), linkage disequilibrium and haplotype analyses were performed. SNP rs918592, found in an intron near the 5' end of the gene, was significantly associated with stroke (age- and race-adjusted odds ratio (OR=1.5, P=0.007), with four other SNPs showing significant, albeit less strong, associations. The magnitude of association was similar across African-Americans and Caucasians and across multiple stroke subtypes (e.g. atherosclerotic, lacunar and non-lacunar of undetermined etiology). The association of rs918592 with stroke was confined exclusively to current smokers (OR=3.2, P=0.00014), with no association observed among never-smokers (OR=0.9, P=0.75) or former smokers (OR=1.2, P=0.66), demonstrating a gene–environment interaction (P=0.03). A strong dose–response relationship was also seen among current smokers. No specific risk haplotypes were identified.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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