Newswise — In an important confirmation of genetic influences in stroke, researchers have found an association between a major risk gene and stroke in young adults, according to a report presented at the 130th annual meeting of the American Neurological Association in San Diego.
The gene, called phosphodiesterase 4D (PDE4D), had first been found to increase the risk of stroke in a study in Iceland, and other studies involving primarily older white populations have lent support for this finding.
A team of researchers from several institutions has now confirmed this result in a biracial group of young American women. They identified a structural variation, or polymorphism, in the gene that was associated with increased risk of stroke in both young black women and young white women. Furthermore, this association is present for small blood vessel disease as well as for large artery atherosclerosis.
The import of these results is confined to research for the moment. "Before our results can be used clinically, the underlying biological mechanisms for this association must be understood," said study author John W. Cole, MD, MS, of the Baltimore Department of Veterans Affairs Medical Center and the University of Maryland School of Medicine, Baltimore, MD.
Identifying risk genes in stroke is particularly difficult because many genes appear to combine with a variety of environmental risk factors ranging from smoking to use of oral contraceptives.
The identification of the PDE4D gene is thus an important advance. Several other studies have examined the association of PDE4D with stroke in different populations and most studies provide support for the original Icelandic findings. The next challenge is to determine the specific gene variations responsible for the association and how they influence the proteins that are coded for by the PDE4D gene.
"For example, does the genetic variant cause one to produce a defective protein, or decrease or increase the level of a protein, thereby predisposing to stroke? Does the variant make an individual more susceptible to stroke given a specific environmental exposure?" said Cole.
Only when these questions have been answered, would there be a value in developing a genetic test to determine which polymorphisms are present in a person's genome.
"The results of these tests would allow practitioners to counsel patients on stroke risk and to warn patients that specific environmental factors, such as oral contraceptive use, diet or smoking may be particularly harmful," said Cole.
Another important application will be to develop drugs that reduce stroke risk by specifically targeting the gene or its products.
Phosphodiesterase 4D Polymorphisms and the Risk of StrokeQing Song, PhD, John W Cole, MD, MS, Jeffrey R O Connell, PhD, Oscar C Stine, PhD, Margaret Gallagher, PhD, Wayne H Giles, MD, Braxton D Mitchell, PhD, Laurie J Reinhart, MS, Jian Wang, MS, Gary H Gibbons, MD, PhD and Steven J Kittner, MD, MS. Baltimore, MD.
Icelandic studies found phosphodiesterase 4D gene (PDE4D) polymorphisms are associated with ischemic stroke. Using a non-Icelandic population, we searched for novel genetic variants in PDE4D and determined stroke risk of these variants. A population-based case-control study of stroke among women aged 15-49 identified 300 cases of first ischemic stroke (51.2% African-American) and 225 age-comparable control subjects (44.2% African-American). A systematic polymorphism search in the highly evolutionary conserved regions of PDE4D was performed on 48 African-American and 48 Caucasian participants. Polymorphisms were genotyped in the entire study population and assessed for association with stroke. Forty-one polymorphisms with a major allele frequency greater than 0.05 were found in PDE4D among the sample population. Among the 26 polymorphisms analyzed to date, three polymorphisms were found to be significantly associated with stroke among African-Americans (p = 0.039 0.007; OR = 1.7 2.4) and one among Caucasians (p = 0.035; OR = 1.7). All polymorphisms are located in the promoter region of the gene. We identified PDE4D polymorphisms associated with stroke in African-American and Caucasian females, providing the first support for association of this gene with stroke in non-Icelandic populations.