For release: Monday, November 6, 2006
Specific variants of a gene called phosphodiesterase 4D (PDE4D) significantly increase the risk of stroke in women aged 15-49, a new study shows. The risk is magnified in women who smoke cigarettes. The study is the first to identify a possible interaction between this gene and an environmental factor in triggering stroke. The results help to show how the gene contributes to stroke risk and may lead to new ways of preventing stroke.
"This is the first time anyone has looked at PDE4D in early-onset stroke," says Steven J. Kittner, M.D., M.P.H., of the Veterans Administration Medical Center and University of Maryland School of Maryland in Baltimore, who led the new study. The research was part of a larger effort called the Stroke Prevention in Young Women Study 2, which is designed to identify genetic and environmental risk factors for ischemic stroke (stroke that results from blockage in artery) in young women. The work was carried out in collaboration with investigators at Morehouse School of Medicine in Atlanta. It was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) and appeared in the August 15, 2006, issue of Human Molecular Genetics.*
While most strokes occur in people older than 50, about one in 5,000 women ages 15-49 suffers a stroke each year. The risk increases with smoking, obesity, diabetes, high blood pressure, and a variety of other factors. These strokes are often devastating, with long-lasting and costly effects on productivity and quality of life.
“Stroke is the third most common cause of death in the U.S. and the major cause of adult disability. Because of the large economic impact of stroke: lost lives, lost productivity, and financial burden on families and society, it is important to develop novel determinants and potential disease modifying agents for stroke. Genetic vulnerability may, at least in part, explain the excess burden of stroke in African Americans and/or the increased prevalence of stroke in women," says Richard T. Benson, M.D., Ph.D., a program director with the NINDS Office of Minority Health and Research.
"We are just entering the era when genetics studies may be able to inform us regarding the risk for a number of common diseases, including stroke,” adds program director Katrina Gwinn-Hardy, M.D., Ph.D., of the NINDS Neurogenetics Cluster.
In the study, the investigators studied 48 African-American and 48 Caucasian women to identify variations called single-nucleotide polymorphisms, or SNPs, in the PDE4D gene. Each SNP represents a variation of one DNA base, or letter, in a gene. Genes can have many SNPs. Each person inherits two copies of each gene – one from each parent – and therefore each person has two versions of every SNP.
In a second part of the study, the researchers selected 23 of the most common SNPs for analysis in 445 women between the ages of 15 and 49. About half of the participants were African-American; the other half were Caucasian. A total of 224 of the participants had suffered an ischemic stroke. The others were similar in ages and ethnicity but had not suffered a stroke.
A total of five SNPs showed significant associations with stroke in these women. The magnitude of the associations between these SNPs and stroke risk was similar in African-American and Caucasian women. It was also similar for different types of ischemic stroke.
One SNP, called rs918592, showed a particularly strong association with stroke. People with a specific variant of this SNP had a greatly increased risk of stroke if they smoked. The investigators found a strong relationship between the number of cigarettes smoked and the magnitude of the risk. People with this gene variant who smoked less than 10 cigarettes a day had approximately twice the risk of stroke as non-smokers, while people who smoked 11 or more cigarettes a day had eight times the risk. Former smokers and people who had never smoked did not have any increased risk with this gene variant.
The high-risk version of SNP 918592 was present in about 18 percent of Caucasians and 55 percent of African-Americans in the control group, Dr. Kittner says. Only participants with two copies of this version of the SNP had an increased risk of stroke.
The findings improve understanding of how the PDE4D gene may increase the risk of stroke, says Dr. Kittner. Previous reports have suggested that the gene primarily affects risk of stroke from atherosclerosis (narrowing of the arteries due to buildup of cholesterol and other substances) and cardioembolism (clots that originate in the heart and block blood flow to the brain). However, in young adults, atherosclerosis is rare. The study also found an increased risk of strokes that are not linked to atherosclerosis, and no association with cardioembolism.
It is unclear why smoking interacts with a specific variant of PDE4D to increase the risk of stroke, the investigators say. However, previous studies have shown that cigarette smoking changes the expression of many genes in the endothelium that lines blood vessels. These changes may interact with PDE4D to increase the risk of stroke. A mouse study also has shown that prenatal exposure to cigarette smoking increases the expression of PDE4D. "It is important for other studies to now look at those potential interactions," Dr. Kittner notes. However, "there is ample evidence that cigarette smoking is harmful, regardless of genotype."
While five of the SNPs investigated in this study appeared to affect the risk of stroke, there are many SNPs in the PDE4D gene and researchers may not yet have identified the most important ones for stroke risk, Dr. Kittner says. Additional studies are needed to identify other SNPs that may play a role. "Ultimately, as we learn more, we might be able to identify genetically susceptible individuals," Dr. Kittner comments. "We are far from that now, but it is one goal of this research.”
The investigators are now carrying out a study of stroke risk factors in young men using tissue samples from the NINDS Human Genetics Repository. They also are planning studies to further clarify the role of the PDE4D gene in stroke. This research could lead to development of PDE4D inhibitors or other new types of medicines that may prevent stroke.
The NINDS is a component of the National Institutes of Health (NIH) in Bethesda, Maryland, and is the nation’s primary supporter of biomedical research on the brain and nervous system. The NIH is comprised of 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.
*Song Q, Cole JW, O'Connell JR, Stine OC, Gallagher M, Giles WH, Mitchell BD, Wozniak MA, Stern BJ, Sorkin JD, McArdle PF, Naj AC, Xu Q, Gibbons GH, Kittner SJ. "Phosphodiesterase 4D Polymorphisms and the Risk of Cerebral Infarction in a Biracial Population: The Stroke Prevention in Young Women Study." Human Molecular Genetics, August 15, 2006, Vol.15, pp: 2468-2478.
Last Modified January 31, 2007