Genetic Abnormality May Increase Stroke Risk Fourfold Among Young

This was the first study to investigate an association between a genetic abnormality known as PON1 polymorphism with stroke in adults younger than age 45. PON1 stands for paraoxonase, an enzyme that helps HDL (good) cholesterol prevent the oxidation of LDL (bad) cholesterol. LDL oxidation promotes heart and blood vessel disease.

Stroke most often occurs in older individuals, most of whom have identifiable stroke risk factors. Stroke is much less common in the under-45 age group. About 30 percent of strokes in younger patients have no clear causes, says Barbara Voetsch, M.D., lead author of the study.

Comparing blood samples of 118 men and women who had ischemic or clot-related strokes before age 45 to 118 stroke-free men and women of similar age, researchers focused on two types of genetic polymorphisms in the PON1 gene, one at position 192 and one at position 55. Genetic polymorphisms are sequence variations in the gene code. Comparing the patients and the control group, Voetsch and her colleagues found no difference in the frequency of the 55 polymorphism. However, the paraoxonase 192 polymorphic variant occurred significantly more often in the stroke patients. After accounting for other stroke risk factors, the researchers found that presence of the 192 variant increased stroke risk by a factor of 4.10 compared to absence of the genetic abnormality.

“This particular polymorphism is a surprisingly strong risk factor for stroke,” says Voetsch. “Most other genetic polymorphisms that predispose to clotting that have been identified so far do not confer such a strong increase in stroke risk.”

The fourfold increased risk associated with the PON1 192 polymorphism makes the abnormality a more potent stroke risk factor than several better-known risks, including smoking and diabetes. Overall, in this young population, the presence of the genetic abnormality was the second most potent stroke risk factor, trailing only high blood pressure.

“There is really a great need to find the causes and risk factors for stroke in younger people,” she says. “The need is important not only to help prevent strokes in young people, but also in older people, because factors we identify in younger patients may apply to older patients as well.”

PON1 was also found to interact with conventional stroke risk factors, such as smoking and high blood pressure, to multiply stroke risk, says Voetsch. For example, smoking more than doubled stroke risk in this population, but when a smoker had the PON1 polymorphism, stroke risk was 20 times higher compared to the risk in a non-smoker who did not have the genetic abnormality.

“The interaction between the polymorphism and other risk factors is one of the most interesting findings of the study,” said Voetsch, a post-doctoral fellow and research associate at the Whitaker Cardiovascular Institute at Boston University School of Medicine.

The results of the study emphasize the importance of controlling risk factors that can be minimized or eliminated altogether, such as smoking, she adds.

“Researchers now think that at least part of HDL’s beneficial effect is related to paraoxonase,” says Voetsch. “Paraoxonase has antioxidant effects and protects against atherosclerosis. Higher levels of PON1 mean more protection against the risk of stroke or vascular disease in general, including heart attacks. Paraoxonase levels don’t correlate directly with the amount of HDL a person has, but the enzyme does appear to play a role in HDL function.”

If these findings are confirmed in larger studies, the PON1 polymorphism may be a genetic marker for which to screen in the future to assess an individual’s risk for stroke, she adds.

Co-investigators in the study included Joseph Loscalzo, M.D., Ph.D., director of the Whitaker Cardiovascular Institute and chief of Medicine at Boston University School of Medicine; Kelly S. Benke, Lucia H. Siqueira and Benito P. Damasceno, M.D.

The study was funded in part by the National Institutes of Health.