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October 25, 2006

Genetic Susceptibility to Inflammation Increases Risk of Cardiovascular Disease

Study of Dialysis Patients Shows Increase in Disease and Mortality

New research from the Johns Hopkins Bloomberg School of Public Health and other institutions has shed light on the relationship between genetic susceptibility to inflammation in the blood and risk of cardiovascular disease and mortality in dialysis patients. Over 20 percent of dialysis patients die each year—heart disease is the leading cause of mortality. In a systematic study of several genes, the researchers demonstrated that certain genetic variants are associated with higher susceptibility to inflammation in the blood and subsequent cardiac risk and mortality, while other patients carry more resistant genetic variants.

In a study of 775 dialysis patients, the researchers tested the genetic variation in the lymphotoxin-alpha and interleukin 6 genes as independent predictors of cardiovascular disease risk. At follow-up 2.6 years later, 294 study participants had experienced a cardiovascular event such as heart attack, stroke or sudden death.

“Individuals who carried two copies of the lymphotoxin-alpha gene variant and one or more copies of interleukin 6 gene variants had a 2.1-fold higher risk of cardiovascular disease and 2.7-fold higher risk of mortality. These individuals had higher blood markers of inflammation , suggesting that susceptibility to inflammation is the mechanism for increased risk,” said Yongmei Liu, lead author of the study and a doctoral student in the Bloomberg School of Public Health’s Department of Epidemiology at the time the study was completed. She is now on the faculty at the Wake Forest University School of Medicine

The study authors report that the genetic variants studied were quite common in the gene pool. The higher risk genetic variant of lymphotoxin-alpha, was present in 37 percent of the genes among white patients and 50 percent of the genes among black patients. The study authors also examined other variants and found them to be less common yet protective against inflammation.

“Now that we know this, we’ll be able to better understand which dialysis patients will have a higher risk of mortality and why. The challenge will be to find treatment which lowers this risk by targeting inflammation or other pathways, such as cholesterol reduction” said Liu.

Josef Coresh, PhD, MD

“It is exciting that we’ve been able to unravel a part of the basis for genetic risk of cardiovascular disease in dialysis patients. We hope that we’ll soon be able to apply what we’ve learned in dialysis patients to the general population and identify which genetic variants make people more susceptible to heart disease than others,” said Josef Coresh, PhD, MD, senior author of the study and a professor in the Bloomberg School’s Department of Epidemiology. “It is our hope that we can pursue more genes so we are able to create a genetic risk score in order to guide treatment and therapy.”

“Functional Variants in the Lymphotoxin a Gene Predict Cardiovascular Disease in Dialysis Patients” was co-authored by Yongmei Liu, Yvette Berthier-Schaad, Laura Plantinga, Nancy E. Fink, Russell P. Tracy, Wen Hong Kao, Michael J. Klag, Michael W. Smith and Josef Coresh.

The research is published in the November 2006 issue of the Journal of the American Society of Nephrology. It was supported by grants from the Intramural Research Program of the National Institutes of Health, National Cancer Institute and Center for Cancer Research.

Public Affairs media contacts for the Johns Hopkins Bloomberg School of Public Health: Kenna Lowe or Tim Parsons at 410-955-6878 or paffairs@jhsph.edu.