Researchers Find Gene Determinants Of C-Reactive Protein

Researchers at Brigham and Women's Hospital (BWH) have found that variation in several genes that are associated with metabolic and inflammatory regulation - in diseases such as diabetes and heart disease - also have significant effects on C-reactive protein (CRP) levels.

CRP is a marker of inflammation in the bloodstream, measured by a simple blood test that has been shown to predict heart attack, stroke, and cardiovascular death, even among individuals with low levels of cholesterol. Lifestyle modifications, such as weight loss and regular exercise, has been shown to lower CRP levels, but there has also been concern that genetics might impact CRP because high CRP often runs in families, specifically families with high cardiovascular risk and diabetes.

These results come on the heels of an announcement that the JUPITER trial, designed to test whether cholesterol-lowering statins can prevent heart disease in people with normal cholesterol but increased CRP levels, was terminated early by its Independent Data and Safety Monitoring Board.

"Half of all heart attacks and strokes occur among apparently healthy individuals with normal or even low levels of cholesterol" said Paul Ridker, MD, MPH, director of the Center for Cardiovascular Disease Prevention at BWH and lead author of the paper and the Principle Investigator of the JUPITER trial. "Defining the core genetic determinants of CRP is an important step toward understanding what it is about CRP that is driving cardiovascular risk."

Researchers evaluated genetic variations in segments of DNA from 6,345 healthy women to determine which genes, or variations in gene sequences, play a role in regulating levels of CRP. The women are participants in The Women's Genome Health Study, a unique collaboration between the National Heart, Lung and Blood Institute, Amgen and BWH. The project brings together government, academic researchers and industry in a model partnership designed to answer genetic questions in an effort to realize the goal of personalized medicine that would allow for patient-specific preventive programs in advance of symptoms.

Ridker and colleagues found that much of the common genetic variation that contributes to CRP levels is closely related to genes responsible for insulin resistance, weight gain, metabolism, and the early development of plaque build up in heart arteries. These results provide insight into the relationship that CRP has with metabolic syndrome, diabetes, and vascular events such as heart attack or stroke and coincide with the fact that interventions such as diet, exercise, and statin medications lower both cardiovascular risk and levels of CRP.

"The exciting finding is that some of the genes we identified are directly involved in metabolic syndrome pathways which could eventually be targeted for clinical therapies" said Dr. Daniel Chasman, director of Computational Biology in the Center for Cardiovascular Disease Prevention at BWH and a coauthor on the paper. "We also found for the first time that a part of the genome lacking known genes, often called a 'gene desert,' influences CRP levels. This is exciting because such areas have no known function, yet we now have evidence that this gene region influences inflammation in a direct way."