Are Gene Polymorphisms Responsible for Higher Risk of Congestive Heart Failure in African-Americans?

Stephen B. Liggett
University of Cincinnati College of Medicine, and Howard Hughes Medical Institute
P30ES06096

Background: Congestive heart failure (CHF) is one of the leading causes of death in the U.S. and is the result of diverse insults to the heart including previous incidences of ischemia, hypertension, and infections. Frequently, no cause can be identified and these patients carry a diagnosis of idiopathic cardiomyopathy. Nearly five million people in the U.S. suffer from the most common forms (idiopathic and ischemic) of heart failure and about half of the patients die within 5 years. Predicting who develops CHF in the general population, or in those with some preexisting cardiac disease, has been an elusive goal. However, racial differences in the incidence, progression, and response to therapy suggest that a genetic component is having an influence.

Physiologically, the presynaptic α2c- and the postsynaptic β1- adrenergic receptors work in combination to control the release of norepinephrine and the resulting force of the heart muscle contraction. Polymorphic variations in these receptors, which cause increased amounts of norepinephrine release and enhanced activity in the heart, could result in more forceful heart contractions over a period of years, leading to higher incidences of heart failure. These researchers investigated the incidence of these polymorphisms in a group of 348 blacks and whites who were either healthy or heart failure patients.

Advance: In black subjects homozygous for the variant α2c receptor, the risk of developing congestive heart failure was over 5 times higher than those subjects with other receptor types. There was no increase in risk with the β1 variant alone. However, among subjects who had both variant receptors, the risk for heart failure was over 10 times higher than subjects without the variant receptors. White subjects with either one or the combination of variant receptors had no significantly increased risk. This is most likely due to the fact that the α2c is so uncommon in whites. The allele frequency of the α2c variant occurs is about 40% in blacks and only about 4% in whites.

Implication: Although this was a small study which needs to be replicated in a study with many more subjects, it could have important practical implications. It could explain the higher rates of morbidity and mortality from CHF in blacks than in whites. It suggests that genetic screening would help to determine high risk individuals and families. This knowledge would also have implications in treatment and prevention practices. For instance, for those individuals with both variant receptors, reduction of all other risk factors, such as smoking, high cholesterol, obesity, and inactivity, may be of extra importance. Screening tests for heart enlargement and the possible use of beta-blockers prophylactically could also be indicated.

Citation: Small KM, Wagoner LE, Levin AM, Kardia SLR, Liggett SB. Synergistic Polymorphisms of β1- and α2c-Adrenergic Receptors and the Risk of Congestive Heart Failure. New England Journal of Medicine. 2002 October 10; 347:(15):1135-1142.