Genetic susceptibility: a higher risk of congestive heart failure in blacks: genetics may be responsible. (Headliners: NIEHS-supported research).

Small KM, Wagoner LE, Levin AM, Kardia SLR, Liggett SB. 2002. Synergistic polymorphisms of [[beta].sub.1] and [[alpha].sub.2c]-adrenergic receptors and the risk of congestive heart failure. N Engl J Med 347(15):1135-1142.

Congestive heart failure (CHF) is one of the leading causes of death in the United States: nearly 5 million people suffer from the most common forms of heart failure (idiopathic and ischemic), and about half of CHF patients die within five years. Predicting who in the general population or among those with some preexisting cardiac disease will develop CHF has been an elusive goal. However, racial differences in the incidence and progression of CHF and its response to therapy suggest that a genetic component is at play.

Two receptors--the presynaptic [[alpha].sub.2c]-adrenergic receptor and the postsynaptic [[beta].sub.1]-adrenergic receptor--work together to control the release of norepinephrine and the resulting force of the heart muscle contraction. Polymorphic variations in these receptors that increase the release of norepinephrine could result in more forceful heart contractions over a period of years, leading to more heart failure. NIEHS grantee Stephen B. Liggett, of the University of Cincinnati College of Medicine and Howard Hughes Medical Institute, and colleagues investigated the incidence of these polymorphisms in a group of 348 black and white subjects who were either healthy or had heart failure. The results could explain why blacks have higher rates of CHF morbidity and mortality than whites.

For black subjects homozygous for the Del322-325 variant of the [[alpha].sub.2c]-adrenergic receptor, the risk of developing CHF was more than five times higher than for those subjects with other variants of this receptor. Among subjects who had not only the [[alpha].sub.2c]Del322-325 variant but also the Arg389 variant of the [[beta].sub.1]-adrenergic receptor, the risk for heart failure was more than 10 times higher than for other subjects. (There was no increase in risk with the [[beta].sub.1]Arg389 variant alone.) These subjects were invariably black; the [[alpha].sub.2c]Del322-325 variant is much less common in whites, occurring in only about 4% of this population (versus about 40% of blacks). In white subjects, the frequency of this variant was greater among patients with heart failure than among those without, but the extent of the risk to whites remains less well-defined.

Although the study was small and needs to be replicated in more subjects, it suggests that genetic screening could help to determine high-risk individuals. For people with both the [[alpha].sub.2c]Del322-325 and [[beta].sub.1]Arg389 receptor variants, reduction of all other risk factors, such as smoking, high cholesterol, obesity, and inactivity, may be of added importance.