Perspective:

The four genetic variants identified in this study are also present among individuals of African ancestry without known cardiovascular disease. Thus, these variants, which have previously been labeled as benign or indeterminate mutations, are not causative of disease. However, these variants were associated with worse combined outcomes in heart failure. Several important issues are raised: 1) There are complex interactions between genetic modifiers and other biological and environmental factors that may contribute to disease manifestation. 2) The presence of these genetic variants among individuals with African ancestry but not among individuals with European ancestry highlights the importance of conducting genetic studies in racially/ethnically diverse populations. 3) Future studies of genetic variants that may modify the outcomes of various disease processes are necessary. From a clinical standpoint, it remains unclear whether the detection of such a genetic variant should in some way influence the type of treatment or counseling given to an individual. There is still much to learn about the genetic basis of heart failure, but it is clearly essential to conduct these studies in diverse populations.