Mechanisms of Disease: the genetic basis of coronary heart disease

Understanding the genetic basis of coronary heart disease (CHD) could refine cardiovascular risk stratification, facilitating the development of new therapies. Here Kullo and Ding focus on the genetics behind the clinical manifestations rather than the risk factors for CHD, and provide an update on the findings to date, the challenges faced and new techniques for identifying clinically relevant genetic determinants of CHD. Since completion of the human genome sequence, considerable progress has been made in determining the genetic basis of human diseases. Understanding the genetic basis of coronary heart disease (CHD), the leading cause of mortality in developed countries, is a priority. Here we provide an update on the genetic basis of CHD, focusing mainly on the clinical manifestations rather than the risk factors, most of which are heritable and also influenced by genetic factors. The challenges faced when identifying clinically relevant genetic determinants of CHD include phenotypic and genetic heterogeneity, and gene–gene and gene–environment interactions. In addition, the etiologic spectrum includes common genetic variants with small effects, as well as rare genetic variants with large effects. Advances such as the cataloging of human genetic variation, new statistical approaches for analyzing massive amounts of genetic data, and the development of high-throughput single-nucleotide polymorphism genotyping platforms, will increase the likelihood of success in the search for genetic determinants of CHD. Such knowledge could refine cardiovascular risk stratification and facilitate the development of new therapies. Key Points Understanding the genetic basis of coronary heart disease (CHD) is a priority as it is projected to become the leading cause of mortality worldwide Challenges in identifying clinically relevant genetic determinants of complex diseases such as CHD include phenotypic and genetic heterogeneity, gene–gene and gene–environment interactions, and the fact that the etiologic spectrum includes both common genetic variants with small effects as well as rare genetic variants with large effects Linkage and association mapping are two conventional approaches in identifying genetic determinants of CHD Advances such as cataloging of human genetic variation, the development of high-throughput single-nucleotide polymorphisms genotyping platforms and genome-wide association studies will increase the likelihood of success in the search for genetic det