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Table 1.  

Challenges in Identifying Genetic Determinants of Coronary Heart Disease

Table 2.  

Linkage Studies of Myocardial Infarction and Coronary Artery Disease

Table 3.  

Examples of Single-nucleotide Polymorphism or Haplotype Association Studies of Coronary Heart Diseasea

Box 1.  

Glossary of Common Genetic Terms

Box 2.  

Linkage Studies Versus Association Studies

Mechanisms of Disease: The Genetic Basis of Coronary Heart Disease

Authors: Iftikhar J. Kullo, MD ; Keyue Ding, MDFaculty and Disclosures


Summary and Introduction


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.


In 2003 in the US alone, there were an estimated 1.2 million cases of coronary heart disease (CHD), resulting in 479,000 deaths.[1] Although recognition and treatment of established risk factors for CHD will reduce the disease burden considerably, simultaneous efforts aimed at unraveling the genetic basis of CHD are important for the development of novel diagnostic and therapeutic methods.

Considerable progress has been made in determining the genetic basis of human diseases since the human genome has been sequenced. The genetic determinants of more than 1,600 Mendelian diseases are now known, and discovery of genomic regions and genetic polymorphisms that influence susceptibility to common 'complex' diseases is accelerating. In this Review, we discuss the challenges of elucidating the genetic basis of CHD, focusing mainly on its clinical manifestations rather than its risk factors, and summarize the studies that have yielded insights into the genetic basis of this common, complex disease. We also discuss how recent advances in this field will increase the likelihood of identifying genetic determinants of CHD.

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