Molecular Genetics of Susceptibility to Coronary Heart Disease


Coronary heart disease (CHD) is a leading cause of mortality and morbidity worldwide and delineating the molecular genetics of susceptibility to CHD is an urgent task. Traditional approaches such as genome‐wide linkage scans and candidate‐gene‐based association studies, yielded frustratingly little progress in identifying genetic determinants of ‘complex’ diseases. However, the completion of the Human Genome Project and the International HapMap Project set the stage for genome‐wide association (GWA) studies, resulting in significant advances in ‘complex disease’ genetics. In this review, we provide an update on the molecular genetics of CHD and its risk factors, most of which are heritable and also significantly influenced by genetic factors. We also summarize recent advances including GWA studies for CHD and its risk factors. Increased knowledge of the molecular genetics of CHD susceptibility will enable more accurate cardiovascular risk stratification and the development of new therapies.

Keywords: complex diseases; coronary heart disease; genetics; linkage; association; genome‐wide association (GWA)

Figure 1.

Multipoint linkage–analysis results for plasma homocysteine levels on chromosomes 1, 14 and 19 in African Americans. Genetic distance (in cM) is plotted on the X‐axis against the LOD score. Candidate‐genes for homocysteine metabolism under the linkage peaks are shown close to their approximate location. MTR, 5‐methyltetrahdrofolate‐homocysteine methyltransferase; CARM, Coactivator‐associated arginine methyltransferase 1; DNMT1, DNA (cytosine‐5)‐methyltransferase 1; GAMT, Guanidinoacetate N‐methyltransferase. Adapted from Kullo et al., with permission from Wolters Kluwer. © Wolters Kluwer.

Figure 2.

Linkage disequilibrium pattern at the chromosome 9p21 locus in persons of European ancestry (HapMap Data). The two variants (rs10757278 and rs10811661) were associated with coronary heart disease and type 2 diabetes, respectively. There is a recombination hotspot between these two variants.



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Further Reading

Kullo IJ and Ding K (2007) Mechanisms of disease: the genetic basis of coronary heart disease. Nature Clinical Practice: Cardiovascular Medicine 4: 558–569.

Lusis AJ (2000) Atherosclerosis. Nature 407: 233–241.

Lusis AJ, Mar R and Pajukanta P (2004) Genetics of atherosclerosis. Annual Review of Genomics and Human Genetics 5: 189–218.

McCarthy MI, Abecasis GR, Cardon LR et al. (2008) Genome‐wide association studies for complex traits: consensus, uncertainty and challenges. Nature Reviews: Genetics 9: 356–369.

Topol EJ, Smith J, Plow EF and Wang QK (2006) Genetic susceptibility to myocardial infarction and coronary artery disease. Human Molecular Genetics 15(Spec No 2): R117–R123.

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Kullo, Iftikhar J, and Ding, Keyue(Mar 2009) Molecular Genetics of Susceptibility to Coronary Heart Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0021453]