TABLE 1 Challenges in identifying genetic determinants of coronary heart disease.
From the following article:
Mechanisms of Disease: the genetic basis of coronary heart disease
Iftikhar J Kullo and Keyue Ding
BACK TO ARTICLE| Challenge | Comment |
|---|---|
Abbreviation: CHD, coronary heart disease. | |
| Phenotypic heterogeneity | CHD can manifest as several clinical phenotypes, including chronic stable angina, acute coronary syndrome, myocardial infarction, sudden cardiac death, and history of coronary revascularization. Measures of coronary atherosclerotic burden such as coronary artery calcium or angiographic coronary artery disease are objective and quantitative, unlike the dichotomous characterization (presence or absence) of a history of a cardiovascular event. Atherosclerotic disease burden and cardiovascular events such as myocardial infarction are distinct phenotypes, however, the latter being related more to plaque instability and rupture rather than plaque burden. |
| Genetic heterogeneity | Genetic heterogeneity is likely, given the multiple causal pathways that lead to CHD. For example, low plasma levels of HDL cholesterol can result from variation in genes from multiple metabolic pathways. Similarly, the transition from a stable coronary atherosclerotic plaque to an unstable inflamed plaque could be the result of genetic variation in multiple genes that participate in the inflammatory cascade and matrix degradation. |
| Small gene effects | A single genetic variant can constitute only a small proportion (e.g. 1– 2%) of the total genetic contribution towards complex disease phenotypes, and an odds ratio of 1.1–1.5 is typical for a susceptibility variant of a candidate gene.86 Uncovering such small effects requires large sample sizes, and recognition of this fact has motivated assembly of the so-called Biobanks in several European countries, including Iceland, England and Estonia.87 |
| Gene–gene and gene–environment interactions | Identification of gene–gene and gene–environment interactions is essential for identification of genes responsible for complex diseases, and will require large sample sizes and adequate computational resources. |
| Rare variants causing complex disease | Most current genetic epidemiology studies of complex diseases such as CHD assume that common variants (i.e. minor allele frequency  5%) account for much of the susceptibility to the disease. Both common and rare variants, however, probably influence CHD susceptibility. To uncover rare variants that influence susceptibility to CHD, resequencing or very large sample sizes will be required. |
