Although the common forms of atherosclerosis are multifactorial, studies of rare mendelian forms have provided the most important insights into the disease (). Studies of familial hypercholesterolaemia helped unravel the pathways that regulate plasma cholesterol metabolism, knowledge of which was important for the development of cholesterol-lowering drugs. In the past year, Tangier disease, a rare recessive disorder characterized by the virtual absence of circulating HDL, was shown to be due to mutations in the gene for the ATP-binding-cassette (ABC) transporter 1, providing an excellent candidate cause for more common forms of HDL deficiency45,46
. Recently found mutations in the mineralocorticoid receptor, a kidney protein that is involved in the body’s handling of salt, explain why some women have a sharp rise in blood pressure during pregnancy47
Mendelian disorders relevant to atherosclerosis
In contrast to the mendelian disorders, attempts to identify genes for the common, complex forms of atherosclerosis have met with mixed success. Studies of candidate genes have revealed a number that show significant or suggestive association or linkage with traits relevant to atherosclerosis, but our understanding remains incomplete (). Large-scale sequencing is now underway to identify polymorphisms for many other candidate genes for hypertension, diabetes and other traits relevant to atherosclerosis48
. In an attempt to identify atherosclerosis genes, whole-genome scans for loci associated with diabetes, hyperlipidaemia, low HDL levels and hypertension have been performed49
. But few loci with significant evidence of linkage have been found, emphasizing the complexity of these traits.
Common genetic variations contributing to CHD and its risk factors
The use of animal models is a potentially powerful way of identifying genes that contribute to common forms of atherosclerosis. Mice and rats—the most useful mammals for genetic studies—have common variations in many traits relevant to atherosclerosis, and orthologous genes frequently contribute to a trait in rodents and humans50
. Mapping and identification of genes contributing to complex traits is easier in rodents than in humans, as shown by the recent identification of a diabetes gene in the SHR rat model51
. Studies in animal models should be particularly useful for the identification of genetic factors influencing vascular cell functions; for example, differences in susceptibility to atherosclerosis between certain strains of mice seem to be due to variation that affects EC responses to oxidized LDL52
. During this decade it is likely that genome-wide approaches, such as expression array studies and large-scale animal mutagenesis studies, will become widely used in atherosclerosis research.
As a result of the genome projects and large-scale sequencing, tens of thousands of single-nucleotide polymorphisms are being identified and a catalogue of all common variations in humans will be generated over the next few years. This raises the possibility of whole-genome association studies. Given the rapid development of DNA chip technology, it should be possible to type large numbers of polymorphisms in many thousands of individuals. There are, however, significant unresolved issues involving linkage disequilibrium and statistical analysis53
in this approach.