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22 july 2010 - Press release

Rare genetic variants also contribute to the appearance of complex diseases

This study will be published online on 25 July in the prestigious journal Nature Genetics

An international study, in which researchers from the IMIM (Hospital del Mar Research Institute) have participated as the only Spanish researchers, has shown that rare genetic variants, which are present in less than 1% of the population, also contribute to determining individual susceptibility to suffer from complex diseases such as hypertriglyceridemia (high levels of triglycerides).

In the last 4 years much progress has been made in the knowledge of the genetic bases of diseases referred to as complex. These diseases are characterised by their relation to environmental factors such as tobacco, diet, etc. and to numerous genetic factors which determine the susceptibility of each person to suffer from them.

Using whole genome association studies, in which over 2,000,000 genetic variants in each person are studied, many of these common genetic variants have been found, that is they are observed in more than 1% of the population, and they are associated with the presence of a disease. Nevertheless, the effects of these genetic variations are slight and explain a small part of the variability in the population of the disease under study.

Hypertriglyceridemia is present in 10% of the Spanish adult population and it is a risk factor for myocardial infarction. Different studies have identified various genes in which there are genetic variants that are associated with these high levels of triglycerides. These variants explain less than 10% of the triglyceride differences that exist between people. Where are the genetic variants which explain the rest of the variability in relation to genetic aspects (heritability) and how can we identify them? One of the possible explanations is that there are rare genetic characteristics present in at least 1% of the population and that they have important effects which are still unknown.

Patients with very high levels of triglycerides were analysed in this study and 7 genes were identified in which there are common genetic variants that are associated with triglycerides. 469 patients were selected and 4 of these 7 genes were sequenced, that is, all of the letters on the DNA fragments where these 4 genes are located were read, and it was confirmed that 10% of the patients had some rare variant on these analysed fragments, while of the 94 healthy people analysed, a rare variant was identified in only 2% of them. The identified rare variants were changes in the base sequence (in the letters) which meant a change in the amino acid sequence of synthesized proteins, either insertions or losses of a DNA fragment, which also altered the synthesized protein.

This study shows that in the genes identified in whole genome association studies in which common genetic variants that are associated with high levels of triglycerides had already been identified, there are also rare variants which explain part of that heritability that has still to be discovered. The discovery of these rare variants will contribute to knowing more about the molecular mechanism of complex diseases and to identifying new treatment targets.

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