Coronary heart disease is a leading cause of death worldwide. Abnormal levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C, or 'bad' cholesterol), high-density lipoprotein cholesterol (HDL-C) and triglycerides are all known to be major risk factors for heart disease and represent important drug targets.
In their paper, the scientists describe how they carried out a genome-wide association study (GWAS), scanning the genomes of 100,000 people of European descent and looking for changes in the genetic material that are associated with changes in lipid levels.
"Although blood concentrations of cholesterol and triglycerides have long between known as risk factors for cardiovascular disease, the extent to which genetics contributes to those concentrations and just how alterations in the underlying genes leads to the development of disease has been incredibly difficult to piece together," explained Dr Sekar Kathiresan of Massachusetts General Hospital in the US.
The researchers' analyses uncovered 95 genetic variants, 59 of which were previously unknown. According to the team, taken together the 95 variants 'explain 10%-12% of the total variance (representing 25%-30% of the genetic variance'.
Many of the variants are located in genes known to be linked to lipid levels and heart disease. "Closer scrutiny of the gene loci revealed genetic variants which we know offer a molecular target for cholesterol-lowering drugs," commented Professor Thomas Meitinger of the German Research Center for Environmental Health.
The scientists also scanned the genomes of thousands of people of East Asian, south Asian and African American descent. This revealed that the majority of the variants are shared across diverse ethnic groups.
"The new findings point us to specific genetic signposts that allow us to understand more fully why many people from all walks of life have abnormal levels of cholesterol and other blood lipids that lead to heart disease," said Christopher O'Donnell of the National Institutes of Health (NIH) in the US. "What's really exciting about this work is that we are moving from discovery to understanding brand-new information about how genes alter the lipids that contribute to heart disease."
As well as shedding light on the genetic causes of abnormal lipid levels, and, by extension, heart disease risk, the study validates the use of GWAS involving ever larger numbers of people. Previous studies of the genetic factors behind high lipid levels involved 20,000 people, and some had suggested that carrying out larger studies would result in no new variants or variants whose effect is so small as to be of negligible interest from a biological or clinical point of view.
"It is often argued that large-scale meta-analyses with more than 100,000 test subjects have little significance for the biology of complex diseases," said Professor H.-Erich Wichmann of the German Research Center for Environmental Health. "Our study impressively refutes this assertion. On the contrary, some of the newly discovered gene loci have clear biological and clinical relevance."
EU support for the work came from several projects. The ENGAGE (European network for genetic and genomic epidemiology) project is financed through the Health Theme of the Seventh Framework Programme (FP7). INGENIOUS HYPERCARE (Integrated genomics, clinical research and care in hypertension), DIABESITY (Novel molecular drug targets for obesity and type 2 diabetes) and EUROSPAN (European special populations research network: quantifying and harnessing genetic variation for gene discovery) are all funded under the 'Life sciences, genomics and biotechnology for health' Thematic area of the Sixth Framework Programme (FP6). Finally, the GENOMEUTWIN (Genome-wide analyses of European twin and population cohorts to identify genes in common diseases) project was supported under the 'Quality of life and management of the living resources' programme of the EU's Fifth Framework Programme (FP5).
- Nature, http://www.nature.com/nature
- German Research Center for Environmental Health, http://www.helmholtz-muenchen.de
- National Institutes of Health (NIH), http://www.nih.gov
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