04 August 2010

Uncovering the heart of genetic influence on cholesterol and triglyceride levels in the blood

Worldwide research study reveals 95 genetic risk factors that alter levels of blood fats in multiple human populations

Space-fill model of a cholesterol molecule. This study has identified 95 genetic markers that influence cholesterol and triglyceride levels in blood, offering new therapeutic targets for coronary heart disease.

Space-fill model of a cholesterol molecule. This study has identified 95 genetic markers that influence cholesterol and triglyceride levels in blood, offering new therapeutic targets for coronary heart disease. [Andrew Ryzhkov, Wikimedia Commons]

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The value of genomic research lies in its ability to help scientists understand biological processes, particularly those that - when altered - may lead to disease. In this context, an international collaboration has described 95 separate variations across the genome that influence levels of cholesterol and triglycerides in the bloodstream in a range of human populations. These findings, published in the 4 August issue of Nature, provide a map for future research to unravel the biological connections between the levels of these blood fats and coronary heart disease, and lay the foundation for the development of new therapeutics.

"Although blood concentrations of cholesterol and triglycerides have long been 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," said Dr Sekar Kathiresan, director of Preventive Cardiology at Massachusetts General Hospital (MGH), an associate member of the Broad Institute of Harvard and MIT, and co-senior author of the study. "In this study, we provide 95 signposts indicating genes that contribute to plasma lipid concentrations."

Diseases of the heart and circulatory system are the main cause of death in the UK. Every year 94,000 people in the UK die as a result of coronary heart disease, which is the cause of death for one in five men and one in seven women. Alongside genetic risk factors, a number of environmental or lifestyle risk factors - such as lack of exercise, an unhealthy diet and smoking - are associated with the disease.

The study involved the coordinated efforts of investigators from 17 countries to examine genetic scans of more than 100,000 individuals. They identified 95 genetic regions - 59 of which were previously unknown - that are significantly associated with blood lipid levels. These associations were validated across a range of human populations (Eastern and Southern Asian, European, and African-American).

" This initial step in linking genomic studies of human populations with biological models in mice provides novel insights into the mechanisms regulating lipid metabolism "

Dr Manj Sandhu

By using the mouse as a model, the researchers went on to functionally validate three genes - GALNT2, PPP1R3B and TTC39B. By manipulating the expression of their equivalent genes in mice liver cells, the researchers showed that these three genes had clear effects on levels of HDL cholesterol and total cholesterol in the blood.

"This initial step in linking genomic studies of human populations with biological models in mice provides novel insights into the mechanisms regulating lipid metabolism. The genetic markers identified in this study will provide new opportunities for researchers worldwide to look in more detail at individual genetic variants associated with blood lipid levels," says Dr Manj Sandhu, one of co-senior authors of the study from the Wellcome Trust Sanger Institute, and Department of Public Health and Primary Care, University of Cambridge. "The key step will now be to extend the work on reliably identifying the underlying genes responsible for these changes in blood lipids and their function."

"This work shows the power of large-scale genome wide association studies to identify a range of genes that influence the risk of developing a disease," says Inês Barroso, joint acting head of human genetics at the Sanger Institute.

The paper is dedicated to the memory of Professor Leena Peltonen, one of the senior co of the study and former head of human genetics at the Wellcome Trust Sanger Institute. Sadly, Professor Peltonen passed away on 11 March 2010 without being able to see the publication of this study.

Notes to Editors

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A full list of funding agencies is available at the Nature website.

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A full list of funding agencies is available at the Nature website.

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The Wellcome Trust Sanger Institute, which receives the majority of its funding from the Wellcome Trust, was founded in 1992. The Institute is responsible for the completion of the sequence of approximately one-third of the human genome as well as genomes of model organisms and more than 90 pathogen genomes. In October 2006, new funding was awarded by the Wellcome Trust to exploit the wealth of genome data now available to answer important questions about health and disease.

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