viernes, 13 de agosto de 2010

Genome Scanning Finds Genes For Cholesterol And Heart Disease That Could Be Important Targets For Treatment



Genome Scanning Finds Genes For Cholesterol And Heart Disease That Could Be Important Targets For Treatment
Featured Article
Main Category: Genetics
Also Included In: Cardiovascular / Cardiology; Cholesterol; Heart Disease
Article Date: 05 Aug 2010 - 2:00 PDT


Two international studies published in a leading journal this week have pinpointed genes for cholesterol and heart disease that could be important targets for treatment, and demonstrate the potential clinical value of "genome scanning" or GWAS, genome wide association studies, in developing new diagnostic tests and therapies for diseases with genetic risks.

In the first study, researchers showed how a region on chromosome 1 that earlier GWAS research had already linked to "bad" cholesterol (low-density lipoprotein cholesterol, LDL-C) and heart attacks (myocardial infarction, MI) regulate the LDL-C pathway.

In the second study, a GWAS consortium with some of the same researchers in the first study, analysed the genomes of over 100,000 people of European descent and found 95 variants, including 59 previously unknown, that influence lipid traits linked to coronary heart disease.

Both studies were published online in Nature on 5 August.

Dr Daniel J Rader, professor of Medicine and Pharmacology at the University of Pennsylvania School of Medicine in Philadelphia, was co-lead author of the first study and also worked on the second. He told the media that:

"One of the criticisms of genome-wide association studies has been that they fail to identify specific genes that cause disease."

Commenting on the importance of the first study, he said it was:

"One of the first examples in which a spot on a chromosome identified by GWAS has been extended to pinpoint the causal gene and relevant physiology."

He said of the second study that:

"This remarkable international consortium highlights scores of genes not previously implicated in lipoprotein metabolism."

In the first study, Rader and colleagues showed that a common gene variant on chromosome 1 (specifically a locus on chromosome 1p13) creates a transcription factor binding site that alters the amount of certain genes expressed in the liver. One of these genes is Sort1, which codes for the protein sortilin, already known to be responsible for the cardiovascular effects of chromosome 1.

Using lab mice, the researchers found that two weeks after they silenced the Sort1 gene, the sortilin level went down by 90 per cent, and there was a 30 per cent increase in plasma cholesterol. Conversely, mice treated with an an adeno-associated virus (AAV) that increased liver sortilin protein showed an 80 per cent drop in plasma cholesterol at two weeks.

They found that the fall in plasma cholesterol was due to lower secretion of the LDL precursor VLDL into the blood. (Previous studies have already shown a link between lower LDL and reduced risk of heart attacks).

Rader and colleagues concluded that their findings show "functional evidence for a novel regulatory pathway for lipoprotein metabolism", and that changing the Sort1 pathway may alter the risk for heart attack in humans.

"We also demonstrate that common noncoding DNA variants identified by GWASs can directly contribute to clinical phenotypes," added the authors.

This would be an important breakthrough in the treatment of cardiovascular disease, said Rader since many people do not respond well to cholesterol-lowering medications such as statins, despite their widespread use.

In the second study, which describes the work of an international GWAS consortium that found 95 points (including 59 previously unknown) on the human genome were significantly tied to lipid-related traits for coronary artery disease, the researchers reported that among these, Sort1 showed the strongest statistical link with LDL-C levels in the human genome.

Rader said that:

"The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and impact lipid traits in multiple non-European populations, such as East Asians, South Asians, and African Americans."

"These results identify several novel loci associated with serum lipids that are also associated with coronary artery disease, highlighting potential targets for new therapies," he added.

Some of the funding for the research came from an American Recovery and Reinvestment Act grant which paid for the siRNA technology used to knock out the Sort1 gene in the first study. The technology was provided by a private company, Alnylam, for which Rader is a consultant on an unrelated cholesterol research project, according to a statement from the University of Pennsylvania.

"From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus."
Kiran Musunuru, Alanna Strong, Maria Frank-Kamenetsky, Noemi E. Lee, Tim Ahfeldt, Katherine V. Sachs, Xiaoyu Li, Hui Li, Nicolas Kuperwasser, Vera M. Ruda, et al.
Nature, 466, 714-719, Published online 5 August 2010.
DOI:10.1038/nature09266

"Biological, clinical and population relevance of 95 loci for blood lipids."
Tanya M. Teslovich, Kiran Musunuru, Albert V. Smith, Andrew C. Edmondson, Ioannis M. Stylianou, Masahiro Koseki, James P. Pirruccello, Samuli Ripatti, Daniel I. Chasman, Cristen J. Willer, et al.
Nature, 466, 707-713, Published online 5 August 2010.
DOI:10.1038/nature09270

Additional source: Penn Medicine.

Written by: Catharine Paddock, PhD
Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today


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Genome Scanning Finds Genes For Cholesterol And Heart Disease That Could Be Important Targets For Treatment

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