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CHORI Scientist's Research Featured in Two Nature Publications
Two groundbreaking studies by interdisciplinary researchers working collectively to confirm the benefit of genome-wide association studies (GWAS) were published in the August 5 issue of Nature. The first study, a landmark collaboration with over 100 experts, tripled the capability of GWAS to identify variations in the human genome associated with lipid disorders known to impact heart disease. The second study carried out a series of investigations based on a GWAS finding that identified for the first time the sortlin pathway as a major player in increasing levels of low-density lipoproteins (LDL), which are associated with increased risk for heart disease.

"There has been a debate as to how effective GWAS are for capturing the genetic variations responsible for complex diseases," explains CHORI senior scientist, Ronald Krauss, MD, whose lab participated in the collective efforts.
“The idea was to increase these genome searches to as large a scale as possible by collaborating with other labs, and to then target the genetic variations identified for deeper analysis.”

The human genome is composed of 3 billion base pairs that contain the genetic information that makes up any given individual. GWAS allow researchers to search the genome from many individuals for single nucleotide polymorphisms (SNPs) variations in the base pairs that do not correspond to the normal human genome, and thus may influence the development of disease. However, individual labs using GWAS to search for a genetic basis for increased risk of heart disease the leading cause of death in the United States rarely have access to DNA samples from more than 30 thousand individuals.

"Earlier studies using these numbers of individuals have only identified about 30 genetic traits that appeared to have significant associations with various lipid profiles known to significantly increase heart disease risk," says Dr. Krauss.

By combining sample resources across the 100 investigators, the collaborative group was able to test over 100 thousand individuals in order to increase the power of GWAS. As a result, the new study identified 95 SNPs as having significant associations with various blood lipid disorders tied to increased heart disease risk.

"The importance of these GWAS is that they provide the opportunity to delve deep into the genome to see if we can pluck out some new characters, novel genes that could lead us to a better understanding, or hopefully new approaches to treatment, based on previously undiscerned determinants," Dr. Krauss explains.
“GWAS provide the opportunity to delve deep into the genome to see if we can pluck out some new characters - novel genes that could hopefully lead us to new approaches to treatment, based on previously undiscerned determinants.”
"This was in fact exactly what we were able to show in the second study, in which we were able to do an in-depth analysis of one of the individual associations identified by the GWAs."

In this study, Dr. Krauss collaborated with 29 other researchers to investigate a particular genetic variation in a region that had previously not been associated with blood lipid levels but happened to be the strongest and most consistent variant associated with LDL in the GWAS.

"LDL is of course one of the biggest players in heart disease risk, so being able to identify the SNP responsible for the association has enormous import in guiding new forms of treatment," Dr. Krauss says.

In fact, the collaborative group was able to determine not only the specific DNA variant responsible for the association, but also to show that this played a significant role in the regulation of gene expression. The group then identified the effect that variation in the expression of that gene called sortilin produced.
"We were able to identify the entire sortilin pathway from the SNP to the biological end point, and this pathway turned out to result in specific modulation of blood levels of very small LDL particles which we had shown previously to be highly associated with progression of coronary heart disease. The collaborative effort really was a tour de force in applying multiple types of analyses to show how a specific SNP influences heart disease risk," says Dr. Krauss.

"What we did in this paper was to blend molecular genetics and molecular biology with clinical information, thereby completely spanning the range of scientific inquiry needed to follow a significant SNP association from its origin to its endpoint."


Tuesday, May 17, 2011 8:19 AM

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