Single letter in the human genome points to risk for high cholesterol

Dec 16, 2008

(PhysOrg.com) -- Write out every letter in the human genome, one A, C, T or G per millimeter, and the text would be 1,800 miles long, roughly the distance from New York to Colorado. Now, in the search for genes that affect how humans synthesize, process and break down cholesterol, a consortium of researchers led by Rockefeller University scientists has found a single letter among this expanse of code that is associated with elevated LDL cholesterol levels, one of the leading health concerns that has come to dominate the 21st century.

The research, led by Jan L. Breslow, head of the Laboratory of Biochemical Genetics and Metabolism, brings a new level of understanding to an enzyme called HMGCR, the rate-limiting catalytic engine of cholesterol biosynthesis and the target of the much-revered cholesterol-lowering drugs known as statins. For years, scientists have known that HMGCR (the enzyme’s full name is 3-hydroxy-3-methylglutaryl coenzyme A reductase) plays a key role in cholesterol metabolism, but there was no evidence that common genetic variants existed in the gene that could affect how people metabolize cholesterol, an artery-clogging fat when produced (or consumed) in excess.

“In fact, HMGCR became the poster boy for how genes without common variation can still be good drug targets,” says first author Ralph Burkhardt, a postdoctoral fellow in the Breslow lab.

The work builds upon ongoing research involving the inhabitants of the Micronesian island of Kosrae, who have a higher burden of risk factors associated with obesity and heart disease. By taking advantage of the growing power of genomic databases and genetic and biochemical techniques, Burkhardt, Breslow and their colleagues showed that a single letter difference, known as a single nucleotide polymorphism or SNP, in the HMGCR gene was linked to higher LDL cholesterol levels in the 4,947 people whose blood was analyzed: a population of 2,346 Kosraeans and a European sample that was included for statistical power.

“At this point, nobody had an idea what biological effect this SNP would have,” says Burkhardt. “So we went on to look for a mechanism, one that could explain how this variant affects HMGCR expression and/or function.”

From the literature, the researchers, including Jeffrey M. Friedman, a Howard Hughes Medical Institute investigator and head of the Laboratory of Molecular Genetics, and Markus Stoffel, now of the Institute of Molecular System Biology in Switzerland, knew that people produce two forms of the HMGCR enzyme: a short form and a long one. Now they've discovered that the SNP in question modulates how much of each form each person produces, and that those with higher cholesterol levels produce more of the long form than the short one. Through a process called alternative splicing, the researchers further showed that when the cell transcribes the HMGCR gene, it skips a region of it called exon 13, leading to the shorter enzyme. This process, they believe, ultimately reduces cholesterol production in the body.

“Genes that affect the synthesis, processing and breakdown of these lipoproteins are closely linked to heart disease,” says Burkhardt. “This research has helped us to better understand atherosclerosis susceptibility and its complex genetic basis.”

Article: Arteriosclerosis, Thrombosis, and Vascular Biology 28 (11): 2078–2084 (November 1, 2008)

Provided by Rockefeller University

Explore further: A better way to track emerging cell therapies using MRIs

add to favorites email to friend print save as pdf

Related Stories

Prosecutors target credit card thieves overseas

11 hours ago

Criminals from around the world buy and sell stolen credit card information with ease in today's digital age. But if they commit their crime entirely outside the United States, they may be hard to prosecute.

SpaceX's next cargo launch set for Sept 20

11 hours ago

SpaceX's next unmanned cargo trip to restock supplies at the International Space Station is scheduled for September 20, the US space agency said Friday.

'Grand Theft Auto V' to hit PS4 and Xbox One

13 hours ago

Rockstar Games on Friday announced that the latest installment of its crime-themed blockbuster video game "Grand Theft Auto" will hit PlayStation 4 and Xbox One consoles in November.

Tropical Storm Odile taken on by two NASA satellites

14 hours ago

As Tropical Storm Odile continues to affect Mexico's west coast and stir up dangerous surf, NASA's TRMM and Aqua satellites provided forecasters information on clouds and rainfall in the coast-hugging storm. ...

Recommended for you

A better way to track emerging cell therapies using MRIs

11 hours ago

Cellular therapeutics – using intact cells to treat and cure disease – is a hugely promising new approach in medicine but it is hindered by the inability of doctors and scientists to effectively track the movements, destination ...

New biomedical implants accelerate bone healing

18 hours ago

A major success in developing new biomedical implants with the ability to accelerate bone healing has been reported by a group of scientists from the Department of Restorative Dentistry, University of Malaya. ...

User comments : 0