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



Scientists have discovered a new way for bacteria to transfer toxic genes to unrelated bacterial species, a finding that raises the unsettling possibility that bacterial swapping of toxins and other disease-aiding factors may be more common than previously imagined. In a laboratory experiment, the scientists from NYU School of Medicine discovered that Staphylococcus aureus, a

Full Post: Discovery of new way for bacteria to transfer toxic genes to unrelated bacterial species

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.”

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

http://www.rockefeller.edu

Link




An international research team has identified 11 novel locations in the human genome where common variations appear to influence cholesterol or triglyceride levels, bringing the total number of lipid-associated genes to 30. While major mutations in some of these genes have been known to underlie rare lipid metabolism disorders, it is becoming apparent that common

Full Post: Discovery of 11 new gene sites that influence cholesterol or triglyceride levels



Scientists have identified 12 new genes that are somewhat strange bedfellows: Some link gallstones and blood cholesterol levels, others link melatonin and sleep patterns to small increases in glucose levels and larger jumps in the risk of diabetes. While these associations are surprising, all the genes are potential new drug targets and some of them

Full Post: Scientists find 12 new genes with potential as drug targets



A new study presages a real aim of genetics: to look at whole populations to in order determine the significance of individual genetic variants for individual health. The research team, whose work is published in Nature Genetics, find six novel genetic variants that are associated with lipid levels, a common indicator of heart or artery

Full Post: Discovery of six novel genetic variants associated with lipid levels



Abnormalities in genes that repair mistakes in DNA replication may help identify people who are at high risk of developing pancreatic cancer, a research team from The University of Texas M. D. Anderson Cancer Center reports in the Jan. 15 issue of Clinical Cancer Research. Defects in these critical DNA repair genes may act alone

Full Post: Defects in critical DNA repair genes may predict pancreatic cancer risk



Having discovered how a lowly, single-celled fungus regulates its version of cholesterol, Johns Hopkins researchers are gaining new insight about the target and action of cholesterol-lowering drugs taken daily by millions of people to stave off heart attacks and strokes. Their work appears in the December issue of Cell Metabolism. In humans, statin drugs inhibit

Full Post: Yeast provides new insight into cholesterol-lowering drugs