ew loci for blood lipids identified; functional role of 1p13 locus detailed

Bethesda, MD and Boston, MA - Two new studies published this week provide further insights into the genetic underpinnings of variations in blood lipid levels [1,2]. In one large-scale genomewide association study (GWAS), researchers identified 95 loci that showed associations with blood lipid levels, while another group performed a detailed functional genomics analysis showing how a locus on chromosome 1p13, previously associated with low LDL-cholesterol levels and MI, regulates LDL-cholesterol levels.

"The two papers are highly complementary," Dr Sekar Kathiresan (Massachusetts General Hospital, Boston), a senior investigator of both studies, told heartwire. "The reason they're so complementary is that the first paper, the GWAS paper, puts down 95 stakes in the sand, while the second paper drills down on one of those stakes. We think the mapping effort, the GWAS paper, is incredibly important simply based on the scale of the effort. It's safe to say it's the largest genetics study done to date, and these 95 loci explain about 25% of the genetic component for lipid levels, which is among the largest proportion of variation evaluated to date."

The two studies are published in the August 5, 2010 issue of Nature...

To show that SORT1 is the causal gene, the researchers manipulated the gene in mice. With small interfering RNA "knockdown" and "viral overexpression" in the mouse liver, the researchers showed that the upregulation of SORT1 led to significantly lower LDL-cholesterol levels, as much as 80% lower, and that silencing SORT1 increased LDL cholesterol approximately 200%.

"Using these experiments in mice, we were able to prove that sortilin is the right gene for the LDL effect at the chromosome 1 locus," Kathiresan told heartwire. "And then, finally, if sortilin is the right gene, how does sortilin lower LDL cholesterol? We showed that the physiologic mechanism is that higher levels of sortilin lead to less secretion of very low-density lipoprotein (vLDL) from the liver, and vLDL is the precursor to LDL. Having less of the precursor around leads to less LDL, and this was the final piece of the puzzle."...