Genetic studies bolster understanding of lipid regulation
MedWire News: Two major research studies published in the journal Nature offer important new insights into the regulation of blood lipoproteins and identify potential targets for drug development.
In the first study, Tanya Teslovich (University of Michigan, Ann Arbor, USA) and team performed a genome-wide association study, looking for common variants associated with plasma lipids in more than 100,000 individuals of European ancestry.
Their analysis identified 95 genetic loci, 59 of which were previously unknown, which were significantly associated with blood lipids. These associations were validated across multiple human populations and several were also validated in mouse models.
Of the 95 loci examined, a site on chromosome 1 (1p13) was strongly linked with variations in plasma levels of low-density lipoprotein (LDL) cholesterol. A particular variant, rs12740374, carried by 20% of the population, was associated with reduced LDL cholesterol levels, but was located in a non-coding region of the chromosome.
The second study, by Kiran Musunuru (Massachusetts General Hospital, Boston, USA) and co-workers, was a functional validation study of the locus identified by Teslovich's team.
Musunuru et al showed that the non-coding variant, rs12740374, in the 1p13 locus creates a transcription factor binding site, which allows for increased transcription of certain genes in the liver.
Using a combination of over-expression and RNA silencing techniques, they identified SORT1, the gene that encodes the protein sortilin, as being the gene actually responsible for the variation in lipid levels associated with rs12740374.
Specifically, animals treated with a silencing RNA capable of reducing liver sortilin by 90% had a 30% increase in plasma LDL cholesterol, while mice injected with an adeno-associated virus to increase liver sortilin protein had an 80% reduction in LDL cholesterol.
Further studies showed that this effect was due to reduced secretion of the LDL precursor, very-low-density lipoprotein.
Taken together, these findings provide evidence for a new regulatory system for lipoprotein metabolism and suggest that activating the SORT1 pathway may alter cardiovascular risk in humans, say the investigators.
"These studies demonstrate that genome-wide association studies - done at the proper scale and with the proper tools - remain a powerful approach to understanding biology and disease, and that even non-coding variants can have a clinical effect," Musunuru remarked.
"The SORT1 pathway is an unexpected but promising new target for therapeutic intervention to reduce LDL cholesterol and, in turn, heart attacks."
MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2010
By Joanna Lyford