BioWorld International Correspondent

LONDON - A study of almost 12,000 individuals has identified a previously unknown genetic variant that influences levels of LDL cholesterol.

The region of the genetic variation, on chromosome 1, has never been linked previously to lipid metabolism, so the discovery could lead to completely new approaches for treating coronary artery disease and related disorders.

Manjinder Sandhu, lecturer in epidemiology at the department of public health and primary care, University of Cambridge, UK, told BioWorld International: "We have found a locus on chromosome 1 that is consistently associated with differences in levels of cholesterol in the blood. Further functional investigations of this region may help us to understand the reasons for these differences."

Once scientists gain a good understanding of the role of the gene, and how it links in to the metabolism of LDL cholesterol, he added, "there will clearly be an opportunity to screen for molecules or targets that have an impact on the expression of the genes involved, or which up- or downregulate their expression, to find out if these have an impact on LDL cholesterol levels."

The study is reported in Feb. 7, 2008, issue of The Lancet, in a paper titled: "LDL-cholesterol concentrations: a genome-wide association study."

Sandhu and his colleagues and collaborators set out to discover novel genes that play a role in LDL cholesterol metabolism, with a genomewide association study. That method involved scanning the genomes of many people with different levels of LDL cholesterol to detect small variants such as single nucleotide polymorphisms (SNPs), and seeing whether those variants are associated with differences in LDL cholesterol.

The researchers decided to examine whether differences in LDL were explained by each of nearly 300,000 genetic variants. By applying a stringent test of statistical significance, and carrying out two more studies to see whether the same genetic variants were associated with LDL in other populations, they were able to show that one particular locus was indeed associated with blood levels of LDL.

When the researchers examined the region they had pinpointed in more detail, they found that it was linked to three genes, none of which had been implicated in lipid metabolism. Further studies showed that the strongest signal from that region was from a gene called CELSR2. No one knows what the function of the gene is.

Sandhu said: "We know that this locus on chromosome 1 is important in determining LDL levels, and we have some evidence that suggests that the gene responsible may be CELSR2. But we can't reliably discriminate between that gene and the contiguous genes that lie close to it - we need to do additional studies to resolve exactly where this signal is being generated."

Since submitting this work for publication, the collaborators have gone on to show that the same locus is linked to LDL levels in a population cohort from Pakistan. Sandhu explained: "For the Lancet study, we mainly looked at people from European populations, but the latest finding suggests that the association is consistent across different populations."

Large-scale studies also are planned, to confirm if there is an association between genetic variants at the locus identified and the risk of coronary artery disease.

"We will also be carrying out large-scale expression studies in various populations, to try to understand some of the mechanisms that link in to generate the association," Sandhu said.

"This may help us disentangle which gene is responsible for the association with LDL cholesterol."

In the long term, it will be helpful to examine whether mutations in the gene have an impact on clinical phenotypes. "For example, we know that a large proportion of people with familial hypercholesterolemia do not have the classic mutations associated with this syndrome," Sandhu said.

Summing up, he concluded: "One reason why this study is so important is because it provides an exemplar of the genomewide association approach. It shows scientists that taking a hypothesis-free approach - as you do with a genomewide association study - can provide new and novel insights into the biological mechanisms and aetiology of disease. Our study also shows how the expertise of academic and industry scientists can be combined to provide novel insights into disease mechanisms, providing the potential for new therapeutic targets. We hope to extend this approach to other research areas."