Boston MA, Ann Arbor MI, and London, UK - Three new genomewide association studies have identified seven new genetic loci associated with lipids. The papers appear online January 13, 2007 in Nature Genetics, and the researchers say the work represents one of the first attempts to report on the applicability of common polymorphisms to blood cholesterol levels.

Two of the groups are based in the US and worked very closely together, the study led by Dr Sekar Kathiresan (Massachusetts General Hospital) and colleagues [1] and that by Dr Cristen J Willer (University of Michigan) et al [2]. Both identified six new loci, with Willer et al discovering one further locus. Willer et al also looked at whether any of the new loci were linked with CAD by using data from the Wellcome Trust Case Control Consortium study published last year. The third study [3], by Dr Jaspal S Kooner (Imperial College London, UK) et al, independently identified one of the same new loci associated with triglycerides (TG) that was found by both US teams.

Kathiresan told heartwire there are three benefits of the new research. "First, it helps to inform potential new biology. Second, some of these novel gene regions may end up, in due course, as new drug targets, and finally—and most important, to my mind—is their applicability to disease. What most people care about is the clinical-event issue—is this, for example, related to disease and not just the LDL level? It really looks like, mostly from the data reported by Willer et al, that the additive effects, the combination of multiple polymorphisms related to LDL particularly, are going to be importantly related to CAD."

However, Dr James Scott (Imperial College London), a coauthor on the British paper by Kooner et al, told heartwire that while the work is obviously important, "not very many of these things are going to be of diagnostic value until you've got a whole bunch of them and have sorted them out. We are looking through a really new window on how complex genetics works. It's going to be quite challenging, as the effects are so relatively small in terms of the total variance in phenotype."

Kathiresan explained to heartwire that while there has been prior research identifying specific cholesterol genes, these have for the most part applied to conditions where there are very abnormal levels of LDL cholesterol, HDL cholesterol, and/or TG "and where that abnormality clearly tracks in families." But what has not been clear before, he says, is how relevant these genes are to "garden-variety" cholesterol. "In most people, their cholesterol levels are not due to a single gene defect but probably due to the additive effect of many genes and also the environment."

Senior author on the Willer et al paper, Dr Goncalo R Abecasis (University of Michigan), expands upon this. "The majority of prior discoveries have focused on extreme cholesterol phenotypes—you'd find maybe a variant that would change your cholesterol by 60 mg/dL. But most of the ones we found are changes of 2 to 10 mg/dL. They are smaller effects, but they are much more common—perhaps they are found in every other person rather than one in 10 000 [as are the rarer genes]."

Hence, this new research is among the first to report on the applicability of common polymorphisms to blood cholesterol levels, "and that's probably the unique thing here," says Kathiresan.

Abecasis says it was fun, for a change, to work together with another group. "Usually we'd be racing against each other, but this time we were trading back and forth, exchanging information as we went along, and in the end we both found a bit more than we would have on our own."

The two US groups both examined the same 8816 individuals from three studies—the Diabetes Genetics Initiative, the FUSION study of type 2 diabetes, and the Sardinia study of aging-associated variables. In each of these individuals, they looked at more than 2.2 million polymorphisms for a relationship to LDL, HDL, or TG. "Then we took the 30 best results and tried to validate them in independent samples," Kathiresan explains. His team validated their findings in another 18 554 people, and Willer et al took their best 100 results and validated them in 11 569 people.

Seven loci are entirely new, and these are by far the most important to my mind.

"So in more than 37 000 people studied in both phases, we found 19 different regions of the genome that were associated with LDL, HDL, or TG," he continues. "Nine of these had previously been discovered, and we confirmed these. For three of the loci there was mixed evidence prior to this work, but we were able to convincingly confirm that these genes play a role in LDL, HDL, or TG. And seven loci are entirely new, and these are by far the most important to my mind."

The new loci identified by Kathiresan et al are: two associated with LDL (on chromosome 1p13 and 19p13); one with HDL cholesterol (on chromosome 1q42); and five with triglycerides (7q11, 8q24 1q42, 19p13, and 1p31). In addition, the Willer et al team identified one more locus associated with HDL, on 12q24.

The separate British study, by Kooner and colleagues, set out to look for genetic loci associated with the metabolic syndrome. They examined three distinct ethnic groups—whites, Indian Asians, and Mexicans. "This was a completely independent study that confirmed the association of 7q11 with TG, something that is very satisfying," says Kathiresan.

Willer et al then went on to test the loci to see if they were associated with CAD using the Wellcome Trust Case Control Consortium Study, by Samani et al, published in the New England Journal of Medicine last summer [4]. Abecasis takes up the story: "We found that only the loci that influenced LDL really showed a very clear association with CAD. We didn't see such a clear pattern for those that were associated with TG or HDL."

Kathiresan believes the most important new locus is 1p13: "Samani et al established this SNP as being related to CAD but did not establish a relation to cholesterol, and we come along and do an independent study for cholesterol and find the same darn SNP related to cholesterol. So we think this locus is very important because now there is human evidence that this SNP not only relates to LDL cholesterol but also to what everybody cares about, which is the clinical disease."

He explains further that 1p13 is in fact a protective allele. "People who carry two copies of 1p13 have an approximately 16-mg/dL lower LDL level than those who carry two copies of the normal allele."

Now there is human evidence that this SNP not only relates to LDL cholesterol but also to what everybody cares about, which is the clinical disease.

But Scott believes the more significant findings are related to HDL. "Our group, which was bankrolled by Pfizer, set out to look for new HDL loci—and we looked quite hard for them but did not find them. So I think the new HDL loci [identified by the Americans] are quite important."

Scott also thinks the TG locus identified by his group as well as the Americans is of interest. "Triglycerides are important because it is only now that TG are beginning to be seen as an independent risk factor for heart disease, particularly TG measured in the postprandial state.

"In our case, we rather directly made the association to fat storage, and therefore it links into the 'thrifty-gene' type thing and so on. It puts it at the center of what you do with glucose when you've got too much."

Kathiresan also said that the work gives insights into the potential mechanisms by which the SNPs may be acting, and there are important implications for future drug discovery, too.

Of the 19 gene regions they initially identified, "many are established and emerging drug targets, such as the target enzyme for statins," he says. "Also included are apolipoprotein B and [cholesteryl ester transfer protein] CETP. The fact that existing drug targets are being found by this approach lends credence to the idea that some of the new loci we found may eventually become drug targets," he says.

Scott says while the implications regarding drug discovery are "valid, they are standard boilerplate."