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Consortium Members Link Loci to Lipid Levels, Explore Ties to Heart Disease

NEW YORK (GenomeWeb News) – A pair of studies published online yesterday in Nature Genetics is expanding — and starting to delve into — the list of genetic loci associated with blood lipid levels.

The lipid-linked SNP set includes variants associated with other conditions, too, the papers suggest, pointing to particular ties between some variants influencing levels of blood triglycerides and those contributing to coronary artery disease risk.

For the first of the studies, members of the Global Lipids Genetics Consortium used genotyping data for nearly 189,000 individuals of European ancestry to look for new variants involved in blood levels of lipids, such as cholesterol and triglycerides. That approach, coupled with the large sample set, also made it possible to get a better sense of key players acting at loci unearthed in past studies.

Amongst those of European descent, 94,595 individuals had been genotyped using arrays that scan across the genome for prior genome-wide association studies, authors of the study explained. Another 93,982 had been genotyped on a custom array called Metabochip that's designed to target SNPs in sequences suspected of contributing to lipid profiles, propensity for CAD, and related traits.

After sifting through this SNP data, the researchers landed on 157 loci showing ties to blood lipid levels. Of those, 62 had not been linked to such traits previously, though 32 of the sites did fall near genes with potential roles in blood lipid regulation based on information in the literature.

Variants in a subset of the 62 newly detected regions coincided with expression levels of nearby genes in the liver, the group noted, an organ tasked with producing many of the lipids that ultimately turn up in the blood.

Together with pathway, fine mapping, and other types of follow-up analyses performed for the study, such findings are beginning to offer hints about biological processes that produce lipid patterns found in the blood.

They also provide information on the potential overlap between lipid players and genetic factors that dial the risk of related conditions such as heart disease up or down. Across the complete set of sites implicated in blood lipid levels, for example, that team saw many of the same loci that have been linked to CAD risk and to conditions such as type 2 diabetes, obesity, and high blood pressure.

"These results give us 62 new clues about lipid biology, and more places to look than we had before," co-first author Cristen Willer, a genetics, computational medicine, and bioinformatics researcher at the University of Michigan, said in a statement. "Once we take the time to truly understand these clues, we'll have a better understanding of lipid biology and cardiovascular disease — and potentially new targets for treatment."

In particular, she and her co-authors short-listed 70 genes at 44 of the new loci that they believe are promising candidates for further functional studies based on integrated analyses of the 62 new lipid loci so far.

"It is our hope that the next round of genetic studies will build on these results, using new sequencing, genotyping, and imputation technologies to examine rare loss-of-function variants of clear functional impact to accelerate the translation of these leads into mechanistic insights and improved treatments for CAD," authors of the study concluded.

In an accompanying paper in Nature Genetics, researchers from Massachusetts General Hospital, Harvard Medical School, the Broad Institute, and elsewhere tapped Global Lipids Consortium data for a more in-depth look at the role that triglyceride lipids play in CAD.

That group focused on 185 lipid trait-associated SNPs from the other Global Lipids Consortium analysis to explore this potential relationship, using a statistical approach designed to consider variants' potential causation in triglyceride features and CAD.

Among the SNPs found to influence both overall blood triglyceride levels and levels of low-density lipoprotein, or LDL, cholesterol in the blood in the same direction, the researchers saw corresponding increases or decreases in CAD risk. And loci that appeared to have especially pronounced effects on triglyceride levels alone typically showed strong ties to CAD, too, they noted.

In contrast, a handful of variants linked to a rise in blood triglyceride levels and a dip in LDL cholesterol levels or vice versa weren't associated with CAD, the team found. Likewise, the investigators saw only tenuous ties between high-density lipoprotein cholesterol-associated variants and CAD, suggesting that form of cholesterol is not a major CAD contributor.

"[O]ur data are consistent with the hypothesis that both LDL cholesterol and triglyceride levels but not HDL cholesterol levels are causally related to CAD risk," Global Lipids Genetics Consortium members wrote in the meta-analysis paper. "HDL cholesterol, LDL cholesterol, and triglyceride levels summarize aggregate levels of different lipid particles, each with potentially distinct consequences for CAD risk."