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Team Finds Functional Role for Blood Lipid Locus Detected By GWAS

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – A pair of studies appearing online today in Nature are uncovering genetic variants involved in elevated blood lipid levels — and offering functional insights into how one GWAS-identified locus influences blood lipid levels.

In the first of these studies, researchers from 17 countries used a meta-analysis of dozens of genome-wide association studies on more than 100,000 individuals to pin down 95 variants linked to blood lipid levels in European and other populations.

As reported in a second paper, some members of the same team then used human cohort, cell line, and mouse model studies to focus in on one chromosome 1 locus identified through that GWAS. In the process, they demonstrated that a non-coding variant in this locus alters the expression of a gene called SORT1 in the liver, leading to changes in liver secretion of low density lipoprotein cholesterol and its precursor.

"[W]e are moving from discovery to understanding brand-new information about how genes alter the lipids that contribute to heart disease," GWAS co-author Christopher O'Donnell, a researcher affiliated with the National Heart, Lung, and Blood Institute and Harvard Medical School, who helped lead the Framingham Heart Study, said in a statement.

"These results help refine our course for preventing and treating heart disease, a health problem that affects millions of Americans and many more people worldwide," National Institutes of Health Director Francis Collins, a co-author on the GWAS paper, said in a statement.

The researchers started by doing a meta-analysis of 46 GWAS involving roughly 100,000 individuals of European ancestry from the US, Europe, and Australia.

In particular, they looked for genetic variants associated with total plasma cholesterol levels, as well as blood levels of LDL cholesterol, or "bad cholesterol," high density lipoprotein cholesterol, and triglycerides, using previously collected data to look at about 2.6 million directly genotyped or imputed SNPs.

Using this approach, the team found 95 loci associated with one or more of the blood lipid traits tested, including dozens of previously detected loci and 59 loci not found in past studies.

While some of these variants fell in and around genes known to regulate lipid levels, others were found in parts of the genome that offered no obvious clues about their function.

The team found that most of the loci detected through the meta-analysis were associated with blood lipid levels in other populations as well, based on their analyses of some 15,000 East Asian individuals from China, Korea, and the Philippines, about 9,000 South Asian individuals, 8,000 African-Americans, and genotyping studies of thousands more Europeans.

"These observations indicate that most (but probably not all) of the 95 lipid loci identified in this study contribute to the genetic architecture of lipid traits widely across global populations," they wrote.

Moreover, follow-up studies of 24,607 individuals of European ancestry with coronary artery disease risk and 66,197 unaffected control individuals suggest a subset of the loci influence coronary artery disease risk.

Some of the variants that were most strongly associated with levels of LDL cholesterol, a heart attack risk factor, fell in a chromosome 1 locus previously implicated in myocardial infarction or heart attack risk.

In the accompanying study, members of the team began exploring the functional consequences of these chromosome 1p13 variants, bringing information from cohort studies together with expression and other experiments using cell lines and mouse models.

"[W]e delve deeper into one specific signpost and move from genomic localization to biologic understanding by discovering how genetic variation leads to clinical symptoms in living organisms," Massachusetts General Hospital Director of Preventive Cardiology Sekar Kathiresan, co-corresponding author on both papers, said in a statement.

They found that SNPs between the CELSR2 and PSRC1 genes in the 1p13 locus apparently influence the expression of certain genes in the liver, including SORT1, which codes for the protein sortilin.

Indeed, their subsequent experiments suggest that the causal variant for LDL cholesterol levels in this locus, rs12740374, alters transcription factor binding patterns in such a way that the expression of SORT1 shifts in the liver. This altered expression, in turn, appears to influence the amount of very low density lipoprotein, an LDL precursor, secreted from the liver.

"[W]e provide functional evidence for a novel regulatory pathway for lipoprotein metabolism and suggest that modulation of this pathway may alter risk for [myocardial infarction] in humans," the researchers wrote.

Those involved in the study say the findings may eventually prove useful for designing new treatments for elevated blood lipid levels and/or heart disease risk.

"The SORT1 pathway is an unexpected but promising new target for therapeutic intervention to reduce LDL cholesterol and, in turn, heart attacks," co-lead author Kiran Musunuru, a clinical and research fellow affiliated with the Massachusetts General Hospital and the Broad Institute, said in a statement.

And, researchers say, the studies support the idea that clinically important genetic changes can be identified using the GWAS approach.

"These studies demonstrate that GWAS — 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 said in a statement.

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