A research team from the University of Michigan and the Norwegian University of Science and Technology say they have discovered a previously unrecognized gene variation that makes humans have healthier blood lipid levels and reduced risk of heart attacks. They believe their finding can open the door to using this knowledge in testing or treatment of high cholesterol and other lipid disorders.

But, the scientists add, even more significant is how they found the gene, which had been hiding in plain sight in previous hunts for genes that influence cardiovascular risk.

This region of DNA where it was found had been implicated as being important in controlling blood lipid levels in a report from several members of the same research team in 2008. But although this DNA region had many genes, none of them had any obvious link to blood lipid levels. The promise of an entirely new lipid-related gene took another six years and a new approach to find, as described in a paper (“Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk”) published in Nature Genetics.

The researchers scanned the genetic information available from a biobank of thousands of Norwegians, focusing on variations in genes that change the way proteins function. Most of what they found turned out to be already known to affect cholesterol levels and other blood lipids.

But one gene, dubbed TM6SF2, wasn't on the radar at all. In a minority of the Norwegians who carried a particular change in the gene, blood lipid levels were much healthier, and they had a lower rate of heart attack. And when the researchers boosted or suppressed the gene in mice, they saw the same effect on the animals’ blood lipid levels.

“Transient TM6SF2 overexpression or knockdown of Tm6sf2 in mice alters serum lipid profiles, consistent with the association observed in humans, identifying TM6SF2 as a functional gene within a locus previously known as NCAN-CILP2-PBX4 or 19p13,” wrote the investigators. “This study demonstrates that systematic assessment of coding variation can quickly point to a candidate causal gene.”

“While genetic studies that focused on common variations may explain as much as 30 percent of the genetic component of lipid disorders, we still don’t know where the rest of the genetic risk comes from,” added Cristen Willer, Ph.D., the senior author of the paper and an assistant professor of Internal Medicine, Human Genetics and Computational Medicine & Bioinformatics at the U-M Medical School. “This approach of focusing on protein-changing variation may help us zero in on new genes faster.”

Dr. Willer and colleagues suggest the same gene may also be involved in regulating lipid levels in the liver, a finding confirmed by the observations of another team that proposes a role for the gene in liver disease in the same issue of Nature Genetics.

“These are exciting times for disease genetics,” said Oddgeir Holmen, Ph.D., of Norwegian University of Science and Technology. “The combination of large population-based studies and the rapid development in genotyping technologies will probably help us understand a great deal more about cardiovascular disease, and other diseases, in the next few years.” 

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