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Blood cholesterol linked with new genetic variation

By Julia Liss, Daily Staff Reporter
Published March 19, 2014

A team of University researchers, lead in part by Cristen Willer, assistant professor of internal medicine, human genetics and computational medicine and bioinformation, published findings Sunday linking a previously unknown gene variation with healthier blood cholesterol levels and lower risk of cardiovascular disease.

The work expanded on research published by the same team in 2008 where they had found an association between a particular region of the genome — the genetic material in an organism’s cells — and blood cholesterol levels. It then took six years for them to figure out exactly which gene in that region was responsible.

Willer, the senior author of the paper that was published in “Nature Genetics,” worked closely with a team of scientists and doctors around the world, including Kristian Hveem, a gastroenterologist at the Norwegian University of Science and Technology.

Through their work with the Norwegian scientists, Willer gained access to a Norwegian biobank of over 80,000 donated tissue samples, from which she and her team selected 10,000 samples to study. Willer said they chose people who had previously experienced a heart attack, and then a control sample of people who were the same age and sex as the first group, but hadn’t had any heart problems.

Hveem said they were able to conduct a longitudinal, prospective follow-up study by collecting data from registries over many years without having to physically examine the patients after their initial registration.

The study design focused only on differences in DNA across people that also changed proteins.

“By looking at that smaller set of all the DNA changes that are possible between individuals we were able to focus much more quickly on a specific gene called TM6SF2,” Willer said.

To test their hypothesis that TM6SF2 was responsible for changing the blood cholesterol levels and risk of heart attack in the Norwegian subjects, the researchers disrupted the same gene in mice, either by overexpressing it or down-regulating it. The resulting effects in the mice’s blood cholesterol levels were exactly what the researchers had expected.

“That was pretty clear evidence that this indeed was the gene responsible,” Willer said.

Both Hveem and Willer plan to continue studying the gene in the hope that they may find a way to design a new drug that would target this gene in a way that hasn’t been possible before.

Willer said he believes the same gene might be associated with fatty liver disease and plans to research the topic further.

They also both said how rewarding it was to work together on this project.

“For me, one of the exciting and rewarding things about this work is when people collaborate to do much better science than they can do by themselves,” Willer said.