1222-Feature-Top Ten-controlling cholestoral_Blog

Editor’s note: This is one in a 10-part series of the top medical research advances as determined by American Heart Association volunteer and staff leaders.

Using powerful genetic survey techniques in an innovative way, researchers have uncovered four tiny snippets of genetic material that affect the way a person metabolizes cholesterol and triglycerides.

Because lipid metabolism – the process in which fat and cholesterol are broken down and stored for energy – is so critical in the development of cardiovascular disease, the discovery could lead to novel treatments for atherosclerosis, Type 2 diabetes and more.

The study is among the first to methodically analyze a class of so-called non-coding RNA molecules in the context of human disease, said Anders Näär, Ph.D., the study’s lead researcher and a professor of cell biology at Harvard Medical School.

“The results challenge the gene-centric view of current human genetics efforts,” he said. “We believe that miRNAs, as well as other types of non-coding RNAs, have been overlooked as important contributors to human physiology and disease.”

The study, published in Nature Medicine in December, was selected as one of the top 10 research advances in 2015.

DNA directs the production of RNA, which then directs the production of proteins that the body needs to function and grow. Less than 2 percent of human DNA is made up of genes that code – or hold instructions – for the production of proteins.

In the past, many scientists called the other 98 percent “junk DNA.” But more recently, researchers have discovered that non-coding DNA sequences are critical for determining how, when and where protein-coding DNA is expressed.

One such method involves single-stranded bits of microRNA, or miRNA, tiny strands that can block the expression of genes. In previous work, Näär and his colleagues found that a miRNA called miR-33 can stop the production of beneficial HDL cholesterol. By blocking miR-33, the researchers could produce higher HDL levels in animal models.

For the current study, they used data from more than 188,000 people to look for any miRNAs that were physically close to gene variants linked to abnormal blood lipid levels. They found 69 matches.

The researchers ran those 69 miRNAs through a genetic database to find out whether any of the strands targeted genes involved in lipid metabolism.

Four were.

“Four of these act to control proteins we know are involved in those metabolic activities,” Näär said.

So far, Näär’s team has verified that two of the miRNAs are essential in controlling cholesterol and other lipids in mice.

The team is now investigating whether blocking the function of the miRNAs could improve or normalize lipid metabolism, which could eventually lead to the prevention or treatment of atherosclerosis, Type 2 diabetes, obesity, and fatty liver diseases.

Although protein-coding genes account for barely 2 percent of the genome, nearly 100 percent of current medicines target proteins, Näär said.

“We believe there is vast potential for roles of non-coding RNAs transcribed from the other 98 percent of the genome in the etiology of human diseases, and which could serve as novel therapeutic targets,” he said.