Skip to main content
Premium Trial:

Request an Annual Quote

NY Team Identifies Point Mutation That May Aggravate -- and Prevent -- Heart Disease

Premium

A team of researchers from Rockefeller University believes that a certain genetic pathway known to contribute to inflammation in coronary vasculature — and thus to myocardial infarction — may protect against the same condition.

The researchers focused on the Nuclear Factor Kappa-B, or NFkB, pathway and had originally set out to identify mechanisms of cardiovascular disease that were not related to one of the primary risk factors for the disease — namely, levels of HDL and LSL cholesterol.

“Having high cholesterol increases your risk, but does not mean that you will get heart disease,” lead author Susanne Idel wrote in her team’s paper, which appears in the Nov. 25 issue of Proceedings of the National Academy of Sciences. “So, there must be genetic pathways other than those connected to cholesterol metabolism.”

“Our research has identified a non-cholesterol related gene that is linked to the development of heart disease in mice,” she wrote. “In the long term, our hope is that we will have a more complex understanding of the genetics involved that gives us new tools for treating heart disease.”

To arrive at their results, Idel and her colleagues focused on the NFkB inflammatory response protein and the A20 gene that regulates it in mice. Though NFkB is activated in response to atherosclerotic plaques, the inflammatory response is not exclusive to them. Rather, the inflammatory cascade is “generally activated” when tissue is “damaged” by agents such as viruses, bacteria, chemicals, or physical trauma.

It is in response to this inflammation that the vascular and arterial intima react in ways associated with inflammation.

(The mechanism of NFkB regulation by A20 is not related to any of the known cholesterol pathways, the authors stressed.)

Because the NFkB pathway up-regulates inflammatory genes, and the subsequent inflammation is associated with atherosclerosis, “some scientists have focused on this pathway as one route” that promotes cardiovascular disease. “But mounting evidence suggests that the reverse may be true,” the team wrote. “Several research groups have created mice in which the pathway has been disabled and the animals’ blood vessels and arteries have actually less atherosclerosis.”

“The idea that NFkB has an anti-atherosclerotic effect is controversial,” Idel said in a statement issued by Rockefeller University. “But, if it were true that the pathway had only harmful effects, then turning it off should have protected the mice. This is not what we have observed. NFkB does turn on inflammatory genes, but you can’t disregard that it also turns on other genes that may be important for cell survival.”

For example, she added, NFkB regulates genes that promote anti-inflammatory and anti-apoptotic mechanisms. These other genes may play crucial roles, important, so it “might be beneficial” that the NFkB pathway remains active.”

The team identified A20 as a candidate gene for the “athero-related” study because it is within the locus of interest — chromosome 10. They also chose it because it regulates NFkB, and that its basic structure in the athero-protected mice differs slightly from the A20 in the athero-prone mice. The two versions differ by a single point mutation, the team said.

“The NFkB pathway turns on some genes that would be expected to ameliorate atherosclerosis and some genes that make it worse,” Idel said. “In the mice, an active pathway seems to be preferable, but more research is required to determine how the effects balance out.

“There is still much that is unknown about the genetics of heart disease, but A20 and the NFkB pathway offer promising leads worthy of more study,” the researcher said.

— KL

Filed under

The Scan

Germline-Targeting HIV Vaccine Shows Promise in Phase I Trial

A National Institutes of Health-led team reports in Science that a broadly neutralizing antibody HIV vaccine induced bnAb precursors in 97 percent of those given the vaccine.

Study Uncovers Genetic Mutation in Childhood Glaucoma

A study in the Journal of Clinical Investigation ties a heterozygous missense variant in thrombospondin 1 to childhood glaucoma.

Gene Co-Expression Database for Humans, Model Organisms Gets Update

GeneFriends has been updated to include gene and transcript co-expression networks based on RNA-seq data from 46,475 human and 34,322 mouse samples, a new paper in Nucleic Acids Research says.

New Study Investigates Genomics of Fanconi Anemia Repair Pathway in Cancer

A Rockefeller University team reports in Nature that FA repair deficiency leads to structural variants that can contribute to genomic instability.