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Genetic research identifies new risk factor in heart disease

Scientists using information from the Human Genome Project have identified a new apolipoprotein that appears to play a significant role in controlling triglyceride levels in the blood



Plasma triglyceride and cholesterol levels for APOAV transgenic and knockout mice on standard chow diet. (A) Human APOAV transgenic mice compared with isogenic FVB strain control littermates (n = 48 for transgenics; n = 44 for controls; Student's t test *P < 0.0001 for transgenic versus control). (B) Mice lacking Apoav compared with mixed 129Sv/C57BL6 strain controls littermates (n = 13 for wild-type, +/+; n = 22 for heterozygotes, +/-; n = 10 for homozygous knockouts, -/-; Student's t test, **P < 0.001 for wild-type versus knockout). Error bars correspond to the standard deviation for both graphs. No differences were found in HDL-cholesterol levels in transgenic or knockout mice compared with controls.

October 8—Dr. Edward Rubin, who heads the Genome Sciences Department in the Life Sciences Division of the Lawrence Berkeley National Laboratory (Berkeley Lab), and Len Pennacchio, an Alexander Hollaender Distinguished Fellow working in Rubin's research group, led a study in which the new gene—named apoAV—was identified by comparing the DNA sequences of humans and mice. ApoAV's function was tested first in genetically engineered mice then in human clinical studies and shown to significantly influence triglyceride levels in both mammals. Triglycerides are one of the two major blood fats, along with cholesterol, that are important risk factors in the development of heart disease.

"By comparing the sequence of the genomes of humans and mice we have found a genetic jewel that had been missed when the sequence of the human genome alone was analyzed," says Rubin. "ApoAV appears to have a major role in lipid metabolism in both humans and mice."

Heart disease remains the leading cause of death in the United States and the majority of these deaths are the result of atherosclerosis—the hardening of arteries. Arterial hardening is caused by the rate at which plaque accumulates. This rate is accelerated when an individual has high cholesterol and triglyceride levels.

It is well established that a cluster of apolipoprotein genes along human chromosome 11—known as the apoAI/CIII/AIV region—has a major influence on plasma lipid profiles and, consequently, atherosclerosis susceptibility. It is also well known that mutations in DNA sequences within this region can contribute to severely elevated triglyceride levels. Since the DNA for the apoAI/CIII/AIV region has now been fully sequenced as a result of the Human Genome Project, Rubin, Pennacchio, and their colleagues searched for additional functional elements around the region by looking for any sequences that had been conserved through evolution in both humans and mice.

Explains Rubin, "The approach we took was based on the concept that if a segment of the human and mouse genomes has been conserved over the 60 to 80 million years that have elapsed since these two organisms are believed to have diverged from a common ancestor, then the sequence within the segment probably encodes an important biological function. Accordingly, in scanning the genomes of mice and humans we focused our attention specifically on those sequences shared by humans and mice."

Adds Pennacchio, "The availability of sequences within this region of the human genome led us to sequence the corresponding region of mouse DNA to compare the two. Through this analysis we found a large evolutionarily conserved sequence that was the next door neighbor to the apoAI/CIII/AIV region." This candidate human gene, which Rubin and Pennacchio dubbed "apoAV," was introduced into a line of mice through standard transgenic technology and engineered to over-express itself. Using gene "knockout" technology, they also engineered mice that lacked apoAV. Comparing the two groups revealed a dramatic contrast.

"Mice with increased expression of apoAV (the ApoAV transgenics) showed a 70 percent decrease in plasma triglyceride concentrations while mice lacking apoAV (the apoAV knockouts) showed a 400 percent increase," says Pennacchio. "Sometimes when you do mouse studies, the knockout results will contradict results from the transgenic studies. In this case, the results from the two studies strongly supported one another."

Having discovered the apoAV gene and shown that it influences triglyceride concentrations in mice, the researchers next examined the relationship between the human apoAV gene and plasma lipid levels.

"To see whether there was any connection between what we had seen in mice and the normal role of this gene in humans, we carried out two large clinical studies," says Pennacchio.

"In the first study we looked at 500 random Caucasians who had been examined for multiple different lipid parameters. In the second study we looked for these same common sequence variations in a different group of 400 individuals with extremely high and extremely low triglyceride levels. In both studies, a strong link was found between plasma triglyceride levels and particular sequence variations within and surrounding the apoAV gene."

Says Rubin, "The two human studies indicated that a common sequence variation in the vicinity of apoAV that is present in more than 10 percent of the population results in a 20 to 30 percent increase in an individual's blood triglyceride levels. With an individual's triglyceride level being an important atherosclerosis susceptibility risk factor, this finding, especially if confirmed in follow-up studies, should be extremely relevant to a large number of people."

In the Science paper, the researchers conclude that it may be possible to use apoAV polymorphisms as prognostic indicators for hyper-triglyceridemia susceptibility and that apoAV modulation could be a potential strategy to reduce this cardiovascular disease risk factor.

The next step, they say, will be to look into the mechanism by which apoAV polymorphisms influence triglyceride levels and try to identify the specific DNA sequence changes that lead to lower apoAV protein concentrations in the blood.

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Coauthoring the paper in the October 5th issue of Science with Rubin and Pennacchio were Ron Krauss, also with Berkeley Lab, Michael Olivier and David Cox, at Stanford University's Human Genome Center, Jaroslav Hubacek and Jonathan Cohen of the University of Texas's Southwestern Medical Center, and Jean-Charles Fruchart of the Pasteur Institute in Lille, France.—by Lynn Yarris

 

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