Scientists ID gene that controls dietary cholesterol absorption

Using DNA from 1,000 inhabitants of the Micronesian island of Kosrae, scientists have discovered a mutant gene that affects an individual’s absorption of dietary cholesterol. The researchers hope their discovery will help tease apart the tangle of genes that control cholesterol absorption, one of the factors that contributes to high blood cholesterol levels, which are a major risk factor for heart attacks.
From Rockefeller University :
Through population screening on the island of Kosrae, Rockefeller scientists discover a mutant gene that controls dietary cholesterol absorption

Findings may contribute to revealing genetic underpinnings of high cholesterol

Using DNA from 1,000 inhabitants of the Micronesian island of Kosrae, Rockefeller University scientists have discovered a mutant gene that affects an individual’s absorption of dietary cholesterol. The findings are reported in the Journal of Lipid Research, published online June 21. The researchers hope their discovery will help tease apart the tangle of genes that control cholesterol absorption, one of the factors that contributes to high blood cholesterol levels, which are a major risk factor for heart attacks.

”This is the first time such a gene has been discovered through population-wide screening,” says first author and principle investigator Ephraim Sehayek, M.D. ”This study clearly shows that under specific conditions, like those that shaped the Kosraen population, a mutant gene may have a population-wide impact on the absorption of cholesterol from the intestines.”

”This will encourage the scientific community to search for gene mutations in other populations that affect cholesterol absorption,” adds Sehayek.

High blood cholesterol, which affects over half the adult population in the United States alone, is one of the major risk factors for heart attacks. While a high cholesterol diet is one of the known causes, its effect on blood cholesterol levels varies a lot from person to person and the genetic basis of this is poorly understood. Genes that regulate cholesterol absorption, such as the one discovered on Kosrae, could play an important role.

Cholesterol and Kosrae

At normal levels, cholesterol is a good thing: a fatty molecule that is used to build cell walls and produce hormones such as cortisone, estrogen and testosterone. But when too much cholesterol is in the bloodstream, the waxy molecules can enter artery walls, thereby setting the stage for obstructions that impair blood circulation and that trigger heart attacks and strokes.

Understanding the different factors that lead to too much blood cholesterol will help scientists devise new ways to control it. Some cholesterol in the body is produced in the liver in a process called biosynthesis; still more cholesterol is absorbed into the bloodstream through the diet, especially from meats, eggs and cheeses. But because it is difficult to distinguish between biosynthesized cholesterol and cholesterol absorbed from the diet, researchers use plant-derived cholesterol-like molecules called plant sterols as a proxy measure for dietary cholesterol absorption.

Sehayek measured plant sterol levels from Kosraean blood samples, which were obtained as part of a long-term study conducted by Rockefeller University scientists and study co-authors Jeffrey M. Friedman, M.D., Ph.D., Markus Stoffel, M.D., Ph.D., and Jan L. Breslow, M.D., and the island’s Department of Health. Sehayek then was able to correlate plasma plant sterol levels to genetic markers in Kosraens, which had been determined as part of a general effort to pinpoint errant genes that contribute to the high incidence of obesity, diabetes, high blood pressure and high cholesterol among the people who live on the island of Kosrae.

The Kosraean islanders have been studied for 10 years because of their genetic history. In the 1800s the Micronesian islanders of Kosrae married European Caucasians and about 120 years ago, because of western diseases, the population of the island was reduced to a few survivors. The modern population has resulted from a relatively few individuals — ”founders” — who were a mixture of the two genetic backgrounds. This population structure is very favorable for finding genes for common diseases, and in 1994 Friedman, Stoffel and Breslow began a study to find genes for Syndrome X, an umbrella term for the clustering of conditions including obesity, diabetes, blood pressure and high cholesterol, which dramatically increases the risk of heart attacks. In two population screenings, in 1994 and 2001, more than 90 percent of the population was studied. This has provided scientists with an invaluable database of blood samples, a virtual living genetic library, that Sehayek and his colleagues used to test plasma plant sterol levels against genetic profiles to determine a link.

Using the living library of samples and genetic data, Sehayek measured plasma plant sterols as a surrogate marker for dietary cholesterol absorption, and genotyped the DNA of over 1,000 Kosraean islanders to find genes that control cholesterol absorption. In the course of this study, three Kosraens were identified who had plasma plant sterol levels 25 to 50 times normal. This finding suggested they had a disease called ?sitosterolemia. This is a rare genetic disease that causes high plasma plant sterol levels, cholesterol bumps in the skin and early heart attacks. The disease is caused by mutations in one of two genes ABCG5 and ABCG8. Affected individuals have two mutant copies: one from their mother and the other from their father. All the affected Kosraens inherited the same two bad copies of the ABCG8 gene, but did not have cholesterol bumps in their skin or early heart attacks.

”This indicates that this disorder may be more common than previously thought,” says Sehayek, ”because the presence of the disease without the symptoms may mean it goes undiagnosed.”

Sehayek was able to trace genealogical data showing that two of the individuals who inherited two copies of the mutant gene were siblings born to a married couple who were second cousins. Because mutant genes that run in families are more likely to be present in both parents of such intrafamilial marriages, it is much more likely that some of their offspring will inherit two of the mutant genes, making the offspring more prone to develop severe congenital difficulties that would ordinarily be offset by the presence of at least one normal gene.

In additional, 13.8 percent of the people in the Kosrae study were carriers of the same mutant ABCG8 gene — that is, they inherited one mutant gene from one parent, and a normal gene from the other. This high frequency strongly suggests that one of the ancestors or ”founders” of present-day Kosraeans was the carrier of this mutated ABCG8 gene.

Comparing the plasma plant sterol levels in the carriers and non-carriers, Sehayek and his colleagues determined that the plasma plant sterol levels were significantly higher in carriers, suggesting that cholesterol absorption from their diets was also higher.

But the carriers of the mutant ABCG8 gene also showed a moderate decrease in a marker for cholesterol biosynthesis, and did not actually have higher overall plasma cholesterol levels than non-carriers. This finding indicated that their bodies may have compensated for increased dietary cholesterol absorption by lowering the biosynthesis of cholesterol.

This finding has opened up the possibility of looking at the genetic basis of cholesterol absorption from several new angles. It may be possible to determine whether some of the carriers make up for high dietary cholesterol absorption by effectively shutting down biosynthesis of cholesterol when dietary absorption is too high.

”It is also possible, however, that some individuals are not as effective at decreasing the biosynthesis, leading to high blood cholesterol levels,” Sehayek says.

In addition to Sehayek, Breslow, Friedman and Stoffel, authors are Hannah J. Yu, Klaus von Bergmann, Dieter Lutjohann, Elizabeth M. Duncan, Laura Garcia-Naveda, Jacqueline Salit and Maude L. Blundell.

This research was supported by the American Hearst Association and Bundesministerium f?r Bildung, Forschung, Wissenschaft und Technologie.

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