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Investigating cholesterol
Scientists identify genes linked to sitosterolemia; study finds influence of familial traits
on response to diet
Edward R. Winstead

Two groups of researchers have identified genes that may cause sitosterolemia, an uncommon genetic cholesterol disorder. The disorder is due to defects in cells that distinguish and selectively eliminate different types of dietary cholesterol. Sitosterolemia patients have elevated levels of cholesterol in blood and accumulate plant 'sterols' in tissues, putting them at risk for heart disease at an early age. (The primary plant sterol is sitosterol; hence the name, sitosterolemia.)

Shailendra B. Patel, of the Medical University of South Carolina, in Charleston, and colleagues report this month that nine unrelated individuals with sitosterolemia have defects in the ABCG5 gene. Patel's group hypothesizes that the ABCG5 gene is important in the regulation of cholesterol absorption, a process that has long been a mystery in the lipid metabolism field. The findings appear in Nature Genetics.

The researchers screened 30 families of sitosterolemia patients for ABCG5 defects, but they identified mutations in only nine families. They write in their paper that additional mutations in ABCG5—or a second gene—may be involved in the other families. Two years ago, Patel and colleagues mapped the gene to a region of chromosome 2.

The mapping of ABCG5 facilitated another recent study. Last month, Helen H. Hobbs, of the University of Texas Southwestern Medical Center, Dallas, and colleagues implicated ABCG5 and a related gene, ABCG8, in the mechanics of excluding plant sterols from animal cells. The researchers identified seven different mutations in the ABCG5 and ABCG8 genes in nine patients with sitosterolemia. Both genes are expressed at high levels in cells of the liver and the intestine, and they encode proteins that belong to a family of transporter proteins that ferry material across cell membranes.

In a third study, also published last month, researchers investigated the reasons for different success rates among individuals who modify their diet to lower cholesterol levels. The study found that individual variation in response to a cholesterol-lowering diet is a familial trait, and that body weight is an important modifiable factor that influences response. For researchers, identifying individuals who will respond well to changes in diet aimed at lowering cholesterol has proved difficult. They can reliably predict the effectiveness of dietary modifications in populations but not in individuals.

Margo A. Denke, of the University of Texas Southwestern Medical Center, Dallas, and colleagues evaluated dietary responsiveness in families who shared lifestyle and dietary habits as well as genes. In contrast, much of the literature on dietary responsiveness involves unrelated individuals who may share specific genes of interest.

Forty percent of the variability in response to cholesterol-lowering diets in the study was due to shared genetic and environmental factors, the researchers found. Their analysis of the data did not reveal a single genetic factor that accounted for individual differences in responsiveness. The ApoE and 7 a-hydroxylase genes, for example, may influence dietary responsiveness, but they did not have a statistically significant influence on the variability of response among the study population. The findings appeared in The Journal of the American Medical Association.

The study compared butter vs. margarine as the primary source of dietary fat. Forty-six families completed a trial of butter-only or margarine-only diet for five weeks, then crossed over to the other diet. The researchers taught families how to measure portion sizes at home and provided detailed low-fat dietary prescriptions for each family member.

The margarine diet produced significantly lower levels of LDL, or 'bad,' cholesterol than the butter diet. According to the researchers, margarine intake lowered LDL cholesterol levels by 11 percent in adults and 9 percent in children.

Body weight was a predictor of dietary responsiveness among children and adults in the study. This confirmed previous findings. "People who are overweight achieve less of a cholesterol reduction by diet than people who are lean," the researchers write.

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Lee, M. H. et al. Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption. Nat Genet 27, 79-83 (January 2001).
Berge, K.E. et al. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science 290, 1771-1775 (December 1, 2000).
Denke, M.A. et al. Individual cholesterol variation in response to a margarine- or butter-based diet: A study in families. JAMA 284, 2740-2747 (December 6, 2000).

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