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Gary Nelsestuen, biochemist

A discovery by professor Gary Nelsestuen and colleagues links an unusual form of a cholesterol-transporting protein to higher body weight and the potential for developing diabetes.

Unusual protein linked to diabetes

New form of a cholesterol-transporting protein found in some of American Indian, Mexican descent

By Deane Morrison

Feb. 20, 2007

A tiny variation in a protein that transports cholesterol in the blood may predispose many people of American Indian and Mexican descent to diabetes, University biochemistry professor Gary Nelsestuen and his colleagues have found. The researchers discovered the variant form, which they have detected only in people of American Indian or Mexican descent, last fall. This week, they report in the International Journal of Obesity that those who carry the variant are more likely to be overweight or obese and to have parents with diabetes. It is the first genetic variation ever found in the protein, which is called apolipoprotein C1 and is found in all human beings. "Obesity and diabetes are serious health problems for Americans and especially for those with American Indian or Mexican ancestry," Nelsestuen says. "This protein may contribute to the elevated rates of diabetes in relevant ethnic groups and might be more common in isolated populations." In beginning the study, Nelsestuen and his team were looking for new ways to spot variations in the structures of proteins. Such studies are part of the new science of proteomics, where large numbers of proteins are studied at the same time. (Its name comes from "genomics," the study of many or all of an organism's genes together.) Proteins consist of building blocks called amino acids, and in a protein with hundreds of building blocks, a different one in just one position can make a big difference in how the protein functions. In the case of C1, that's all it was-a single substitution of one amino acid for another. The researchers found the variant in a survey of blood proteins from more than 1,000 people of American Indian, European, African and Asian descent. Of 228 American Indians in the study, it occurred in 36, and of 86 Mexicans, 10 had it. It was not found in anyone from the other groups. In the company of dangers In a study of the body mass index (BMI; an index relating weight to height) among American Indians in the study, those with the variant protein had, on average, a nine percent higher BMI than those with the common form of the protein, an effect that was stronger in males than females. Among the Mexican-descended subjects, five of those with the variant had a sibling of the same sex with the ocmmon form. Among them the average BMI was 27.2 for those with the common form and 36.2 for those with the variant. A BMI of 30 or above is defined as obesity, and 27 indicates overweight or near-overweight.

The variant form of [the protein] may have survived because it conferred an advantage that has been masked or even turned into a disadvantage by changes in diet and lifestyle.

If the variant form of C1 predisposes a person to diabetes, rates of the disease should be higher in individuals with the variant trait. This wasn't the case, however, among American Indians in the study. Although rates were indeed higher in the variant group, the difference wasn't significant.

Small change is no small change

In the bloodstream, the common form of C1 tends to be found in HDL, the high-density protein complexes that ferry cholesterol to storage depots in the body and are linked to lower cardiovascular disease risk. But Gary Nelsestuen and his team found that the variant form of C1 tends to become part of low (LDL)- or very low-density protein complexes, which transport cholesterol to arterial walls and are associated with higher cardiovascular disease risk. Thus, having the variant could tip the balance of cholesterol carriers and may possibly lead toward depletion of HDL-also a risk factor for heart disease.

But diabetes often develops later in life. And, since the form of the protein a person has is genetically determined, it follows that differences in diabetes rates ought to show up among parents of people in the study. And so it was: Parents of those with the variant form had a significantly higher rate of diabetes (66 percent) than parents of those with the common form (41 percent). The variant form of C1 may have survived because it conferred an advantage that has been masked or even turned into a disadvantage by changes in diet and lifestyle. "An increased BMI is consistent with an impact on fat storage, which is advantageous in certain circumstances during human evolution," says Nelsestuen. "An important future goal is to identify an adult population of New World descent who have the variant trait but no diabetes or increases in BMI. Such a population may reveal dietary and lifestyle factors that would benefit all individuals with the trait." It is possible that in the future, finding that a person has the variant will become akin to finding that someone carries a breast cancer gene: It will make people monitor aspects of their health more closely, he adds. Nelsestuen sees great value in studying proteins rather than genes when looking for variations among individuals. Genes may differ from one person to another, but some differences have no effect. In studying proteins, however, researchers are looking at the actual agents that carry out the myriad tasks of cells and tissues. By looking at the C1 molecule rather than the gene for it, Nelsestuen's team could immediately see a difference in how the protein functioned. "This helps illustrate the value the new field of proteomics brings to biomedical research," he says. "This is about as important a discovery as you can make by proteomic methods." Read on

Learn about other University efforts to Defeat diabetes.