Apolipoprotein C1 protein linked to elevated BMI in people of American Indian and Mexican ancestry

University of Minnesota researchers have discovered a variant of a common blood protein, apolipoprotein C1, in people of American Indian and Mexican ancestry that is linked to elevated body mass index (BMI), obesity and Type 2 diabetes.

The finding were published in the Feb. 20 online issue of the International Journal of Obesity.

Lead investigator Gary Nelsestuen, a professor in the College of Biological Sciences' department of biochemistry, said the abnormal protein may promote metabolic efficiency and storage of body fat when food is abundant. This could have provided a survival advantage to American Indians in the past when food was scarce. The discovery can be used to identify those who are at risk for diabetes and to guide diet and lifestyle choices to prevent diabetes.

Apolipoprotein C1 is a component of high density lipoprotein (HDL) and low density lipoprotein (LDL). HDL cholesterol is often referred to as good cholesterol, while LDL is called bad cholesterol. The common form of C1 tends to be found in the high-density protein complexes (HDL) that ferry cholesterol to storage depots in the body and are linked to lower cardiovascular disease risk. But the variant form of C1 tends to become part of low density protein complexes (LDL), 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 lead toward depletion of HDL-also a risk factor for heart disease. The variant differs from the normal protein by a single change in one of its 57 amino acids.

Among 1500 subjects from widely divergent genetic backgrounds, the variant was found in 35 of 228 persons with American Indian ancestry and in 10 of 84 persons with Mexican ancestry. The average body mass index (BMI) of persons with the variant protein was 9 percent higher and the diabetes rate 50 percent higher among study subjects and their parents. Parents were included because type 2 diabetes often doesn't appear until later in life.

This project has been a departure for Nelsestuen, who has made important discoveries related to blood coagulation proteins involved in bleeding disorders such as hemophilia and coagulation disorders such as sepsis and thrombosis. The university has licensed these proteins to three pharmaceutical companies who are developing them as therapeutic agents. Nelsestuen is recognized on the university's Wall of Discovery for some of these achievements.

Nelsestuen used income from the blood coagulation protein licenses and his endowment from the Samuel Kirkwood Chair to support the research that led to finding the abnormal variant of C1 lipoprotein.

The funds were used to apply new proteomics technology to screen blood samples for proteins related to disease. This type of protein screening is often described as "discovery" research. In its purest form, proteomics discovery research looks for abnormal proteins in what seems like a random process.

"This type of research is often dismissed as a fishing expedition by funding agencies," Nelsestuen said. "But our finding shows the value of discovery research and of having unrestricted funds to pursue it."

Nelsestuen's interest in education of minority graduate students provided many of the connections to the communities that became involved in this research. Former student Michael Martinez, helped establish a collaboration with Kenneth McMillan, medical director of the American Indian Community Development Corporation in Minneapolis, and Cristina Flood-Urdangarin of St. Mary's Health Clinics in St. Paul.

Nelsestuen's next steps will be to expand the study to the Turtle Mountain Indian Reservation in North Dakota and the Cheyenne River Indian Reservation in South Dakota.

"I hope that this discovery will ultimately lead to a Minnesota center for research on minority health issues that can deliver actual health benefits to these communities," Nelsestuen said.