High-cholesterol pigs provide research model for heart disease

A team of scientists from UW–Madison have established a unique population of pigs that can help heart disease research. A recent study, published in the American Journal of Medical Genetics, strengthens the claim that these particular swine are an exceptional animal model of human coronary artery disease.

The study shows that in addition to developing high cholesterol levels and clogged arteries that are similar to human symptoms, these pigs share an underlying genetic similarity with humans. The similarities are important to scientists who study cholesterol metabolism and evaluate diet and pharmaceutical therapies to reduce blood cholesterol as well as other procedures to open blocked coronary arteries.

The researchers, along with colleagues from the Swedish University of Agricultural Sciences, have found a genetic mutation in swine which they believe causes the animals’ total blood cholesterol to be twice its normal level. Defects in the same gene in humans causes familial hypercholesterolemia – an inherited, sometimes-lethal type of heart disease characterized by high blood cholesterol levels.

Coronary heart disease kills and disables many in their most productive years. An estimated 1.5 million Americans suffer heart attacks each year. One-third of those heart attacks are fatal, according to the National Heart, Lung and Blood Institute. The disease costs an estimated $21 billion in medical care and $31 billion in indirect economic cost each year.

Elevated blood cholesterol is a major risk factor for coronary artery disease. Scientists know that many genes govern the complex processes by which animals absorb, manufacture, transport, use and break down cholesterol. Researchers have linked mistakes, or mutations, in the genetic code of several genes to elevated cholesterol levels and heart disease.

The new findings are the latest by the husband and wife team of Jan Rapacz and Judith Hasler-Rapacz, and their colleagues. Animal geneticists at the College of Agricultural and Life Sciences, Rapacz and Hasler-Rapacz have studied for more than 20 years how genetic mutations influence blood cholesterol levels and coronary artery disease in swine.

Leonardo da Vinci was among the first to use swine in medical studies of the heart, according to Rapacz. During the past 40 years pigs have become useful in heart disease research because the animals are similar to people in size, physiology, coronary anatomy and their wide ranging diet. Only the Wisconsin swine population, however, has a genetic predisposition to coronary artery disease.

The development of coronary artery disease in the Wisconsin pigs is strikingly similar to that in humans. Rapacz says the symptoms in swine are more complex and human-like than those of rhesus monkeys and rabbits, two other common animal models of human heart disease.

Because the Wisconsin pigs would be even more valuable in heart research if the reason for their heart disease were known, the scientists set out to track down the underlying genetic cause.

The researchers employed sophisticated tools to trace the problem in these swine to a minor error in a gene that codes for a receptor that spans cell membranes. That receptor’s job is to bind to low density lipoproteins (LDL) – molecules that carry cholesterol in the blood – and transport the cholesterol inside cells.

According to Rapacz, the research illustrates the value of comparative genomics, that is, knowing the location and sequence of genes in humans and different animals.

“We were able to use the better-known genetic maps of humans and mice – where the gene for the low density lipoprotein receptor has been well-studied – to identify it as the likely gene responsible for the elevated cholesterol levels of these swine,” he says.

The researchers were the first to identify and sequence most of the low density lipoprotein receptor (LDLR) gene in swine. They found that 85 percent of the bases and amino acids encoded in the swine LDLR gene are the same as the human LDLR gene. This means that the swine LDLR gene is more similar to humans than is the LDLR gene of rats, rabbits or hamsters.

The scientists found that a single nucleotide substitution correlated perfectly with elevated cholesterol in pigs.

“Although this is not conclusive, we are nearly certain that this mutation causes elevated cholesterol in the pigs,” Rapacz says. “To be 100-percent certain, we need studies to understand how this mutation changes the LDL receptor. We don’t know exactly what happens to the protein encoded by this gene when it has this mutation. We suspect it alters the protein’s shape and disrupts its ability to remove low density lipoprotein from the blood of these pigs.”

The paper’s authors also included Brian Kirkpatrick and Scott Kirk of the UW–Madison Department of Animal Sciences; and Hans Ellegren, Anna Karin Fridolfsson and Leif Andersson of the Departments of Animal Breeding and Genetics at the Swedish University of Agricultural Sciences in Uppsala, Sweden.