“The genetic variant is located between genes in the DNA that do not have a previously known function, but it affects the SORT1 gene and results in lower levels of the sortilin protein. Consequently, a larger amount of LDL cholesterol leaves the liver and enters the blood stream. The small LDL particles are of particular relevance because these are known to harm the blood vessels and heart”, explains Marju Orho-Melander, Professor at Lund University Diabetes Centre (LUDC) who co-authored the article.
Cardiovascular disease is the most common cause of death in the general population. The disease is caused in part by blood lipid disorders such as excessively high levels of LDL cholesterol in the blood.
Drugs that lower blood LDL levels have been shown to diminish the risk of heart attack in many different studies. “But despite treatment, many patients’ LDL levels are still too high. Therefore, we really need to find other ways of reducing LDL cholesterol”, says Olle Melander, senior physician at Akutcentrum SUS Malmö, who is one of the other co-authors of the article. The recently discovered signalling pathway that involves the SORT1 gene indicates an alternative target for lowering blood lipid levels.
Patients can’t be directly treated with sortilin. In order to lower the levels of LDL cholesterol in the blood, the protein must act in the liver to block the transportation of blood lipids into the blood. Through animal models, the research group has shown that blood cholesterol levels decrease if expression of the SORT1 gene is increased in the liver. Now that the underlying mechanism is known, the task is to develop drugs that have the same effect as the SORT1 gene.
Behind the discovery are the very large ongoing gene mapping projects where disease causing genes are being sought out. These projects seek to define statistical associations between genetic variants and disease, but statistical associations do not explain the underlying mechanisms of disease. In an article in Nature Genetics two years ago, Prof. Orho-Melander identified six new genetic risk variants for blood lipid disorders. One of these variants was in the SORT1 gene. “The first task is to identify risk variants. The second is to characterize the underlying mechanisms. This is exactly what we have now done with the SORT1 gene together with our American collaborators”, she says.
Both Olle Melander and Marju Orho-Melander are also co-authors of another article that appears in the same issue of Nature. In this article, the results of a large international collaboration project, where other Swedish groups also participate, are presented. This work includes genetic mapping of 100 000 individuals through which 59 new risk variants that increase blood lipid levels have been identified. With the 36 previously identified lipid-associated variants, the total number of validated lipid-associated variants now approaches 100, which in combination have a powerful effect on lipid levels and cardiovascular disease. For example, the one in four people who have the highest number of risk variants for elevated blood lipid levels are roughly 13 times more likely to suffer pathologically elevated cholesterol levels compared to the one in four individuals carrying the lowest number of such gene variants. “This is a solid basis that provides both a deeper understanding of the background of cardiovascular disease and that outlines potential targets for disease prevention”, says Marju Orho-Melander.
Contact: Marju Orho-Melander, +46 40 39 12 10, +46 70 739 82 89
Marju [dot] Orho-Melander [at] med [dot] lu [dot] se (Marju[dot]Orho-Melander[at]med[dot]lu[dot]se)
Olle Melander, +46 40 391209, +46 70 454 68 20,
Olle [dot] Melander [at] med [dot] lu [dot] se (Olle[dot]Melander[at]med[dot]lu[dot]se)